Pamela Munster

All Publications

• Cracks in the Estrogen Carcinogenesis of Breast Cancer JOURNAL OF CLINICAL ONCOLOGY Kim, J., Munster, P. N. 2026; 44 (18): 1660-1664

  View details for DOI 10.1200/JCO-25-03084

  View details for Web of Science ID 001790931900004

  View details for PubMedID 41785447

• Combined PARP inhibition and immune checkpoint blockade elicit differentially improved survival in BRCA1, BRCA2 vs CHEK2, ATM deficient breast cancer by promoting an anti-tumor immune response through tertiary lymphoid structure formation Chaudhuri, S., Emata, A., Thomas, S., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2026: 6557

  View details for DOI 10.1158/1538-7445.AM2026-6557

  View details for Web of Science ID 001734095600035

• Sequencing full-length mRNA in whole blood of breast cancer patients for antibody-drug conjugate therapy selection Bradley, J., Benitez, G., Barnett, M., Eve, O., Ivanova, I., Morris, K., Seguret, A., Zyoud, A., Davey, J., Cheng, Y., Robinson, A., Turnbull, A., Dixon, M., Chuang, H., Hockett, R., Kuo, R., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-3843

  View details for Web of Science ID 001734050100046

• The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial CLINICAL CANCER RESEARCH Schram, A. M., Naqash, A., Haura, E. B., Riess, J. W., Ulahannan, S. V., Ou, S. I., Munster, P. N., Cheng, M. L., Gustafson, W., Bitman, B., Friedman, R., Penn, R., Kar, S., Seshadri, V., Wang, Z., Tao, L., Yang, Y., Singh, M., Burris, H. A., Meyerowitz, J. G. 2025; 31 (23): 4933-4943

  Abstract

  PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTOR complex 1 (mTORC1)-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates eukaryotic initiation factor 4E-binding protein-1 and S6 kinase and exhibits selectivity for mTORC1 over mTORC2. In this study, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952).The safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg intravenous infusion weekly) were evaluated in 57 patients.The most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Consistent with mTORC1 selectivity, treatment-related hyperglycemia incidence was generally low (4%) and not dose limiting. Additionally, we tested potential prophylaxis with tacrolimus mouthwash (TM), which was predicted to block the mechanism of action of RMC-5552 locally and alleviate treatment-related oral mucositis. Between 8- and 12-mg dosing, mucositis was 65% without TM versus 31% with TM. In this study, the disease control rate was 64%, and one patient with PTEN- and PIK3CA-altered endometrial cancer had a complete response and treatment was ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among ctDNA was observed.The success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors.

  View details for DOI 10.1158/1078-0432.CCR-25-2112

  View details for Web of Science ID 001628274100020

  View details for PubMedID 41056387

  View details for PubMedCentralID PMC12666311

• Phase Ib study of intratumoral talimogene laherparepvec (T-VEC) in combination with chemotherapy or endocrine therapy in patients with advanced HER2-negative breast cancer NPJ BREAST CANCER Huppert, L. A., Gliwa, A. S., Tait, M., Quintal, L., Starzinski, S., Cheung, A., Moasser, M., Majure, M., Melisko, M., Munster, P., Rugo, H. S., Campbell, M., Fong, L., Chien, A. 2025; 11 (1): 130

  Abstract

  Talimogene laherparepvec (T-VEC) is an oncolytic virus that is hypothesized to enhance responses to systemic therapy. This Phase 1b trial evaluated the safety and efficacy of intratumoral T-VEC plus chemotherapy (CT) or endocrine therapy (ET) for patients with hormone receptor positive (HR + )/HER2- and triple negative (TN) advanced breast cancer (ABC) with injectable locoregional/chest wall disease. The primary endpoint was safety/tolerability. Secondary endpoints were objective response rate by irRECIST 1.1 and clinical assessment of local response. 19 patients enrolled (9 HR + /HER2-; 10 TN; median two lines of prior CT). Intratumoral T-VEC was administered with the following partners: gemcitabine/carboplatin (n = 8), nab-paclitaxel (n = 7), paclitaxel (n = 2), or ET (n = 2). Eight patients in the T-VEC + gemcitabine/carboplatin arm were formally evaluated for dose limiting toxicities (DLTs) based on pre-specified protocol criteria, and one DLT (grade 3 neutropenia leading to carboplatin dose reduction) was identified. Response per irRECIST 1.1 was evaluated in 16 patients: partial response (n = 2, 12.5%), stable disease (n = 7, 43.8%), progressive disease (n = 7, 43.8%). Patients with higher pre-treatment tumor infiltrating lymphocytes (TILs) were more likely to respond, and clinical responders had induction of Ki-67 in multiple peripheral myeloid populations. In conclusion, the addition of intratumoral T-VEC to CT or ET was safe in patients with ABC and injectable locoregional disease, supporting the continued investigation of direct intratumoral immunomodulatory strategies that can enhance local and systemic immune responses. NCT03554044.

  View details for DOI 10.1038/s41523-025-00842-8

  View details for Web of Science ID 001619913400001

  View details for PubMedID 41271741

  View details for PubMedCentralID PMC12638943

• Phase II (Alliance A091802) Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma JOURNAL OF CLINICAL ONCOLOGY Zandberg, D. P., Allred, J. B., Rosenberg, A. J., Kaczmar, J. M., Swiecicki, P., Julian, R. A., Poklepovic, A. S., Bauman, J. R., Phan, M. D., Saba, N. F., Rivera, E., Rowland, K., Davar, D., Cordes, J., Ho, A. L., Zhang, M., Berg, S. A., Munster, P. N., Schwartz, G. K. 2025; 43 (21): 2398-2408

  Abstract

  Continued improvement in outcomes is needed for advanced cutaneous squamous cell carcinoma (cSCC).Alliance A091802 is a randomized phase II trial of avelumab (800 mg IV once every 2 weeks) plus cetuximab (500 mg/m2 IV once every 2 weeks) versus avelumab alone once every 2 weeks for up to 2 years. Cetuximab was given for 1 year in the avelumab + cetuximab arm. Crossover at progression to avelumab + cetuximab was allowed. Randomization was 1:1, stratified by PD-L1 and HIV status. Patients had distant metastatic or unresectable locally advanced cSCC, were anti-PD-1/PD-L1 monoclonal antibody-naive, had no previous cetuximab in the advanced setting, had an Eastern Cooperative Oncology Group performance status of 0-2, and could be HIV+ (CD4 >200, viral load <200). Patients with chronic lymphocytic leukemia, immunosuppression, or active autoimmune diseases were excluded. The primary end point was progression-free survival (PFS; null hypothesis: median = 12 months v alternative hypothesis: 21 months or a 75% improvement, power of 80% with one-sided alpha .2, n = 57, 37 PFS events required). Secondary end points were overall survival, objective response rates (ORRs), clinical benefit rate, and toxicity.Sixty patients were enrolled; 57 patients were evaluable. The median age was 72 years, all were HIV-; 75.4% was PD-L1+, 84.2% had head/neck origin, 47.4% had distant metastasis, and there were no differences in baseline characteristics by arm. Avelumab + cetuximab significantly improved PFS versus avelumab (median, 11.1 [7.6-not reached (NR)] v 3.0 months [2.7-13.6] hazard ratio, 0.48 [95% CI, 0.23 to 0.97], P = .018). Avelumab patients who crossed over (n = 9) to combination had a median PFS after crossover of 11.3 months (5.8-NR). The confirmed ORR was 27.6% with avelumab + cetuximab and 21.4% with avelumab. Grade 3 treatment-related adverse events occurred in 48.3% and 21.5% of patients with avelumab + cetuximab (most common: rash [20.7%], infusion reaction [20.7%]) and avelumab, respectively.Avelumab + cetuximab significantly improved PFS versus avelumab alone in patients with advanced cSCC. Alliance A091802 supports a larger confirmatory study with the combination of cetuximab and PD-1:PD-(L)1 blockade.

  View details for DOI 10.1200/JCO-25-00759

  View details for Web of Science ID 001525661000001

  View details for PubMedID 40448574

  View details for PubMedCentralID PMC12677393

• A phase II (Alliance/A091802) randomized trial of avelumab plus cetuximab vs. avelumab alone in advanced cutaneous squamous cell carcinoma (cSCC). Zandberg, D., Allred, J. B., Rosenberg, A., Kaczmar, J. M., Swiecicki, P., Julian, R., Poklepovic, A., Bauman, J. R., Phan, M., Saba, N. F., Ellerton, J., Ohr, J., Cordes, J., Ho, A., Berg, S. A., Munster, P. N., Schwartz, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2025: 6002

  View details for DOI 10.1200/JCO.2025.43.16_suppl.6002

  View details for Web of Science ID 001690277700006

• Alliance A092104: A randomized phase 2/3 study of olaparib plus temozolomide versus investigator's choice for the treatment of patients with advanced uterine leiomyosarcoma after progression on prior chemotherapy. Van Tine, B., Allred, J. B., Hensley, M., Arend, R., Charlson, J. A., D'Amato, G. Z., Lee, T., Loggers, E., Berg, S. A., Ingham, M., Mandrekar, S. J., Munster, P. N., Schwartz, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2025: 11507

  View details for DOI 10.1200/JCO.2025.43.16_suppl.11507

  View details for Web of Science ID 001690400100048

• A phase I/Ib study of olaparib and ASTX727 in BRCA 1/2-and HRD-mutated tumors Munster, P. N., Kelley, R., Calabrese, S., Walker, K., Clark, E., Lam, P., Berkley, S., Thomas, S., Monga, V. LIPPINCOTT WILLIAMS & WILKINS. 2025: TPS3183

  View details for DOI 10.1200/JCO.2025.43.16_suppl.TPS3183

  View details for Web of Science ID 001690279500040

• Estrogens and breast cancer ANNALS OF ONCOLOGY Kim, J., Munster, P. N. 2025; 36 (2): 134-148

  Abstract

  Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women's Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention.

  View details for DOI 10.1016/j.annonc.2024.10.824

  View details for Web of Science ID 001420606900001

  View details for PubMedID 39522613

  View details for PubMedCentralID PMC12168202

• Characterizing safety, toxicity, and breast cancer risk reduction using a long-term fulvestrant eluting implant SCIENTIFIC REPORTS Thomas, S., Roche, E., Desai, P., Pawlowska, N., Bauer, D., Gingrich, D., Hsu, E., Deitchman, A. N., Aweeka, F., Munster, P. N. 2025; 15 (1): 3028

  Abstract

  For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the 7,12-dimethylbenz[a]anthracene-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, surgical placement of fulvestrant-eluting implants was safe and did not elicit significant breast tissue pathology when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.

  View details for DOI 10.1038/s41598-024-77186-z

  View details for Web of Science ID 001405676800004

  View details for PubMedID 39848945

  View details for PubMedCentralID PMC11758070

• Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors BREAST CANCER RESEARCH Pacaud, R., Thomas, S., Chaudhuri, S., Lazar, A., Timmerman, L. A., Munster, P. N. 2025; 27 (1): 8

  Abstract

  Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes. In an effort to expand the clinical use of PARP inhibitors to HRR proficient tumors, several groups have tested combinations of DNA methyltransferase inhibitors and PARP inhibitors. While this approach attenuated tumor cell proliferation in preclinical studies, subsequent clinical trials revealed little benefit. We hypothesized that benefit for this drug combination would only be specific to HRR deficient tumors, due to their inability to enact high fidelity DNA repair with subsequent cell death.We generated hypomorphic BRCA1 and BRCA2 variants of the HRR proficient triple negative breast cancer cell line MDA-MB-231. We compared therapeutic response features such as RAD51 focus formation, cell cycle fraction alterations, DNA damage accumulation, colony formation, and cell death of these and other cell lines with and without intrinsic BRCA1/2 mutations. Results were confirmed in BRCA1/2 intact and deficient xenografts and PDX.Our targeted variants and cells with intrinsic BRCA1/2 mutations responded to low dose combination therapeutic treatment by G2M stalling, compounded DNA damage, severely attenuated colony formation, and importantly, increased cell death. In contrast, the parental MDA-MB-231 cells and other HRR proficient cell lines produced smaller cell populations with short term treatment, but with much less cumulative DNA damage, and minimal cell death. In animal studies, our BRCA-engineered hypomorphs and several independent PDX models with clinically relevant BRCA mutations were acutely more vulnerable to this drug combination.We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities.

  View details for DOI 10.1186/s13058-024-01954-y

  View details for Web of Science ID 001398759800001

  View details for PubMedID 39819384

  View details for PubMedCentralID PMC11740508

• Phase II Study of Isatuximab, and Weekly Carfilzomib plus Dexamethasone in Relapsed and Refractory Multiple Myeloma (RRMM) Vesole, D. H., Martin, T. G., Trudel, S., Schade, H., Shenoy, S., Biran, N., Wolf, J., Matous, J., Munster, P., Berkeley, S., Berdeja, J. G. ELSEVIER. 2024: 1983

  View details for DOI 10.1182/blood-2024-209597

  View details for Web of Science ID 001412856700006

• Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies JCO PRECISION ONCOLOGY Tsang, E. S., Aggarwal, R. R., Bergsland, E. K., Calabrese, S., Rozie, A., Chaudhuri, S., Dhawan, M. S., Pawlowska, N., Grabowsky, J., Thomas, S., Munster, P. N. 2024; 8: e2400328

  Abstract

  Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition.Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels.Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months (P = .004) for all patients and 43.3 versus 25.1 months for patients with RCC (P = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment (P = .002, P < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated (P = .02).Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.

  View details for DOI 10.1200/PO.24.00328

  View details for Web of Science ID 001359740400002

  View details for PubMedID 39509670

• A phase I/II, open label, multi-center, non-randomized dose escalation and dose expansion study of AMXI-5001 in patients with advanced malignancies Rosen, L. S., Azad, N., Costa, R., Meric-Bernstam, F., Alaoui, H., Jablons, D. M., Munster, P., Hamilton, E. P. ELSEVIER. 2024: S531

  View details for DOI 10.1016/j.annonc.2024.08.747

  View details for Web of Science ID 001326612900673

• ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors. Cancer research communications Chen, C. T., Khanna, V., Kummar, S., Abdul-Karim, R. M., Sommerhalder, D., Tolcher, A. W., Ueno, N. T., Davis, S. L., Orr, D. W., Hamilton, E., Patel, M. R., Spira, A. I., Jauhari, S., Florou, V., Duff, M., Xu, R., Wang, J., Barkund, S. R., Zhou, H., Pankov, A., Kong, W., Jahchan, N. S., Jackson, E. L., Sun, J. D., Junttila, M. R., Multani, P. S., Daemen, A., Chow Maneval, E., Munster, P. N. 2024

  Abstract

  PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of anti-apoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial.PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel.RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naive and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, 5 objective responses were observed. A pre-planned futility analysis in dose expansion showed a 3.2% (95% CI 0.4, 11.2) ORR with a median PFS of 2 months (95% CI 1.8, 2.8) across all 4 cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1.CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play.

  View details for DOI 10.1158/2767-9764.CRC-24-0115

  View details for PubMedID 39177285

• A Phase II Trial of the WEE1 Inhibitor Adavosertib in <i>SETD2</i><i>-</i>Altered Advanced Solid Tumor Malignancies (NCI 10170) CANCER RESEARCH COMMUNICATIONS Maldonado, E., Rathmell, W., Shapiro, G. I., Takebe, N., Rodon, J., Mahalingam, D., Trikalinos, N. A., Kalebasty, A. R., Parikh, M., Boerner, S. A., Balido, C., Krings, G., Burns, T. F., Bergsland, E. K., Munster, P. N., Ashworth, A., LoRusso, P., Aggarwal, R. R. 2024; 4 (7): 1793-1801

  Abstract

  We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

  View details for DOI 10.1158/2767-9764.CRC-24-0213

  View details for Web of Science ID 001274723100005

  View details for PubMedID 38920407

  View details for PubMedCentralID PMC11264598

• BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2-breast cancer (BC) Juric, D., Patel, M. R., Duska, L. R., Jhaveri, K. L., Henick, B. S., Matulonis, U. A., Munster, P. N., Birrer, M. J., Moore, K. N., Curigliano, G., Li, C., Guo, J., He, K., Wu, R., Tamulevich, S., Rinne, M., Yap, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400165

• Alliance EAY191-A6: FOLFOX in combination with binimetinib as second-line therapy for patients with advanced biliary tract cancers (BTCs) with <i>MAPK</i> pathway alterations: A ComboMATCH treatment trial Shergill, A., Liao, C., Elsaid, M. I., Al Baghdadi, T., Ji, Y., Feldman, D., George, S., O'Reilly, E. M., Meyerhardt, J. A., Berg, S. A., Schwartz, G. K., Munster, P. N., Bekaii-Saab, T. S., Abou-Alfa, G. K., Shroff, R. T., Shapiro, G. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557406191

• First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors CANCER RESEARCH COMMUNICATIONS Yarchoan, M., Powderly, J. D., Bastos, B. R., Karasic, T. B., Crysler, O. V., Munster, P. N., McKean, M. A., Emens, L. A., Saenger, Y. M., Ged, Y., Stagg, R., Smith, S., Whiting, C. C., Moon, A., Prasit, P., Jenkins, Y., Standifer, N., Dubensky, T. W., Whiting, S. H., Ulahannan, S. V. 2024; 4 (4): 1100-1110

  Abstract

  TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents.This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1).A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA.TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers.TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

  View details for DOI 10.1158/2767-9764.CRC-24-0082

  View details for Web of Science ID 001679329700001

  View details for PubMedID 38551394

  View details for PubMedCentralID PMC11025498

• First-in-human Evaluation of a Prostate-specific Membrane Antigen-targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy EUROPEAN UROLOGY ONCOLOGY Nguyen, H. G., van den Berg, N. S., Antaris, A. L., Xue, L., Greenberg, S., Rosenthal, J., Muchnik, A., Klaassen, A., Simko, J. P., Dutta, S., Sorger, J. M., Munster, P., Carroll, P. R. 2024; 7 (1): 63-72

  Abstract

  Men with high-risk prostate cancer undergoing surgery likely recur due to failure to completely excise regional and/or local disease.The first-in-human evaluation of safety, pharmacokinetics, and exploratory efficacy of IS-002, a novel near-infrared prostate-specific membrane antigen (PSMA)-targeted fluorescence imaging agent, designed for intraoperative prostate cancer visualization.A phase 1, single-center, dose-escalation study was conducted in 24 men with high-risk prostate cancer scheduled for robotic-assisted radical prostatectomy with (extended) pelvic lymph node dissection using the da Vinci surgical system.Adverse events (AEs), vital signs, complete blood count, complete metabolic panel, urinalysis, and electrocardiogram were assessed over a 14-d period and compared with baseline. The pharmacokinetic profile of IS-002 was determined. Diagnostic accuracy was assessed for exploratory efficacy.AEs predominantly included discoloration of urine (n = 22/24; expected, related, grade 1). There were no grade ≥2 AEs. IS-002 Cmax and area under the curve increased with increasing dose. Plasma concentrations declined rapidly in a biphasic manner, with the median terminal half-lives ranging from 5.0 to 7.6 h, independent of dose and renal function. At 25 μg/kg, the exploratory efficacy readouts for the negative and positive predictive values were, 97% and 45% for lymph nodes, and 100% and 80% for residual/locoregional disease detection, respectively.IS-002 is safe and well tolerated, and has the potential to enable intraoperative tumor detection that could not be identified using standard imaging.IS-002 is a new imaging agent that specifically targets the prostate-specific membrane antigen receptor. In this study, we tested IS-002 for the first time in men with high-risk prostate cancer undergoing surgery and found that IS-002 is safe, is cleared from the body quickly, and potentially allows identification of prostate cancer in areas that would not be identified by conventional white light imaging.

  View details for DOI 10.1016/j.euo.2023.07.004

  View details for Web of Science ID 001169161200001

  View details for PubMedID 37516587

• Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies CLINICAL CANCER RESEARCH Carneiro, B. A., Cavalcante, L., Mahalingam, D., Saeed, A., Safran, H., Ma, W., Coveler, A. L., Powell, S., Bastos, B., Davis, E., Sahai, V., Mikrut, W., Longstreth, J., Smith, S., Weisskittel, T., Li, H., Borden, B. A., Harvey, R., Sahebjam, S., Cervantes, A., Koukol, A., Mazar, A. P., Steeghs, N., Kurzrock, R., Giles, F. J., Munster, P. 2024; 30 (3): 522-531

  View details for DOI 10.1158/1078-0432.CCR-23-1916

  View details for Web of Science ID 001155669400007

• Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study CANCER RESEARCH COMMUNICATIONS Munster, P., Iannotti, N., Cho, D. C., Kirkwood, J. M., Villaruz, L. C., Gibney, G. T., Hodi, F., Mettu, N. B., Jones, M., Bowman, J., Smith, M., Lakshminarayanan, M., O'Day, S. 2023; 3 (12): 2572-2584

  Abstract

  This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor].Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks).A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR.Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors.PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

  View details for DOI 10.1158/2767-9764.CRC-22-0461

  View details for Web of Science ID 001178977700008

  View details for PubMedID 38115208

  View details for PubMedCentralID PMC10729644

• Safety and efficacy of D-1553 in combination with cetuximab in KRAS G12C mutated colorectal cancer (CRC): A phase II study Xu, R., Xu, Y., Yan, D., Munster, P., Ruan, D., Deng, Y., Pan, H., Underhill, C. R., Richardson, G., Nordman, I., Lee, K., Wei, S., Li, X., Shan, J., Han, G., Henderson, S., Xie, X., Xiang, Z., Shi, Z., Zhang, L. ELSEVIER. 2023: S410-S411

  View details for DOI 10.1016/j.annonc.2023.09.1741

  View details for Web of Science ID 001087480200537

• Phase Ib study of talimogene laherparepvec (T-VEC) in combination with chemotherapy (CT) or endocrine therapy (ET) in patients with metastatic, unresectable, or locoregionally recurrent HER2-negative breast cancer (BC). Huppert, L., Gliwa, A. S., Tait, M., Quintal, L., Starzinski, S., Cheung, A., Moasser, M. M., Majure, M., Melisko, M. E., Rugo, H. S., Munster, P. N., Campbell, M. J., Fong, L., Chien, A. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772000201

• Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas BRITISH JOURNAL OF CANCER Raj, N., Chan, J. A., Wang, S. J., Aggarwal, R. R., Calabrese, S., DeMore, A., Fong, L., Grabowsky, J., Hope, T. A., Kolli, K., Mulvey, C. K., Munster, P. N., Perez, K., Punn, S., Reidy-Lagunes, D., Von Fedak, S., Zhang, L., Bergsland, E. K. 2023; 129 (2): 291-300

  Abstract

  To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation.Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy.objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated.Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours.Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs.ClinicalTrials.gov NCT03136055.

  View details for DOI 10.1038/s41416-023-02298-8

  View details for Web of Science ID 000990913400001

  View details for PubMedID 37208512

  View details for PubMedCentralID PMC10338510

• ARV-471, a PROTAC ® estrogen receptor (ER) degrader in advanced ER plus /human epidermal growth factor receptor 2 (HER2)- breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study Hurvitz, S. A., Schott, A. F., Ma, C., Hamilton, E. P., Nanda, R., Zahrah, G., Hunter, N., Tan, A. R., Telli, M. L., Mesias, J. A., Jeselsohn, R., Munster, P., Lu, H., Gedrich, R., Mather, C., Parameswaran, J., Han, H. S., Wirth, S. CHURCHILL LIVINGSTONE. 2023: S116

  View details for Web of Science ID 001037996400257

• Phase II Study of Enzalutamide for Patients With Androgen Receptor-Positive Salivary Gland Cancers (Alliance A091404). Journal of clinical oncology : official journal of the American Society of Clinical Oncology Ho, A. L., Foster, N. R., Zoroufy, A. J., Campbell, J. D., Worden, F., Price, K., Adkins, D., Bowles, D. W., Kang, H., Burtness, B., Sherman, E., Morton, R., Morris, L. G., Nadeem, Z., Katabi, N., Munster, P., Schwartz, G. K. 2022; 40 (36): 4240-4249

  Abstract

  The androgen receptor (AR) is expressed (+) in a subset of salivary gland cancers (SGCs). This phase II trial evaluated the efficacy of the antiandrogen enzalutamide in AR+ SGC.Patients with locally advanced/unresectable or metastatic AR+ SGCs were enrolled. Enzalutamide (160 mg) was given orally once daily. The primary end point was the best overall response rate per RECIST v1.1 within eight cycles. Confirmed responses in ≥ 5 of 41 patients would be considered promising. Secondary end points were progression-free survival, overall survival, and safety.Forty-six patients were enrolled; 30 (65.2%) received prior systemic therapy, including 13 (28.3%) with AR-targeted drugs. Of seven (15.2%) partial responses (PRs), only two (4.3%) were confirmed per protocol and counted toward the primary end point. Twenty-four patients (52.2%) had stable disease; 15 (32.6%) had progression of disease as best response. Twenty-six patients (56.5%) experienced tumor regression in target lesions; 18 (39.1%) had partial response/stable disease ≥ 6 months. Tumor regressions were observed in female patients (5 of 6 [83.3%]) and those who received prior AR- (6 of 13 [46.2%]) or human epidermal growth factor receptor 2-targeted therapies (5 of 8 [62.5%]). Three patients remained on treatment at data cutoff (duration, 32.2-49.8 months). The median progression-free survival was 5.6 months (95% CI, 3.7 to 7.5); the median overall survival was 17.0 months (95% CI, 11.8 to 30.0). The most common adverse events were fatigue, hypertension, hot flashes, and weight loss. Total and free testosterone levels increased by a mean of 61.2% and 48.8%, respectively, after enzalutamide.Enzalutamide demonstrated limited activity in AR+ SGC, failing to meet protocol-defined success in part because of a lack of response durability. Strategies to enhance the efficacy of antiandrogen therapy are needed.

  View details for DOI 10.1200/JCO.22.00229

  View details for PubMedID 35867947

  View details for PubMedCentralID PMC9916043

• Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors CLINICAL CANCER RESEARCH Munster, P. N., Greenstein, A. E., Fleming, G. F., Borazanci, E., Sharma, M. R., Custodio, J. M., Tudor, I., Pashova, H. I., Shepherd, S., Grauer, A., Sachdev, J. C. 2022; 28 (15): 3214-3224

  Abstract

  Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor (GR) modulator relacorilant with taxanes can enhance antitumor activity.The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel.In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P < 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P < 0.0001). In the heavily pretreated phase 1 population [median (range) of prior regimens: 3 (1-8), prior taxane in 75.3% (55/73)], 33% (19/57) of response-evaluable patients achieved durable disease control (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes.The observed preclinical, clinical, and GR-specific pharmacodynamic responses demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.

  View details for DOI 10.1158/1078-0432.CCR-21-4363

  View details for Web of Science ID 000837838100001

  View details for PubMedID 35583817

  View details for PubMedCentralID PMC9662918

• Phase 1 results of a phase 1/2 trial of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination, in patients with advanced solid and hematologic cancers. Lynch, R. C., Munster, P. N., Advani, R. H., Hamadani, M., Spigel, D. R., Falchook, G., Patel, M. R., Siegel, D., Beri, N., Nowakowski, G. S., Palmisiano, N., Burness, M., Moore, K. N., Shapiro, G., Juric, D., Bradley, W. D., O'Shea, T. J., Renschler, M., Englert, J. M., Yap, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300977

• Updated survival follow-up for phase I study of abexinostat with pazopanib in patients with solid tumor malignancies. Tsang, E. S., Aggarwal, R., Thomas, S., Dhawan, M., Pawlowska, N., Bartelink, I., Grabowsky, J. A., Jahan, T., Truong, T., Ryan, C. J., Munster, P. N. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301043

• First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation Dumbrava, E., Johnson, M., Tolcher, A. W., Shapiro, G., Thompson, J. A., El-Khoueiry, A. B., Vandross, A., Kummar, S., Parikh, A., Munster, P. N., Daly, E., De Leon, L., Khaddar, M., LeDuke, K., Robell, K., Sheehan, L., St Louis, M., Wiebesiek, A., Alland, L., Schram, A. M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300896

• MALIGNANT GLIOMA SUBSET FROM ACTUATE 1801 PHASE 1/2 STUDY OF 9-ING-41, A GLYCOGEN SYNTHASE KINASE 3 BETA (GSK-3.) INHIBITOR, AS A SINGLE AGENT AND COMBINED WITH CHEMOTHERAPY REFRACTORY Odia, Y., Cavalcante, L., Safran, H., Powell, S., Munster, P., Ma, W., Carneiro, B., Bastos, B., Giles, F., Sahebjam, S. OXFORD UNIV PRESS INC. 2021: 61-62

  View details for Web of Science ID 000757356200240

• Interim results from a phase II study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies Aggarwal, R., Umetsu, S., Dhawan, M., Grabowsky, J., Carnevale, J., Howell, M., Wilch, L., Chapman, J., Alvarez, E., Calabrese, S., Smith, S., Shah, N., Dean, E., Munster, P., Collisson, E. ELSEVIER. 2021: S583

  View details for DOI 10.1016/j.annonc.2021.08.1034

  View details for Web of Science ID 000700527700488

• A Phase 1 Dose-Escalation and Expansion Study of Telaglenastat in Patients With Advanced or Metastatic Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research Harding, J. J., Telli, M., Munster, P., Voss, M. H., Infante, J. R., DeMichele, A., Dunphy, M., Le, M. H., Molineaux, C., Orford, K., Parlati, F., Whiting, S. H., Bennett, M. K., Tannir, N. M., Meric-Bernstam, F. 2021

  Abstract

  PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A Phase 1 study of the oral, first-in-class, glutaminase inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity.EXPERIMENTAL DESIGN: Dose escalation by 3 +3 design was followed by exploratory tumor-/biomarker-specific cohorts.RESULTS: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% glutaminase inhibition in platelets at plasma exposures >300 nM; >75% tumoral glutaminase inhibition; and significant increase in circulating glutamine. RP2D was defined at 800mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).CONCLUSIONS: Telaglenastatis safe with a favorable PK/PD profile and signal of antitumor activity supporting further clinical development.

  View details for DOI 10.1158/1078-0432.CCR-21-1204

  View details for PubMedID 34285061

• Specialized computational methods for denoising, B₁ correction, and kinetic modeling in hyperpolarized <SUP>13</SUP>C MR EPSI studies of liver tumors MAGNETIC RESONANCE IN MEDICINE Lee, P. M., Chen, H., Gordon, J. W., Zhu, Z., Larson, P. E. Z., Dwork, N., Van Criekinge, M., Carvajal, L., Ohliger, M. A., Wang, Z. J., Xu, D., Kurhanewicz, J., Bok, R. A., Aggarwal, R., Munster, P. N., Vigneron, D. B. 2021; 86 (5): 2402-2411

  Abstract

  To develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors.Seven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL .Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue.The new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

  View details for DOI 10.1002/mrm.28901

  View details for Web of Science ID 000669191100001

  View details for PubMedID 34216051

  View details for PubMedCentralID PMC8565779

• First-in-human phase I/II study of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination in patients with advanced solid and hematologic cancers. Lynch, R. C., Bendell, J. C., Advani, R. H., Falchook, G., Munster, P. N., Patel, M. R., Gutierrez, M., Burness, M., Palmisiano, N., Hamadani, M., Bradley, W. D., O'Shea, T. J., Doleman, S., Renschler, M., Englert, J. M., Yap, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.3006

  View details for Web of Science ID 000708120601183

• A phase I trial adding poly(ADP-ribose) polymerase inhibitor veliparib to induction carboplatin-paclitaxel in patients with head and neck squamous cell carcinoma: Alliance A091101 ORAL ONCOLOGY Jelinek, M. J., Foster, N. R., Zoroufy, A. J., Schwartz, G. K., Munster, P. N., Seiwert, T. Y., de Souza, J. A., Vokes, E. E. 2021; 114: 105171

  Abstract

  We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC).In a 3 + 3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100 mg/m2, days 1, 8, 15) and veliparib (days 1-7) every 21 days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle.Twenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63 years. Primary disease sites included hypopharynx (n = 5), larynx (n = 5), oral cavity (n = 4), oropharynx (n = 3), and nasal cavity (n = 1). Through all of IC, the most common grade 3 + adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350 mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350 mg BID. With 40.9 month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached.Addition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.

  View details for DOI 10.1016/j.oraloncology.2020.105171

  View details for Web of Science ID 000624972300021

  View details for PubMedID 33513474

  View details for PubMedCentralID PMC7933088

• Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis. Blood cancer discovery Wang, V. E., Blaser, B. W., Patel, R. K., Behbehani, G. K., Rao, A. A., Durbin-Johnson, B., Jiang, T., Logan, A. C., Settles, M., Mannis, G. N., Olin, R., Damon, L. E., Martin, T. G., Sayre, P. H., Gaensler, K. M., McMahon, E., Flanders, M., Weinberg, V., Ye, C. J., Carbone, D. P., Munster, P. N., Fragiadakis, G. K., McCormick, F., Andreadis, C. 2021; 2 (5): 434-449

  Abstract

  Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

  View details for DOI 10.1158/2643-3230.bcd-21-0055

  View details for PubMedID 34514432

  View details for PubMedCentralID PMC8425277

• Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer NATURE COMMUNICATIONS Terranova-Barberio, M., Pawlowska, N., Dhawan, M., Moasser, M., Chien, A. J., Melisko, M. E., Rugo, H., Rahimi, R., Deal, T., Daud, A., Rosenblum, M. D., Thomas, S., Munster, P. N. 2020; 11 (1): 3584

  Abstract

  Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).

  View details for DOI 10.1038/s41467-020-17414-y

  View details for Web of Science ID 000552423000003

  View details for PubMedID 32681091

  View details for PubMedCentralID PMC7367885

• A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms. PloS one Wolin, E., Mita, A., Mahipal, A., Meyer, T., Bendell, J., Nemunaitis, J., Munster, P. N., Paz-Ares, L., Filvaroff, E. H., Li, S., Hege, K., de Haan, H., Mita, M. 2019; 14 (9): e0221994

  Abstract

  Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

  View details for DOI 10.1371/journal.pone.0221994

  View details for PubMedID 31527867

  View details for PubMedCentralID PMC6748410

• A dual pathway inhibition strategy using BKM120 combined with vemurafenib is poorly tolerated in BRAF V600E/K mutant advanced melanoma PIGMENT CELL & MELANOMA RESEARCH Algazi, A., Rotow, J., Posch, C., Ortiz-Urda, S., Algazi, A., Munster, P. N., Daud, A. 2019; 32 (4): 603-606

  View details for DOI 10.1111/pcmr.12777

  View details for Web of Science ID 000471904900014

  View details for PubMedID 30801911

• The PHACT Study: Population Health and Cancer Testing Dhawan, M., Karipineni, S., Budge, J., Mak, J., Zhou, A., Williams, K., Cha, K., Munster, P. N. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.1531

  View details for Web of Science ID 000487345804327

• Exceptional responders to abexinostat (ABX) plus pazopanib (PAZ) in pretreated renal cell carcinoma (RCC) and other solid tumors: Long-term follow-up of a phase 1b study. Aggarwal, R., Thomas, S., Pawlowska, N., Grabowsky, J. A., Calabrese, S., Phu Lam, Comerford, K., Bautista, D., Munster, P. N. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.3022

  View details for Web of Science ID 000487345804612

• Maintenance Lenalidomide in Primary CNS Lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology Rubenstein, J. L., Geng, H., Vu, K., Mannis, G., Formaker, P., Hwang, J., Munster, P. N., Damato, B. 2019

  View details for DOI 10.1093/annonc/mdz142

  View details for PubMedID 31046114

• Coil combination methods for multi-channel hyperpolarized <SUP>13</SUP>C imaging data from human studies JOURNAL OF MAGNETIC RESONANCE Zhu, Z., Zhu, X., Ohliger, M. A., Tang, S., Cao, P., Carvajal, L., Autry, A. W., Li, Y., Kurhanewicz, J., Chang, S., Aggarwal, R., Munster, P., Xu, D., Larson, P. E. Z., Vigneron, D. B., Gordon, J. W. 2019; 301: 73-79

  Abstract

  Effective coil combination methods for human hyperpolarized 13C spectroscopy multi-channel data had been relatively unexplored. This study implemented and tested several coil combination methods, including (1) the sum-of-squares (SOS), (2) singular value decomposition (SVD), (3) Roemer method by using reference peak area as a sensitivity map (RefPeak), and (4) Roemer method by using ESPIRiT-derived sensitivity map (ESPIRiT). These methods were evaluated by numerical simulation, thermal phantom experiments, and human cancer patient studies. Overall, the SVD, RefPeak, and ESPIRiT methods demonstrated better accuracy and robustness than the SOS method. Extracting complex pyruvate signal provides an easy and excellent approximation of the coil sensitivity map while maintaining valuable phase information of the coil-combined data.

  View details for DOI 10.1016/j.jmr.2019.01.015

  View details for Web of Science ID 000462888700009

  View details for PubMedID 30851668

  View details for PubMedCentralID PMC7170546

• CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study. Meric-Bernstam, F., Lee, R. J., Carthon, B., Iliopoulos, O., Mier, J., Patel, M. R., Tannir, N. M., Owonikoko, T., Haas, N. B., Voss, M., Harding, J. J., Srinivasan, R., Shapiro, G., Telli, M. L., Munster, P. N., Carvajal, R. D., Jenkins, Y., Whiting, S. H., Bendell, J. C., Bauer, T. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.7_suppl.549

  View details for Web of Science ID 000489108800550

• A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. Oncology Hong, D. n., Rasco, D. n., Veeder, M. n., Luke, J. J., Chandler, J. n., Balmanoukian, A. n., George, T. J., Munster, P. n., Berlin, J. D., Gutierrez, M. n., Mita, A. n., Wakelee, H. n., Samakoglu, S. n., Guan, S. n., Dimery, I. n., Graef, T. n., Borazanci, E. n. 2019: 1–10

  Abstract

  Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors.This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab.The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%).The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

  View details for DOI 10.1159/000500571

  View details for PubMedID 31230047

• First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy CANCER MANAGEMENT AND RESEARCH Munster, P., Mita, M., Mahipal, A., Nemunaitis, J., Massard, C., Mikkelsen, T., Cruz, C., Paz-Ares, L., Hidalgo, M., Rathkopf, D., Blumenschein, G., Smith, D. C., Eichhorst, B., Cloughesy, T., Filvaroff, E. H., Li, S., Raymon, H., de Haan, H., Hege, K., Bendell, J. C. 2019; 11: 10463-10476

  Abstract

  This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.NCT01353625.

  View details for DOI 10.2147/CMAR.S208720

  View details for Web of Science ID 000502263200001

  View details for PubMedID 31853198

  View details for PubMedCentralID PMC6916675

• Technique development of 3D dynamic CS-EPSI for hyperpolarized C-13 pyruvate MR molecular imaging of human prostate cancer MAGNETIC RESONANCE IN MEDICINE Chen, H., Larson, P. E. Z., Gordon, J. W., Bok, R. A., Ferrone, M., van Criekinge, M., Carvajal, L., Cao, P., Pauly, J. M., Kerr, A. B., Park, I., Slater, J. B., Nelson, S. J., Munster, P. N., Aggarwal, R., Kurhanewicz, J., Vigneron, D. B. 2018; 80 (5): 2062–72

  Abstract

  The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-13 C]pyruvate to [1-13 C]lactate with whole gland coverage at high spatial and temporal resolution.A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time.Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-13 C]pyruvate to [1-13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage.The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure kPL , the kinetic rate constant of [1-13 C]pyruvate to [1-13 C]lactate conversion.

  View details for PubMedID 29575178

  View details for PubMedCentralID PMC6107425

• Talazoparib and decitabine: a promising combination for BRCA-mutated cancers treatment Pacaud, R., Thomas, S., Roche, E., Pawlowska, N., Dhawan, M., Munster, P. ELSEVIER SCI LTD. 2018: E28

  View details for Web of Science ID 000461258600053

• Safety and pharmacokinetics of MM-302, a HER2-targeted antibody-liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: a phase 1 dose-escalation study BRITISH JOURNAL OF CANCER Munster, P., Krop, I. E., LoRusso, P., Ma, C., Siegel, B. A., Shields, A. F., Molnar, I., Wickham, T. J., Reynolds, J., Campbell, K., Hendriks, B. S., Adiwijaya, B. S., Geretti, E., Moyo, V., Miller, K. D. 2018; 119 (9): 1086-1093

  Abstract

  This phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.Patients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.Sixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.MM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w.

  View details for DOI 10.1038/s41416-018-0235-2

  View details for Web of Science ID 000449423700007

  View details for PubMedID 30361524

  View details for PubMedCentralID PMC6219487

• Randomized trial of lisinopril or carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving trastuzumab Munster, P. N., Krischer, J., Tamura, R., Bello-Matricaria, L., Fink, A., McCaskill-Stevens, W., Guglin, M. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277300190

• Effect of JAK/STAT or PI3Kd plus PD-1 inhibition on the tumor microenvironment: Biomarker results from a phase Ib study in patients with advanced solid tumors Kirkwood, J. M., Iannotti, N., Cho, D., O'Day, S., Gibney, G., Hodi, F., Munster, P., Hoyle, P., Owens, S., Smith, M., Mettu, N. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-CT176

  View details for Web of Science ID 000468818900162

• A multicenter study of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib plus durvalumab in patients with relapsed/refractory (R/R) solid tumors. Hong, D. S., Rasco, D. W., Veeder, M. H., Luke, J. J., Chandler, J., Balmanoukian, A., George, T. J., Munster, P., Berlin, J., Gutierrez, M., Mita, A. C., Wakelee, H. A., Samakoglu, S., Guan, S., Dimery, I. W., Borazanci, E. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.2578

  View details for Web of Science ID 000442916001357

• Phase I-b study of isatuximab plus carfilzomib in relapsed and refractory multiple myeloma (RRMM). Chari, A., Richter, J., Shah, N., Wong, S., Jagannath, S., Cho, H. J., Biran, N., Wolf, J., Parekh, S. S., Munster, P. N., Madduri, D., Campana, F., Martin, T. G. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.8014

  View details for Web of Science ID 000442916003061

• TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib plus pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)-Results from ROC cohort. Konstantinopoulos, P. A., Waggoner, S. E., Vidal, G. A., Mita, M. M., Fleming, G. F., Holloway, R. W., Van Le, L., Sachdev, J. C., Chapman-Davis, E., Colon-Otero, G., Penson, R. T., Matulonis, U. A., Kim, Y. B., Moore, K. N., Swisher, E. M., Dezube, B., Wang, J. Y., Buerstatte, N., Arora, S., Munster, P. N. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.106

  View details for Web of Science ID 000442916000008

• Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC). Tannir, N. M., Fan, A. C., Lee, R. J., Carthon, B., Iliopoulos, O., Mier, J., Patel, M. R., Meric-Bernstam, F., DeMichele, A., Voss, M., Harding, J. J., Srinivasan, R., Shapiro, G., Telli, M. L., Munster, P. N., Carvajal, R. D., Jenkins, Y., Whiting, S. H., Bendell, J. C., Bauer, T. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.6_suppl.603

  View details for Web of Science ID 000436179500597

• Phase 1 study of CB-839, a first-in-class oral inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer Kalinsky, K., Harding, J. J., DeMichele, A., Infante, J. R., Gogineni, K., Owonikoko, T. K., Isakoff, S., Iliopoulos, O., Patel, M. R., Munster, P., Telli, M. L., Jenkins, Y., Fiji, G. P., Whiting, S. H., Meric-Bernstam, F. AMER ASSOC CANCER RESEARCH. 2018

  View details for Web of Science ID 000425489402243

• Local delivery of hormonal therapy with silastic tubing for prevention and treatment of breast cancer SCIENTIFIC REPORTS Park, J., Thomas, S., Zhong, A. Y., Wolfe, A. R., Krings, G., Terranova-Barberio, M., Pawlowska, N., Benet, L. Z., Munster, P. N. 2018; 8: 92

  Abstract

  Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer.

  View details for DOI 10.1038/s41598-017-18436-1

  View details for Web of Science ID 000419442500029

  View details for PubMedID 29311658

  View details for PubMedCentralID PMC5758798

• Long-term responders to epigenetic modulators: abexinostat and pazopanib Aggarwal, R., Pawlowsk, N., Grabowsky, J., Harb, A., Abri-Lavasani, K., Thomas, S., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1535-7163.TARG-17-A173

  View details for Web of Science ID 000590008800158

• Pharmacokinetic modeling of differential toxicity to predict alternate dosing schedules Dhawan, M., Bartelink, I., Aggarwal, R., Pawlowska, N., Terranova-Barberio, M., Thomas, S., Munster, P. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1535-7163.TARG-17-A090

  View details for Web of Science ID 000590008800082

• PEGylated human IL-10 (AM0010) in combination with an anti-PD-1 in advanced NSCLC Wong, D., Schneider, J. G., Aljumaily, R., Korn, W. M., Infante, J., Patel, M., Autio, K., Papadopoulos, K., Naing, A., Gabrail, N. Y., Munster, P., Goldman, J., Ratti, N., Van Vlasselaer, P., Hung, A., Oft, M., Garon, E. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000424778900010

• Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors CLINICAL CANCER RESEARCH Dhawan, M. S., Bartelink, I. H., Aggarwal, R., Leng, J., Zhang, J. Z., Pawlowska, N., Barberio, M., Grabowski, J., Gewitz, A., Chien, A. J., Moasser, M., Kelley, R. K., Maktabi, T., Thomas, S., Munster, P. N. 2017; 23 (21): 6400-6410

  Abstract

  Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage.Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity.Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87-68] from baseline in gBRCA carriers and 63% (CI, 72-55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy.Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400-10. ©2017 AACR.

  View details for DOI 10.1158/1078-0432.CCR-17-0703

  View details for Web of Science ID 000414165200005

  View details for PubMedID 28790114

• What advanced cancer patients with limited treatment options know about clinical research: a qualitative study SUPPORTIVE CARE IN CANCER Garrett, S. B., Koenig, C. J., Trupin, L., Hlubocky, F. J., Daugherty, C. K., Reinert, A., Munster, P., Dohan, D. 2017; 25 (10): 3235-3242

  Abstract

  Discussions between oncologists and advanced cancer patients (ACPs) may touch on the complex issue of clinical trial participation. Numerous initiatives have sought to improve the quality of these potentially difficult conversations. However, we have limited data about what ACPs know about clinical research as they enter such discussions as, to date, such research has focused on the period following informed consent. This study examines ACPs' understanding of clinical research in the treatment period before consent.We conducted in-depth interviews with adult ACPs with limited treatment options at four clinics in an academic medical center. So as not to influence patients' perspectives, interviewers probed patients' knowledge of clinical research only if the patient first brought up the topic. Interviews (40-60 min) were audio-recorded, transcribed, and analyzed thematically and via quantitative content analysis by an interdisciplinary team.Of 78 patients recruited, 56 (72%) spontaneously brought up the topic of clinical research during interview and are included in this analysis. Qualitative thematic analysis and quantitative content analysis revealed that patients' knowledge varied in terms of (1) accuracy and (2) specificity (level of detail). ACPs who spoke with high specificity were not always accurate, and ACPs with accurate knowledge included both high- and low-specificity speakers.ACPs' knowledge of clinical research is variable. Patients who can discuss the technical details of their care may or may not understand the broader purpose and procedures of clinical trials. Understanding this variability is important for improving patient-provider communication about clinical research and supporting efforts to provide individualized care for ACPs.

  View details for DOI 10.1007/s00520-017-3734-4

  View details for Web of Science ID 000408727600030

  View details for PubMedID 28488050

  View details for PubMedCentralID PMC5680157

• Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors BREAST CANCER RESEARCH Bartelink, I. H., Prideaux, B., Krings, G., Wilmes, L., Lee, P., Bo, P., Hann, B., Coppe, J., Heditsian, D., Swigart-Brown, L., Jones, E. F., Magnitsky, S., Keizer, R. J., de Vries, N., Rosing, H., Pawlowska, N., Thomas, S., Dhawan, M., Aggarwal, R., Munster, P. N., Esserman, L. J., Ruan, W., Wu, A. H. B., Yee, D., Dartois, V., Savic, R. M., Wolf, D. M., van't Veer, L. 2017; 19: 107

  Abstract

  Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001).PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.

  View details for DOI 10.1186/s13058-017-0896-4

  View details for Web of Science ID 000410043700002

  View details for PubMedID 28893315

  View details for PubMedCentralID PMC5594551

• Efficacy and immune activation with PEGylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC: Update Wong, D. J., Schneider, J. G., Aljumaily, R., Korn, M. W., Autio, K., Infante, J. R., Patel, M. R., Papadopoulos, K., Naing, A., Gabrail, N., Munster, P., Goldman, J., Van Vlasselaer, P., Hung, A., Brown, G., Oft, M., Garon, E. B. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000411324003165

• A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma BLOOD Martin, T., Baz, R., Benson, D. M., Lendvai, N., Wolf, J., Munster, P., Lesokhin, A. M., Wack, C., Charpentier, E., Campana, F., Vij, R. 2017; 129 (25): 3294-3303

  Abstract

  This phase 1b, open-label, dose-escalation study assessed the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab given in 2 schedules (3, 5, or 10 mg/kg every other week [Q2W] or 10 or 20 mg/kg weekly [QW] for 4 weeks and then Q2W thereafter [QW/Q2W]), in combination with lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (QW), in patients with relapsed/refractory multiple myeloma (RRMM). Patients received 28-day treatment cycles; the primary objective was to determine the maximum tolerated dose (MTD) of isatuximab with lenalidomide and dexamethasone. Fifty-seven patients (median 5 [range 1-12] prior regimens; 83% refractory to previous lenalidomide therapy) were treated. Median duration of dosing was 36.4 weeks; 15 patients remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969.

  View details for DOI 10.1182/blood-2016-09-740787

  View details for Web of Science ID 000403895200009

  View details for PubMedID 28483761

  View details for PubMedCentralID PMC5482100

• Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC CANCER IMMUNOLOGY RESEARCH Tumeh, P. C., Hellmann, M. D., Hamid, O., Tsai, K. K., Loo, K. L., Gubens, M. A., Rosenblum, M., Harview, C. L., Taube, J. M., Handley, N., Khurana, N., Nosrati, A., Krummel, M. F., Tucker, A., Sosa, E. V., Sanchez, P. J., Banayan, N., Osorio, J. C., Nguyen-Kim, D. L., Chang, J., Shintaku, I., Boasberg, P. D., Taylor, E. J., Munster, P. N., Algazi, A. P., Chmielowski, B., Dummer, R., Grogan, T. R., Elashoff, D., Hwang, J., Goldinger, S. M., Garon, E. B., Pierce, R. H., Daud, A. 2017; 5 (5): 417-424

  Abstract

  We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis- group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417-24. ©2017 AACR.

  View details for DOI 10.1158/2326-6066.CIR-16-0325

  View details for Web of Science ID 000400624900009

  View details for PubMedID 28411193

  View details for PubMedCentralID PMC5749922

• Glucocorticoid receptor expression in 20 solid tumor types using immunohistochemistry assay CANCER MANAGEMENT AND RESEARCH Block, T. S., Murphy, T. I., Munster, P. N., Nguyen, D. P., Lynch, F. J. 2017; 9: 65-71

  Abstract

  Glucocorticoid receptor (GR) activity plays a role in many aspects of human physiology and may play a crucial role in chemotherapy resistance in a wide variety of solid tumors. A novel immunohistochemistry (IHC) based assay has been previously developed and validated in order to assess GR immunoreactivity in triple-negative breast cancer. The current study investigates the standardized use of this validated assay to assess GR expression in a broad range of solid tumor malignancies.Archived formalin-fixed paraffin-embedded tumor bank samples (n=236) from 20 different solid tumor types were analyzed immunohistochemically. Nuclear staining was reported based on the H-score method using differential intensity scores (0, 1+, 2+, or 3+) with the percent stained (out of at least 100 carcinoma cells) recorded at each intensity.GR was expressed in all tumor types that had been evaluated. Renal cell carcinoma, sarcoma, cervical cancer, and melanoma were those with the highest mean H-scores, indicating high levels of GR expression. Colon, endometrial, and gastric cancers had lower GR staining percentages and intensities, resulting in the lowest mean H-scores.A validated IHC assay revealed GR immunoreactivity in all solid tumor types studied and allowed for standardized comparison of reactivity among the different malignancies.Baseline expression levels of GR may be a useful biomarker when pharmaceutically targeting GR in research or clinical setting.

  View details for DOI 10.2147/CMAR.S124475

  View details for Web of Science ID 000396158700001

  View details for PubMedID 28293120

• Phase 1 study of CB-839, a small molecule inhibitor of glutaminase, in combination with everolimus in patients (pts) with clear cell and papillary renal cell cancer (RCC) Meric-Bernstam, F., Tannir, N., Harding, J., Voss, M., Mier, J., DeMichele, A., Munster, P., Patel, M., Iliopoulos, O., Owonikoko, T., Whiting, S., Orford, K., Bennett, M., Carvajal, R., McKay, R., Fan, A., Telli, M., Infante, J. ELSEVIER SCI LTD. 2016: S12–S13

  View details for DOI 10.1016/S0959-8049(16)32626-0

  View details for Web of Science ID 000390503500021

• PHASE I INVESTIGATION OF LENALIDOMIDE PLUS RITUXIMAB AND OUTCOMES OF LENALIDOMIDE MAINTENANCE IN RECURRENT CNS LYMPHOMA Rubenstein, J., Fraser, E., Formaker, P., Lee, J., Chen, N., Kock, M., Cheung, W., Killea, P., Choi, K., Wang, X., Munster, P., Damato, B. OXFORD UNIV PRESS INC. 2016: 23-24

  View details for Web of Science ID 000398604101028

• Interest in Initiating an Early Phase Clinical Trial: Results of a Longitudinal Study of Advanced Cancer Patients. Psycho-oncology Dunn, L. B., Wiley, J., Garrett, S., Hlubocky, F., Daugherty, C., Trupin, L., Munster, P., Dohan, D. 2016

  Abstract

  Enhanced recruitment of patients with advanced cancer (ACP) to early phase (EP) trials is needed. However, selective recruitment may affect the kinds of patients who are recruited. To address whether ACP who initiate EP trial enrollment differ from those who do not, we prospectively surveyed ACP well in advance of potential trial recruitment and followed them over time to identify those who initiated the recruitment process.EP trial initiation was defined as a patient being referred for screening to an active EP trial. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), respectively. Demographic and disease characteristics, functional status, and patient preferences regarding decision making were examined as possible predictors of EP trial initiation.Of the 78 advanced cancer patients in the cohort studied, 21 (27%) initiated EP trial participation, while 57 (73%) did not. Of those who initiated this process, 14 (67%) went on to enroll in an EP study. Level of depression severity was associated with EP trial initiation, with rates of initiation nearly three times higher (35% vs. 12%, p = 0.054) among patients with minimal to mild levels of depression compared to those with moderate or higher levels of depression. EP trial initiation was not associated with demographic or socioeconomic variables, cancer type, functional status, quality of life, or decision-making variables.The presence of elevated depressive symptoms may be associated with the EP trial recruitment and enrollment processes. This possible relationship warrants further study.

  View details for DOI 10.1002/pon.4179

  View details for PubMedID 27233054

• Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC) Meric-Bernstam, F., Tannir, N. M., Mier, J., DeMichele, A., Telli, M. L., Fan, A. C., Munster, P. N., Carvajal, R. D., Orford, K. W., Bennett, M. K., Iliopoulos, O., Owonikoko, T., Patel, M. R., McKay, R., Infante, J. R., Voss, M., Harding, J. J. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.4568

  View details for Web of Science ID 000404665407141

• Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS) in combination with paclitaxel (Pac) in patients (pts) with triple negative breast cancer (TNBC). DeMichele, A., Harding, J. J., Telli, M. L., Munster, P. N., McKay, R., Iliopoulos, O., Orford, K. W., Bennett, M. K., Mier, J., Owonikoko, T., Patel, M. R., Carvajal, R. D., Meric-Bernstam, F., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.1011

  View details for Web of Science ID 000404665401133

• A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma ANNALS OF ONCOLOGY Thomas, S., Aggarwal, R., Jahan, T., Ryan, C., Troung, T., Cripps, A. M., Raha, P., Thurn, K. T., Chen, S., Grabowsky, J. A., Park, J., Hwang, J., Daud, A., Munster, P. N. 2016; 27 (5): 947-952

  Abstract

  Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma.Patients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m(2) of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated.Forty patients received 20-60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5.Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers.This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.

  View details for DOI 10.1093/annonc/mdw044

  View details for Web of Science ID 000376102300031

  View details for PubMedID 26903311

  View details for PubMedCentralID PMC4843187

• First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies CLINICAL CANCER RESEARCH Munster, P., Aggarwal, R., Hong, D., Schellens, J. H. M., van der Noll, R., Specht, J., Witteveen, P. O., Werner, T. L., Dees, E., Bergsland, E., Agarwal, N., Kleha, J. F., Durante, M., Adams, L., Smith, D. A., Lampkin, T. A., Morris, S. R., Kurzrock, R. 2016; 22 (8): 1932-1939

  Abstract

  GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors.Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts.One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant).Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.

  View details for DOI 10.1158/1078-0432.CCR-15-1665

  View details for Web of Science ID 000374101400014

  View details for PubMedID 26603258

• A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies BREAST CANCER RESEARCH AND TREATMENT Chien, A., Cockerill, A., Fancourt, C., Schmidt, E., Moasser, M. M., Rugo, H. S., Melisko, M. E., Ko, A. H., Kelley, R., Korn, W., Esserman, L. J., van't Veer, L., Yau, C., Wolf, D. M., Munster, P. N. 2016; 155 (3): 521-530

  Abstract

  Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies.We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response.MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.

  View details for DOI 10.1007/s10549-016-3701-7

  View details for Web of Science ID 000371055100013

  View details for PubMedID 26875185

• A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies CLINICAL CANCER RESEARCH Gupta, S., Argiles, G., Munster, P. N., Hollebecque, A., Dajani, O., Cheng, J. D., Wang, R., Swift, A., Tosolini, A., Piha-Paul, S. A. 2015; 21 (23): 5235-5244

  Abstract

  The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction.Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥ 6 months.Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence.

  View details for DOI 10.1158/1078-0432.CCR-15-0180

  View details for Web of Science ID 000365603800009

  View details for PubMedID 26187616

• Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas CANCER DISCOVERY Zill, O. A., Greene, C., Sebisanovic, D., Siew, L., Leng, J., Vu, M., Hendifar, A. E., Wang, Z., Atreya, C. E., Kelley, R. K., Van Loon, K., Ko, A. H., Tempero, M. A., Bivona, T. G., Munster, P. N., Talasaz, A., Collisson, E. A. 2015; 5 (10): 1040-1048

  Abstract

  Patients with pancreatic and biliary carcinomas lack personalized treatment options, in part because biopsies are often inadequate for molecular characterization. Cell-free DNA (cfDNA) sequencing may enable a precision oncology approach in this setting. We attempted to prospectively analyze 54 genes in tumor and cfDNA for 26 patients. Tumor sequencing failed in 9 patients (35%). In the remaining 17, 90.3% (95% confidence interval, 73.1%-97.5%) of mutations detected in tumor biopsies were also detected in cfDNA. The diagnostic accuracy of cfDNA sequencing was 97.7%, with 92.3% average sensitivity and 100% specificity across five informative genes. Changes in cfDNA correlated well with tumor marker dynamics in serial sampling (r = 0.93). We demonstrate that cfDNA sequencing is feasible, accurate, and sensitive in identifying tumor-derived mutations without prior knowledge of tumor genotype or the abundance of circulating tumor DNA. cfDNA sequencing should be considered in pancreatobiliary cancer trials where tissue sampling is unsafe, infeasible, or otherwise unsuccessful.Precision medicine efforts in biliary and pancreatic cancers have been frustrated by difficulties in obtaining adequate tumor tissue for next-generation sequencing. cfDNA sequencing reliably and accurately detects tumor-derived mutations, paving the way for precision oncology approaches in these deadly diseases.

  View details for DOI 10.1158/2159-8290.CD-15-0274

  View details for Web of Science ID 000365595900022

  View details for PubMedID 26109333

  View details for PubMedCentralID PMC4592417

• Pembrolizumab (MK-3475) for PD-L1-positive squamous cell carcinoma (SCC) of the anal canal: Preliminary safety and efficacy results from KEYNOTE-028 Ott, P. A., Piha-Paul, S. A., Munster, P., Pishvaian, M. J., Van Brummelen, E., Cohen, R., Gomez-Roca, C., Ejadi, S., Stein, M., Chan, E., Simonelli, M., Morosky, A., Yuan, S. S., Koshiji, M., Bennouna, J. ELSEVIER SCI LTD. 2015: S102

  View details for DOI 10.1016/S0959-8049(15)30008-3

  View details for Web of Science ID 000361887400310

• Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours EUROPEAN JOURNAL OF CANCER Piha-Paul, S. A., Munster, P. N., Hollebecque, A., Argiles, G., Dajani, O., Cheng, J. D., Wang, R., Swift, A., Tosolini, A., Gupta, S. 2015; 51 (14): 1865-1873

  Abstract

  The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.This phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted.Twenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week+1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ⩾6 months.Combined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development.

  View details for DOI 10.1016/j.ejca.2015.06.115

  View details for Web of Science ID 000360081300002

  View details for PubMedID 26199039

  View details for PubMedCentralID PMC5693226

• A phase I study of MM-302, a HER2-targeted PEGylated liposomal doxorubicin, in patients with HER2+metastatic breast cancer LoRusso, P., Krop, I., Miller, K., Ma, C., Siegel, B. A., Shields, A. F., Molnar, I., Wickham, T., Reynolds, J., Campbell, K., Hendriks, B., McClure, T., Moyo, V., Munster, P. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-CT234

  View details for Web of Science ID 000371597100068

• More Options for Fertility Preservation for Patients With Cancer JOURNAL OF CLINICAL ONCOLOGY Munster, P. N. 2015; 33 (22): 2413-U7

  View details for DOI 10.1200/JCO.2015.61.9304

  View details for Web of Science ID 000361654100002

  View details for PubMedID 26101241

• Association of tamoxifen use and ovarian function in patients with invasive or pre-invasive breast cancer BREAST CANCER RESEARCH AND TREATMENT Chien, A., Duralde, E., Hwang, R., Tsung, K., Kao, C., Rugo, H. S., Melisko, M. E., Esserman, L. J., Munster, P. N., Cedars, M., Kerlikowske, K., McCulloch, C. E., Rosen, M. P. 2015; 153 (1): 173-181

  Abstract

  The impact of long-term tamoxifen therapy on ovarian function is not known. Understanding these effects will help reproductive-aged patients who desire future pregnancy make more informed decisions regarding their treatment. This is a retrospective cohort study in patients identified through the UCSF Cancer Registry and SPORE database. We enrolled women with a history of ductal carcinoma in situ (DCIS) or early stage invasive breast cancer who were premenopausal at diagnosis and did not receive chemotherapy. Menstrual histories were obtained through electronic and paper surveys. We compared the age of menopause onset and menstrual pattern changes between women who received tamoxifen (TAM) and those who did not receive tamoxifen (control). Neither group received chemotherapy. 250 subjects were included in this study (125 TAM, 125 control). Mean age of menopause onset was 51.0 for both the groups and was not associated with duration of tamoxifen use or the age at tamoxifen initiation. Menstrual pattern changes, including amenorrhea, were more frequent in the TAM group than control group (any change: 48% TAM vs. 15 % control, p < 0.001; amenorrhea: 22% TAM vs. 3% control, p < 0.001). Older age was associated with an increased risk of developing amenorrhea within 6 months of starting tamoxifen (HR 1.32, p < 0.001). Menstrual pattern changes are common in premenopausal women taking tamoxifen. Tamoxifen use in the absence of chemotherapy is not associated with an earlier age onset of menopause in patients with DCIS or invasive breast cancer and is unlikely to significantly accelerate ovarian aging.

  View details for DOI 10.1007/s10549-015-3511-3

  View details for Web of Science ID 000359775100017

  View details for PubMedID 26208485

• Safety and tolerability of increasing doses of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors. Harding, J. J., Telli, M. L., Munster, P. N., Le, M. H., Molineaux, C., Bennett, M. K., Mittra, E., Burris, H. A., Clark, A., Dunphy, M., Meric-Bernstam, F., Patel, M. R., DeMichele, A., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.2512

  View details for Web of Science ID 000358036900545

• Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors JOURNAL OF CLINICAL ONCOLOGY Daud, A. I., Ashworth, M. T., Strosberg, J., Goldman, J. W., Mendelson, D., Springett, G., Venook, A. P., Loechner, S., Rosen, L. S., Shanahan, F., Parry, D., Shumway, S., Grabowsky, J. A., Freshwater, T., Sorge, C., Kang, S., Isaacs, R., Munster, P. N. 2015; 33 (9): 1060-+

  Abstract

  We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.

  View details for DOI 10.1200/JCO.2014.57.5027

  View details for Web of Science ID 000356056400017

  View details for PubMedID 25605849

• Phase 1 Expansion Study of an Oral TORC1/TORC2 Inhibitor (CC-223) in Non-Pancreatic Neuroendocrine Tumors (NET) Wolin, E., Mita, M., Meyer, T., Bendell, J., Mahipal, A., Nemunaitis, J., Munster, P., Paz-Arez, L., Hull, W., James, A., Trowe, T., Swaminathan, M., Wu, X., de Haan, H. LIPPINCOTT WILLIAMS & WILKINS. 2015: 362

  View details for Web of Science ID 000349769400077

• Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma Rubenstein, J. L., Formaker, P., Wang, X., Chen, N., Seider, M., Munster, P., Damato, B. AMER SOC HEMATOLOGY. 2014

  View details for DOI 10.1182/blood.V124.21.4470.4470

  View details for Web of Science ID 000349233808044

• Phase 1B study of CC-486 (oral azacitidine) in tumors associated with a viral etiology Von Hoff, D. D., Isambert, N., Lopez-Martin, J., Munster, P. N., Rasco, D. W., Bendell, J. C., Schellens, J. M., Tomaro, J., Sarmiento, R., Liu, K., Nguyen, A., Bray, G. L., Hatty, S. R., DiMartino, J. F., Le Tourneau, C. ELSEVIER SCI LTD. 2014: 179

  View details for DOI 10.1016/S0959-8049(14)70677-X

  View details for Web of Science ID 000347755700552

• A phase I trial of BKM120 combined with vemurafenib in BRAFV600<SUP>E/k</SUP> mutant advanced melanoma. Algazi, A., Posch, C., Ortiz-Urda, S., Cockerill, A., Munster, P. N., Daud, A. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.9101

  View details for Web of Science ID 000358613204386

• Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2-BC). Munster, P. N., Hamilton, E., Franklin, C., Bhansali, S., Wan, K., Hewes, B., Juric, D. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.533

  View details for Web of Science ID 000358613202307

• Safety/efficacy of MK-8669 (ridaforolimus) plus MK-2206 (AKT inhibitor) in patients with advanced breast cancer with low RAS signature and PTEN deficient prostate cancer Gupta, S., Munster, P. N., Hollebecque, A., Argues, G., Dajanl, O., Chang, J. D., Swift, A. M., Tosolini, A., Piha-Paul, S. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.2509

  View details for Web of Science ID 000358613202774

• Results of a phase I trial combining ridaforolimus (mTOR inhibitor) and MK-0752 (Notch inhibitor) in patients with advanced solid tumors. Piha-Paul, S., Munster, P. N., Hollehecque, A., Argiles, G., Dajanl, O., Cheng, J. D., Wang, R., Swift, A. M., Tosolini, A., Gupta, S. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.2601

  View details for Web of Science ID 000358613202866

• Correlation of intratumoral metabolic changes measured with 18F-FDG PET parametric response maps with concentrations of CC-223, a TORC 1/2 kinase inhibitor, in human glioblastoma. Ellingson, B. M., Cloughesy, T., Munster, P. N., Shih, K. C., Bendell, J. C., James, A., Tong, Z., Trowe, T., Chopra, R., Hege, K. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.2609

  View details for Web of Science ID 000358613202873

• Next-generation sequencing of serum microRNA (miRNA) in hepatocellular carcinoma (HCC) patients on targeted therapy. Kelley, R., Chang, A. N., Anguiano, E., Hwang, J., Stoppler, H. J., McWhirter, R. M., Parks, A. L., Hameed, B., Fix, O. K., Wayne, E. M., Nimeiri, H., Munster, P. N., Venook, A. P., Goga, A. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.4096

  View details for Web of Science ID 000358613203259

• Phase Ib/II study of the PI3Kα inhibitor BYL719 in combination with cetuximab in recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) Razak, A. R. A., Ahn, M., Yen, C., Solomon, B. J., Lee, S., Wang, H., Munster, P. N., L-Van Herpen, C. M., Gilbert, J., Pal, R., Blumenstein, L., Gomez-Carrillo, B., Coughlin, C., Lim, W. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.6044

  View details for Web of Science ID 000358613203636

• SAFETY AND EFFICACY OF MK-8669 (RIDAFOROLIMUS) + MK-2206 (AKT INHIBITOR) IN PATIENTS WITH ADVANCED BREAST CANCER WITH PI3K PATHWAY DEPENDENCE Gupta, S., Munster, P., Hollebecque, A., Argiles, G., Guren, T., Cheng, J., Wang, R., Swift, A., Tosolini, A., Piha-Paul, S. OXFORD UNIV PRESS. 2014: 25

  View details for DOI 10.1093/annonc/mdu071.1

  View details for Web of Science ID 000336094500037

• A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with <i>BRAF</i> <SUP><i>V600E</i></SUP> mutation-positive metastatic melanoma CANCER CHEMOTHERAPY AND PHARMACOLOGY Grippo, J. F., Zhang, W., Heinzmann, D., Yang, K. H., Wong, J., Joe, A. K., Munster, P., Sarapa, N., Daud, A. 2014; 73 (1): 103-111

  Abstract

  This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets).Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2.Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h.Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

  View details for DOI 10.1007/s00280-013-2324-5

  View details for Web of Science ID 000329223200013

  View details for PubMedID 24178368

• PET/CT IMAGING OF 64CU-LABELLED HER2 LIPOSOMAL DOXORUBICIN (64CU-MM-302) QUANTIFIES VARIABILITY OF LIPOSOMAL DRUG DELIVERY TO DIVERSE TUMOR LESIONS IN HER2-POSITIVE BREAST CANCER PATIENTS Hendriks, B., Shields, A., Siegel, B. A., Miller, K., Munster, P., Ma, C., Campbell, K., Moyo, V., Wickham, T., LoRusso, P. OXFORD UNIV PRESS. 2014: 19

  View details for DOI 10.1093/annonc/mdu068.1

  View details for Web of Science ID 000336094500029

• Assessment of safety and activity in an expanded phase 1 study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced HER2-positive (HER2+) breast cancer Munster, P., Krop, I. E., Miller, K., Dhindsa, N., Niyijiza, C., Nielsen, U., Odueyungbo, A., Rajarethinam, A., Marande, M., Campbell, K., Geretti, E., Reynolds, J. G., Hendriks, B. S., Wickham, T., Moyo, V., LoRusso, P. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/0008-5472.SABCS13-P4-12-29

  View details for Web of Science ID 000209496902035

• Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR plus ) breast cancer cell lines and patients (pts) with genetically characterized HR plus breast cancer in a Phase I clinical trial. Mita, M. M., Arkenau, H., Bendell, J. C., Munster, P. N., Mahipal, A., Delord, J., Paz-Ares, L. G., Soria, J., Xu, S., Tran, T., Shi, T., Wu, X., Chopra, R., Hege, K., Varga, A. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1535-7163.TARG-13-A68

  View details for Web of Science ID 000209496800064

• Histone Deacetylase Regulation of ATM-Mediated DNA Damage Signaling MOLECULAR CANCER THERAPEUTICS Thurn, K., Thomas, S., Raha, P., Qureshi, I., Munster, P. N. 2013; 12 (10): 2078-2087

  Abstract

  Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.

  View details for DOI 10.1158/1535-7163.MCT-12-1242

  View details for Web of Science ID 000325548400014

  View details for PubMedID 23939379

  View details for PubMedCentralID PMC3821775

• Phase Ib study of eribulin (ERB) and cyclophosphamide (CTX) in metastatic breast cancer (MBC). Truong, T., Pelayo, M., Grabowsky, J. A., Melisko, M. E., Magbanua, M., Moasser, M. M., Reinert, A., Hwang, J., Park, J. W., Munster, P. N., Rugo, H. S. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for DOI 10.1200/jco.2013.31.26_suppl.153

  View details for Web of Science ID 000335564700123

• Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (ESBC): Predictors of cognitive decline. Rugo, H. S., DeLuca, A. N., Heflin, L., Fang, S., Melisko, M. E., Moasser, M. M., Park, J. W., Chien, A., Munster, P. N., Esserman, L., Landau, S. M., Jagust, W. J., Kramer, J. H. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for DOI 10.1200/jco.2013.31.26_suppl.104

  View details for Web of Science ID 000335564700078

• Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (BC): Relationship between perceived and measurable cognitive deficits. Heflin, L., Fang, S., DeLuca, A. N., Melisko, M. E., Moasser, M. M., Park, J. W., Chien, A., Munster, P. N., Landau, S. M., Jagust, W. J., Kramer, J. H., Rugo, H. S. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for DOI 10.1200/jco.2013.31.26_suppl.105

  View details for Web of Science ID 000335564700079

• Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-C-13]Pyruvate SCIENCE TRANSLATIONAL MEDICINE Nelson, S. J., Kurhanewicz, J., Vigneron, D. B., Larson, P. E., Harzstark, A. L., Ferrone, M., Van Criekinge, M., Chang, J. W., Bok, R., Park, I., Reed, G., Carvajal, L., Small, E. J., Munster, P., Weinberg, V. K., Ardenkjaer-Larsen, J. H., Chen, A. P., Hurd, R. E., Odegardstuen, L., Robb, F. J., Tropp, J., Murray, J. A. 2013; 5 (198)

  Abstract

  This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

  View details for DOI 10.1126/scitranslmed.3006070

  View details for Web of Science ID 000323132200008

  View details for PubMedID 23946197

• Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates. Annals of oncology : official journal of the European Society for Medical Oncology Kelley, R. K., Nimeiri, H. S., Munster, P. N., Vergo, M. T., Huang, Y., Li, C., Hwang, J., Mulcahy, M. F., Yeh, B. M., Kuhn, P., Luttgen, M. S., Grabowsky, J. A., Stucky-Marshall, L., Korn, W. M., Ko, A. H., Bergsland, E. K., Benson, A. B., Venook, A. P. 2013; 24 (7): 1900-1907

  Abstract

  BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

  View details for DOI 10.1093/annonc/mdt109

  View details for PubMedID 23519998

• Fertility Preservation and Breast Cancer: A Complex Problem ONCOLOGY-NEW YORK Munster, P. N. 2013; 27 (6): 533-539

  Abstract

  A considerable number of women with breast cancer are diagnosed during their reproductive years. In the short period of time in which newly diagnosed women will need to make decisions about surgical options and adjuvant therapy, younger women with breast cancer also face the potential impairment or complete loss of their fertility. The preservation of fertility should therefore be an integral consideration in the choice of breast cancer therapy. Preserving ovarian function is particularly challenging for women with estrogen receptor-positive tumors, as the suppression of ovarian function has been shown to be beneficial therapy with regard to breast cancer outcomes. The current emerging recommendations of hormonal therapy extending to a 10-year period will likely further impact the timing of any subsequent pregnancy or require an interruption in hormonal therapy. To optimally counsel patients on how to best weigh the risks and benefits of each intervention, both the care provider and the patient must understand the options and the likelihood of their success. Here we summarize the current challenges and options for women diagnosed with breast cancer who wish to preserve their fertility.

  View details for Web of Science ID 000321159200007

  View details for PubMedID 23909066

• BKM120 combined with vemurafenib in vemurafenib-refractory BRAF mutant metastatic melanoma: Two cases. Algazi, A., Posch, C., Ortiz-Urda, S., Cockerill, A., Munster, P. N., Daud, A. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000335419604736

• Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (BC): Relationship between perceived and measurable cognitive deficits. Heflin, L., Fang, S., DeLuca, A. N., Melisko, M. E., Moasser, M. M., Park, J. W., Chien, A., Munster, P. N., Esserman, L., Landau, S. M., Jagust, W. J., Kramer, J. H., Rugo, H. S. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000335419602335

• Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (ESBC): Predictors of cognitive decline. Rugo, H. S., DeLuca, A. N., Heflin, L., Fang, S., Melisko, M. E., Moasser, M. M., Park, J. W., Chien, A., Munster, P. N., Esserman, L., Landau, S. M., Jagust, W. J., Kramer, J. H. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000335419602336

• Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) Goy, A., Ribrag, V., Varga, A., Witzig, T. E., Ocio, E. M., Paz-Ares, L. G., Mita, M. M., Meyer, T., Munster, P. N., Mahipal, A., Delord, J., Arkenau, H., Gutierrez, M., James, A., Wong, L., Xu, S., Wu, X., Carmichael, J., Chopra, R., Hege, K. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000335419602618

• Phase Ib study of safety, tolerability, and efficacy of R1507 a monoclonal antibody to IGF-1R in combination with multiple standard chemotherapy regimens in patients with advanced solid malignancies. Mahadevan, D., Sutton, G., Arteta-Bulos, R., Bowden, C. J., Miller, P. J. E., Swart, R., Walker, M. S., Munster, P. N., Dees, E., Marshall, J., Hamid, O., Kurzrock, R. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000335419603464

• Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma BLOOD Rubenstein, J. L., Li, J., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Hwang, J., Auerback, G., Kadoch, C., Lowell, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. 2013; 121 (5): 745-751

  Abstract

  Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab.Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

  View details for DOI 10.1182/blood-2012-07-440974

  View details for Web of Science ID 000314867200007

  View details for PubMedID 23197589

  View details for PubMedCentralID PMC3563362

• A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab BREAST CANCER RESEARCH AND TREATMENT Lin, N. U., Winer, E. P., Wheatley, D., Carey, L. A., Houston, S., Mendelson, D., Munster, P., Frakes, L., Kelly, S., Garcia, A. A., Cleator, S., Uttenreuther-Fischer, M., Jones, H., Wind, S., Vinisko, R., Hickish, T. 2012; 133 (3): 1057-1065

  Abstract

  Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-competent ErbB family members. This phase II, open-label, single-arm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year. Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.

  View details for DOI 10.1007/s10549-012-2003-y

  View details for Web of Science ID 000305914900023

  View details for PubMedID 22418700

  View details for PubMedCentralID PMC3387495

• A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies. Moore, A., Thach-Giao Truong, Thurn, K., Thomas, S., Ryan, C. J., Jahan, T., DuBois, S. G., Chan, J. K., Rugo, H. S., Collisson, E., Raha, P., Chen, S., Reinert, A., Daud, A., Munster, P. N. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009802195

• Phase Ib study of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) in combination with bevacizumab (bev) with or without paclitaxel. Goldman, J., Gordon, M. S., Munster, P. N., Bergsland, E. K., Moore, A., Bai, S., Hegde, P., Fredrickson, J. O., Chang, I., Chandler, G., Funke, R., Rhee, I., Chen, D. S., Rosen, L. S. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801808

• Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer JOURNAL OF CLINICAL ONCOLOGY Munster, P. N., Moore, A. P., Ismail-Khan, R., Cox, C. E., Lacevic, M., Gross-King, M., Xu, P., Carter, W., Minton, S. E. 2012; 30 (5): 533-538

  Abstract

  Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

  View details for DOI 10.1200/JCO.2011.34.6890

  View details for Web of Science ID 000302622900019

  View details for PubMedID 22231041

  View details for PubMedCentralID PMC3295555

• Multicenter Phase I Trial of Intraventricular Immuno-Chemotherapy in Recurrent CNS Lymphoma 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Rubenstein, J. L., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Kadoch, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. AMER SOC HEMATOLOGY. 2011: 438–39

  View details for Web of Science ID 000299597101230

• Preclinical and clinical activity of the topoisomerase I inhibitor, karenitecin, in melanoma EXPERT OPINION ON INVESTIGATIONAL DRUGS Munster, P. N., Daud, A. I. 2011; 20 (11): 1565-1574

  Abstract

  This review covers the preclinical and clinical activity of the novel camptothecin analog, karenitecin, in melanoma.While the camptothecins are widely used antitumor agents that inhibit topoisomerase I, their utility is limited by instability, high interpatient variability and the development of drug resistance. Karenitecin was rationally designed to overcome these limitations. The authors review the data on karenitecin in preclinical models and in clinical trials in melanoma using studies published in Medline and reports presented at AACR and ASCO.Karenitecin shows activity in melanoma, both as a single agent and in combination. In adverse prognostic factor melanoma, karenitecin showed prolonged disease stabilization in 34% of patients. Because preclinical studies suggested a synergistic interaction between karenitecin and HDAC inhibitors, a schedule-specific combination Phase I-II trial of valproic acid and karenitecin was carried out in heavily pretreated melanoma patients which showed a benefit rate in 47% patients with acceptable toxicity. The treatment for melanoma is in rapid transition and genomic profiling is now an integral part, and hence the optimal use of karenitecin in melanoma should be re-evaluated with regard to specific mutational status.

  View details for DOI 10.1517/13543784.2011.617740

  View details for Web of Science ID 000295718200009

  View details for PubMedID 21985236

• A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer BRITISH JOURNAL OF CANCER Munster, P. N., Thurn, K. T., Thomas, S., Raha, P., Lacevic, M., Miller, A., Melisko, M., Ismail-Khan, R., Rugo, H., Moasser, M., Minton, S. E. 2011; 104 (12): 1828-1835

  Abstract

  Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated.In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.

  View details for DOI 10.1038/bjc.2011.156

  View details for Web of Science ID 000291384700005

  View details for PubMedID 21559012

  View details for PubMedCentralID PMC3111195

• Costello and Cardio-Facio-Cutaneous Syndromes: Moving Toward Clinical Trials in RASopathies AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Rauen, K. A., Banerjee, A., Bishop, W., Lauchle, J. O., McCormick, F., McMahon, M., Melese, T., Munster, P. N., Nadaf, S., Packer, R. J., Sebolt-Leopold, J., Viskochil, D. H. 2011; 157C (2): 136-146

  Abstract

  The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.

  View details for DOI 10.1002/ajmg.c.30294

  View details for Web of Science ID 000290717500008

  View details for PubMedID 21495172

  View details for PubMedCentralID PMC4145816

• Inhibition of class I histone deacetylases attenuates anthracycline induced activation of the ATM pathway Thurn, K., Thomas, S., Raha, P., Qureshi, I., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2011

  View details for DOI 10.1158/1538-7445.AM2011-2614

  View details for Web of Science ID 000209701401097

• The HDAC inhibitor PCI-24781 potentiates the anti-tumor activity of tamoxifen in ER-positive breast cancer cells Thomas, S., Thurn, K., Raha, P., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2011

  View details for DOI 10.1158/1538-7445.AM2011-2631

  View details for Web of Science ID 000209701401116

• Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker BRITISH JOURNAL OF CANCER Munster, P. N., Marchion, D., Thomas, S., Egorin, M., Minton, S., Springett, G., Lee, J., Simon, G., Chiappori, A., Sullivan, D., Daud, A. 2009; 101 (7): 1044-1050

  Abstract

  Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

  View details for DOI 10.1038/sj.bjc.6605293

  View details for Web of Science ID 000270355300003

  View details for PubMedID 19738609

  View details for PubMedCentralID PMC2768109

• Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC CLINICAL CANCER RESEARCH Munster, P., Marchion, D., Bicaku, E., Lacevic, M., Kim, J., Centeno, B., Daud, A., Neuger, A., Minton, S., Sullivan, D. 2009; 15 (7): 2488-2496

  Abstract

  The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies.A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets.Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression.Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.

  View details for DOI 10.1158/1078-0432.CCR-08-1930

  View details for Web of Science ID 000264955800034

  View details for PubMedID 19318486

• Potentiation of a Topoisomerase I Inhibitor, Karenitecin, by the Histone Deacetylase Inhibitor Valproic Acid in Melanoma: Translational and Phase I/II Clinical Trial Daud, A. I., Dawson, J., DeConti, R. C., Bicaku, E., Marchion, D., Bastien, S., Hausheer, F. A., Lush, R., Neuger, A., Sullivan, D. M., Munster, P. N. AMER ASSOC CANCER RESEARCH. 2009: 2479-2487

  Abstract

  The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma.Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function.VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was approximately 200 microg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose.VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.

  View details for DOI 10.1158/1078-0432.CCR-08-1931

  View details for Web of Science ID 000264955800033

  View details for PubMedID 19318485

• Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma Daud, A. I., DeConti, R. C., Andrews, S., Urbas, P., Riker, A. I., Sondak, V. K., Munster, P. N., Sullivan, D. M., Ugen, K. E., Messina, J. L., Heller, R. AMER SOC CLINICAL ONCOLOGY. 2008: 5896-5903

  Abstract

  Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA.A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-mus pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels.Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response.This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.

  View details for DOI 10.1200/JCO.2007.15.6794

  View details for Web of Science ID 000261843600012

  View details for PubMedID 19029422

  View details for PubMedCentralID PMC2645111

• Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters. Commentary re: P. Münster et al., Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. Clin. Cancer Res., 7: 2228-2236, 2001. Clinical cancer research : an official journal of the American Association for Cancer Research Sausville, E. A. 2001; 7 (8): 2155-8

  View details for PubMedID 11489788