Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms.
- 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 BRCA1/2- and 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.
-Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.
- Determine the response rate (CR + 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.
- 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; ECOG performance status less than equal to 2
- Adequate organ function.
- Willingness to undergo tumor biopsies.
- 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
- 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.
- 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 PAR levels, DNA damage response markers such as >=H2AX, cleaved caspase 3, ERCC1, pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ATR/ATM activation, chk1 and chk2
- Blood samples for 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 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 predose and 3-6 hours post dose.
|Advanced Ovarian Cancer Primary Peritoneal Cancer Advanced Breast Cancer Advanced Solid Tumors||Drug: BMN 673||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations|
- Percent of patients who achieve a sustained PD response, defined to be at least 10% nuclear area positive at the day 8 biopsy [ Time Frame: Cycle 1 day 8 ]
|Study Start Date:||November 8, 2013|
|Study Completion Date:||June 13, 2017|
|Primary Completion Date:||June 13, 2017 (Final data collection date for primary outcome measure)|
Drug: BMN 673
PARP inhibitor; has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01989546
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Alice P Chen, M.D.||National Cancer Institute (NCI)|