BMN 673 (Talazoparib), an Oral PARP Inhibitor, in People With Deleterious BRCA1/2 Mutation-Associated Ovarian Cancer Who Have Had Prior PARP Inhibitor Treatment
Condition: Ovarian Cancer
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Intervention: BMN 673 (talazoparib)
Intervention description: 1 mg by mouth (p.o.) once daily on 28-day cycles until disease progression
Intervention MeSH terms: Talazoparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: Female
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Germline BRCA1/2 Mutations (gBRCAm); DNA Damaging Agents; FOX03a, 53BP1 and RAD51

Summary:

      Background:

      - The new drug BMN 673 (talazoparib) has been shown to fight tumor cells in animals and some
      people. It is a poly (ADP-ribose) polymerase (PARP) inhibitor. It works on tumor cell
      deoxyribonucleic acid (DNA) damage repair process. Researchers want to see if BMN 673 shrinks
      cancer again in women with ovarian cancer and whose cancer initially got shrunk but grew back
      on the first PARP inhibitor.

      Objective:

      - To study BMN 673 (talazoparib) in people with ovarian cancer born with a breast cancer
      (BRCA) mutation and whose cancer got shrunk but became worse after they took a similar drug.

      Eligibility:

        -  Women at least 18 years old:

        -  with recurrent and/or metastatic germline breast cancer mutation (gBRCAm)-associated
           ovarian cancer AND

        -  whose disease is growing after already being treated with PARP inhibitors AND

        -  with no other treatment(s) in between the first PARP inhibitors and a screening visit.

      Design:

        -  Participants will be screened with medical history, physical exam, and heart and blood
           tests.

        -  Participants will take the study drug by mouth once daily. They will take the drug in
           28-day cycles.

        -  They will keep a diary of doses and any side effects.

        -  Participants will have 4 study visits in cycle 1, then 1 visit every cycle. Visits may
           include:

        -  Blood tests

        -  Physical exam

        -  Computed tomography (CT) or magnetic resonance imaging (MRI) scans. Participants will
           lie in a machine that takes pictures of their body.

        -  Ultrasound

        -  Participants will have a biopsy before starting the study drug. A small piece of tumor
           tissue will be removed by needle, guided by a scan. They may have two more biopsies
           later.

        -  Participants will be followed for 30 days after taking the last dose of study drug. A
           physical exam, blood tests, and CT or other scans will be done.

        -  Participants will have follow-up calls to ask about any side effects.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Recurrent, and/or metastatic germline breast cancer (BRCA) 1/2 mutation-associated
             ovarian cancer, with progression on a poly (ADP-ribose) polymerase (PARP) inhibitor
             monotherapy after attaining a response to that PARPi (complete response (CR), partial
             response (PR), or stable disease (SD) greater than or equal to 4mo)

          -  Progression should have occurred within the immediate prior 2 months of the time of
             screening visit, with no intervening anti-cancer therapy.

          -  Patients must be at least 4 weeks from the last dose of prior PARP inhibitor.

          -  All patients must have at least one lesion deemed safe to biopsy and be willing to
             undergo mandatory baseline biopsy. It is preferred that this lesion be a lesion that
             progressed or arose while on the prior PARP therapy.

          -  Histopathologic diagnosis of ovarian cancer (including primary peritoneal and
             fallopian tube cancers) must be confirmed in the Laboratory of Pathology, National
             Cancer Institute (NCI).

          -  Age greater than or equal to18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
             (Karnofsky greater than or equal to 60%.

          -  Patients must have normal organ and marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  platelets greater than or equal to100,000/mcL

               -  total bilirubin less than or equal to 1.5X upper limit of normal, unless known
                  Gilberts syndrome

               -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
                  (SGOT)/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)
                  less than or equal to 3 x institutional upper limit of normal

               -  creatinine < 1.5 X upper limit of normal

        OR

          -  measured creatinine clearance >60 mL/min/1.73 m(2) for patients with serum creatinine
             levels > 1.5 x upper limit of normal.

          -  hemoglobin greater than or equal to 10 mg/dL (in the absence of transfusion within 24
             hours prior to dosing).

               -  All patients must have measurable disease by Response Evaluation Criteria in
                  Solid Tumors (RECIST).

               -  Use of raloxifene for bone health is allowed.

               -  Patients must be at least 1 week from the last dose of complementary or
                  alternative medications.

               -  Patients who have had major surgery must be fully recovered and greater than or
                  equal to 4 weeks postoperative prior to enrolling on study.

               -  Women of child-bearing potential 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 at least three months following the last dose of experimental
        therapy and must have a negative urine or serum pregnancy test within 7 days prior to the
        start of the study.

          -  Patient must be able to swallow pills.

          -  Integral biomarkers: all patients who are eligible for the study due to a history of
             positive BRCA1/2 mutation must provide documented evidence of their deleterious
             germline mutation status, obtained in a Clinical Laboratory Improvement Amendment
             (CLIA)-certified laboratory, including but not limited to Myriad Genetics prior to
             study enrollment. Variants of uncertain significance (VUS) of BRCA1/2 and BRCA1/2
             somatic mutations are not considered deleterious germline BRCA1/2 mutations. Due to
             the long acceptance of BRCA 1 and BRCA 2 mutation testing through Myriad, Myriad
             results will be acceptable. If testing for BRCA 1 and BRCA 2 mutation is done by other
             organizations, a genetic consultation report from a qualified medical professional
             confirming that the laboratory results showed a recognized germ line deleterious BRCA
             1 or BRCA 2 mutation or deleterious BRCA 1 rearrangement is required.

          -  Ability to understand and the willingness to sign a written informed consent document.

        EXCLUSION CRITERIA:

          -  Patients who have had prior BMN 673 (talazoparib) therapy.

          -  Patients with known brain metastases diagnosed within 1 year will be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events. Exception: patients with brain metastases diagnosed greater
             than 1 year prior to study entry may be considered if they received sterilizing
             therapy to the central nervous system (CNS) (resection or radiation) and have been CNS
             progression-free for the 1-year period.

          -  Lack of recovery of prior cancer therapy-related adverse events to Grade less than or
             equal to 1 (National Cancer Institute (NCI) Common Terminology Criteria in Adverse
             Events (CTCAE) v4.03; except alopecia). Stable persistent grade 2 peripheral
             neuropathy may be allowed as determined on a case-by-case basis at the discretion of
             the PI. Patients with platinum-related grade 2 or greater hypomagnesemia (on
             replacement) will be eligible.

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically
             significant gastrointestinal (GI) bleeding or hemoptysis within 28 days prior to the
             start of the study, or psychiatric illness/social situations that would limit
             compliance with study requirements.

          -  Patients with active infection will not be eligible, but may become eligible once
             infection has resolved and they are at least 7 days from completion of antibiotics.

          -  Another previous or current invasive malignancy within the last 2 years, with the
             exception of curatively treated stage Ia cervical carcinoma, or resected stage Ia
             endometrial cancer, and noninvasive nonmelanoma skin cancers.

          -  Human immunodeficiency virus (HIV)- positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             BMN 673 (talazoparib). HIV- positive patients who are not on combination
             antiretroviral therapy (cART) and have cluster of differentiation 4 (CD4) counts > 500
             are eligible.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to BMN 673 (talazoparib)

        Patients who are receiving any other investigational or commercial agents with the intent
        to treat the malignancy.

          -  Patients with gastrointestinal conditions that might predispose for drug
             intolerability or poor drug absorption.

          -  Use of nasogastric or gastric (G)-tube administration.