Pamela Munster

All Publications

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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