Publications by authors named "Naseem J Zojwalla"

5 Publications

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Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.

Nat Med 2021 05 22;27(5):802-805. Epub 2021 Apr 22.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.
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http://dx.doi.org/10.1038/s41591-021-01324-7DOI Listing
May 2021

Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma.

J Clin Oncol 2018 03 19;36(9):867-874. Epub 2017 Dec 19.

Kevin D. Courtney and James Brugarolas, University of Texas Southwestern Medical Center; Naseem J. Zojwalla, Ann M. Lowe, Keshi Wang, Eli M. Wallace, and John A. Josey, Peloton Therapeutics, Dallas, TX; Jeffrey R. Infante, TN Oncology and Sarah Cannon Research Institute, Nashville, TN; Elaine T. Lam, University of Colorado Cancer Center, Aurora, CO; Robert A. Figlin, Cedars-Sinai Medical Center, Los Angeles, CA; Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Toni K. Choueiri, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.
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http://dx.doi.org/10.1200/JCO.2017.74.2627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946714PMC
March 2018

Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma.

Cancer 2005 Jun;103(11):2241-51

Division of Medical Oncology, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.

Background: The objective of this study was to assess hormone receptor status as an independent predictor of survival in a population-based cohort of women with breast carcinoma who were followed for up to 11 years.

Methods: Since 1990, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program has collected data on hormone receptor status among patients with breast carcinoma. In a cohort of 205,736 women with breast carcinoma age > or = 20 years at diagnosis who were entered into the SEER data base between 1990 and 2000, the authors analyzed the association of hormone receptor status with year of diagnosis, patient age, disease stage, tumor histology, tumor grade, race/ethnicity, and metropolitan/statewide residence areas. Kaplan-Meier survival curves were compared according to hormone receptor status, and Cox proportional-hazards regression models were used to assess the association of hormone receptor status with breast carcinoma-specific and all-cause mortality controlling for age, disease stage, tumor grade, tumor histology, race/ethnicity, and SEER region.

Results: Women who had tumors that were positive for both estrogen and progesterone hormone receptors had significantly better survival than other women with breast carcinoma in the overall cohort, within each stage, and in the younger and older age groups, although the survival advantage was greater among women age < or = 50 years than among older women. Hormone receptor status was associated with mortality even when patient age, disease stage, tumor grade, tumor histology, race/ethnicity, and metropolitan/statewide residence areas were taken into account.

Conclusions: Hormone receptor status was identified as an independent predictor of outcome in women with breast carcinoma. Data from clinical trials with long follow-up may shed light on whether and how the benefit of hormonal and other treatment varies with hormone receptor status.
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http://dx.doi.org/10.1002/cncr.21030DOI Listing
June 2005
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