Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations

Summary

Background: * The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms. * Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways. * BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations. * This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue. Primary Objective: -Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations. Secondary Objectives: * Determine the response rate (Complete Response (CR) + Partial Response (PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations. * Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations. * Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations. Eligibility: * Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options. * No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels. * Age greater than or equal to 18 years of age; Eastern Cooperative Oncology Group (ECOG) performance status less than equal to 2 * Adequate organ function. * Willingness to undergo tumor biopsies. Study Design: * BMN 673 will be administered orally each day in 28-day cycles. * Dosing will be at the established recommended Phase II dose of 1000 mcg/day each day for 28 days. * We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients. * Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression. SCHEMA * BMN 673 is administered orally each day in 28-day cycles * Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for protease activated receptor (PAR) levels, DNA damage response markers such as \>=H2A.X Variant Histone (H2AX), cleaved caspase 3, excision repair cross-complementing group 1 (ERCC1), pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM) activation, Checkpoint kinase 1 (chk1) and Checkpoint kinase 2 (chk2) * Blood samples for circulating tumor cells (CTC) analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose) * Blood samples for pharmacokinetic (PK) analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 pre-dose and 3-6 hours post dose.

Timeline

Start

2014-02-04

Primary completion

2020-03-26

Completion

2020-03-26

Publications

• Background Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15.
• Background de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov. 2017 Jun;7(6):620-629. doi: 10.1158/2159-8290.CD-16-1250. Epub 2017 Feb 27.
• Results Wilsker DF, Barrett AM, Dull AB, Lawrence SM, Hollingshead MG, Chen A, Kummar S, Parchment RE, Doroshow JH, Kinders RJ. Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers. Clin Cancer Res. 2019 May 15;25(10):3084-3095. doi: 10.1158/1078-0432.CCR-18-2523. Epub 2019 Feb 21.
• Mittra A, Coyne GHOS, Zlott J, Kummar S, Meehan R, Rubinstein L, Juwara L, Wilsker D, Ji J, Miller B, Navas T, Ferry-Galow KV, Voth AR, Chang TC, Jiwani S, Parchment RE, Doroshow JH, Chen AP. Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors. Cancer Chemother Pharmacol. 2024 Mar;93(3):177-189. doi: 10.1007/s00280-023-04600-0. Epub 2023 Nov 27.

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Indications