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.

Conditions

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

Interventions

DRUG

BMN 673

Poly (ADP-ribose) polymerase (PARP) inhibitor; 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 deoxyribonucleic acid (DNA) repair pathways.

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Alice P Chen, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

120 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-02-04

Primary Completion

2020-03-26

Completion

2020-03-26

FDA Drug

Yes

Countries

• United States

Study Locations