Phase 2 N=9 Treatment

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

Advanced Ovarian Cancer · Primary Peritoneal Cancer · Advanced Breast Cancer · Advanced Solid Tumors

Bottom Line

View on ClinicalTrials.gov: NCT01989546 ↗

Enrolled (actual)

Serious AEs

33.3%

Results posted

Jan 2021

Primary outcome: Primary: Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy — 44.4 percentage of participants

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: BMN 673 (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: National Cancer Institute (NCI)
Primary completion: Mar 2020

Outcome Measures

Outcome	Result	p-value
PRIMARY Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy	44.4	—
SECONDARY Response Rate (Complete Response (CR) + Partial Response (PR) of Treatment With Talazoparib (BMN 673) in Participants With Deleterious Breast Cancer (BRCA) Mutations	0; 5	—

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.

Eligibility Criteria

INCLUSION CRITERIA:

Adult patients with documented deleterious breast cancer 1 and breast cancer 2 (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.

Patients with ovarian cancer should have one prior platinum-based

chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted (noncytotoxic) agents or extended therapy administered after surgical or non-surgical

assessment. Ovarian cancer patients with both platinum-sensitive and platinum resistant disease are eligible. Patients with platinum-refractory disease are NOT eligible.

Patients with metastatic disease must have received at least one line of standard of care (SOC) treatment for metastatic disease prior to enrollment

Age greater than or equal to 18 years of age.
Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
Life expectancy of greater than 3 months.
Patients must have normal organ and marrow function as defined below:
leukocytes greater than or equal to 3,000/mcL
absolute neutrophil count greater than or equal to 1,500/mcL
platelets greater than or equal to 100,000/mcL
total bilirubin less than or equal to 1.5 times institutional upper limit of normal
Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 times institutional upper limit of normal
creatinine less than or equal to 1.5 times institutional upper limit of normal

--creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels above institutional normal.

The effects of BMN 673 on the developing human fetus are unknown. For this reason and because PARP inhibitors are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 3 months after completion of BMN 673 administration.

Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube administration is not allowed. Any gastrointestinal disease which would impair ability to swallow, retain, or absorb drug is not allowed.
Ability to understand and the willingness to sign a written informed consent document.
Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer or ovarian cancer should have received at least two lines of systemic therapy in the advanced setting.
Patients with prostate cancer can continue to receive treatment with Gonadotropin-releasing hormone (GnRH) agonists while on study, as long as there is evidence of disease progression on therapy.

EXCLUSION CRITERIA

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who have had prior treatment with any PARP inhibitors are ineligible.
Patients who are receiving any other investigational agents.
Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Pa

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Data sourced from ClinicalTrials.gov (NCT01989546). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.