Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
Condition: Advanced Ovarian Cancer; Primary Peritoneal Cancer; Advanced Breast Cancer; Advanced Solid Tumors
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Detailed description: 
      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. Talazoparib (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.

        -  Talazoparib (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 talazoparib (BMN 673) on
           DNA damage and apoptosis markers in tumor biopsy tissue.

      Primary Objective:

      -Determine the pharmacodynamic effect of talazoparib (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 talazoparib (BMN 673) in patients with 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:

        -  Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.

        -  Dosing will be at the established recommended Phase II dose of 1000 microgram/day each
           day for 28 days.

        -  To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of
           12 patients with matched, evaluable baseline and day 8 biopsies. To allow for some
           patients whose biopsies will not be evaluable (i.e., will contain <5% tumor content),
           the accrual ceiling is 24 patients. The number of patients evaluable for objective
           response, while relevant to the secondary objective of the trial, will not be considered
           in determining completion of accrual.

        -  Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6
           hours post talazoparib (BMN 673) on day 8. One optional tumor biopsy may also be
           collected either on day 1 (+/- 2 days) of the cycle following any restaging at which a
           10-19% increase in tumor volume is observed (according to Response Evaluation Criteria
           in Solid Tumors (RECIST) criteria) if the patient has been on study for at least 4
           cycles, or at time of disease progression.
    

Intervention name(s): BMN 673
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Talazoparib
Intervention MeSH terms: Talazoparib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: DNA Damage; Advanced Solid Tumors; BRCA Mutations; PARP Inhibitor; Pharmacodynamics