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SWOG 1416

The main cohort will temporarily close to accrual.  The brain metastases cohort will remain open.

Phase II Randomized Placebo-Controlled Trial of Cisplatin with or without ABT-888 (Veliparib) in Metastatic Triple-Negative Breast Cancer and/or BRCA Mutation-Associated Breast Cancer

Inclusion Criteria

  • Patients must have metastatic and/or recurrent (distant or locoregionally recurrent*) breast cancer and be HER2 non-over expressing per 2013 ASCO-CAP HER testing guidelines (0 or 1+ by IHC; and/or HER2 ratio < 2.0 and HER2 copy number < 4 signals/cell by ISH).  *Local Regional Recurrence:  In the breast (after preserving therapy), in the chest wall (after mastectomy), in the ipsilateral/parasternal/infra-or supraclavicular lymph nodes, in the skin of the chest wall (not breast), in the reconstructed breast.
  • Patients must also meet at least one of the following criteria: 1) Triple Negative: Histologically confirmed primary and/or metastatic site that is ER-negative (≤ 1%), PR-negative (≤ 1%), and HER2–negative. 2) BRCA mutation: Previously confirmed deleterious BRCA1 or BRCA2 germline mutation or suspected deleterious BRCA1 or BRCA2 germline mutation if the classification being used is the 5-tier classification. Documentation of germline test results are required.
  • Patients must have measurable or non-measurable disease. Patients must have a chest/abdominal/pelvis CT scan (or PET/CT of diagnostic quality, conventional or spiral)  prior to registration. If the patient is unable to undergo CT with IV contrast due to allergy or renal insufficiency, a noncontrast CT may be performed. All scans needed for assessment of measurable disease must be performed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration.
  • Patients must be women or men ≥ 18 years of age.
  • Patients must have adequate tissue available, must agree to have specimens submitted for germline BRCA DNA sequencing and other correlative studies.  Blood for BRCA mutation testing is to be collected and submitted after registration but before treatment. 
  • Patients must have had ≤ 1 prior cytotoxic regimen for metastatic disease (unless enrolling in the Progressive Brain Metastases Cohort).  Note that endocrine and immunotherapies do not count as cytotoxic regimens. 
  • Patients must have completed any prior radiation therapy and hormonal therapy at least 14 days prior to registration.
  • Patients must not have received prior cisplatin or PARP inhibitors. Prior carboplatin in the adjuvant/neoadjuvant setting is allowed, if completed more than 12 months prior to study entry.
  • Patients must not have received any chemotherapy within 14 days prior to registration.
  • Patients must not have received any immunotherapy, biologic or any investigational drug within 28 days prior to registration. Patients must not have received bevacizumab within 42 days prior to registration.
  • Patients may receive bisphosphonates or denosumab concurrently with study treatment.  If started prior to registration, it must be started at least 7 days prior to registration.  
  • Patients must have recovered to ≤ Grade 2 following a significant adverse event or toxicity attributed to previous anti-cancer treatment except neurotoxicity which must be ≤ Grade 1.
  • Patients must have a performance status of 0-2 by Zubrod criteria.
  • Patients must have adequate bone marrow function, as defined by Absolute Neutrophil Count (ANC) of >/= 1,500/mcL, hemoglobin >/= 10 g/dL and a platelet count >/= 100,000/ mcL within 21 days prior to registration.
  • Patients must have adequate hepatic function obtained within 21 days prior to registration and documented by all of the following:
    • Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert’s Syndrome or if liver metastases are present)
    • ALT and AST ≤ 2.5 x Institutional Upper Limit of Normal (IULN) (or ≤ 5 x IULN if liver metastases are present)
  • Patients must have adequate renal function with serum creatinine level ≤ IULN within 21 days prior to registration.
  • Patients must have serum chemistries (including potassium and magnesium) done within 21 days prior to registration to obtain baseline values.
  • Patients must not have a clinically relevant hearing impairment ≥ Grade 2.
  • Patients must be able to swallow whole capsules.
  • Patients with a history of uncontrolled seizure disorder; including focal or generalized seizure may not have had a seizure within one year prior to registration.
  • Patients with known brain metastases must either meet additional criteria specified in the protocol and enroll as part of the Progressive Brain Metastases Cohort, or have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to registration.  Patients with incidentally discovered or asymptomatic brain metastasis(es) must receive surgical excision and/or radiation therapy prior to registation.  Patients with progressive brain metastases following prior treatment are not eligible for the Standard Cohort, but may be considered for the Progressive Brain Metastases Cohort. 
    • Patients with progressive brain metastases must have a baseline brain MRI within 28 days prior to registration. Brain metastases must be progressive and ≥ 10 mm in longest dimension on radiographic imaging AFTER prior intracranial radiation (IR) therapy (i.e., WBRT, SRS, GK or local equivalent). Patients must not have evidence of diffuse leptomeningeal disease on brain MRI or by previously documented CSF cytology. Discrete dural metastases are permitted. There must be no evidence of hemorrhage or impending herniation on baseline brain imaging. Patients with contraindication to gadolinium-enhanced MRI imaging are not eligible.
    • Patients must be on a stable or decreasing dose of steroids for ≥ 7 days prior to registration.
    • If patient has had an open brain biopsy, at least 28 days must have elapsed between biopsy and registration. 
    • Patients enrolling in the Progressive Brain metastases Cohort can have received up to 3 prior lines of cytotoxic chemotherapy for metastatic disease.  Note that for enrollment in the standard cohort, patients must have had < 1 prior cytotoxic regimen for metastatic disease. 
  • Patients must not have any incidence of or uncontrolled medical illness (e.g. active cardiac symptoms, active systemic infection, etc.) that would limit the patient’s ability to participate in the protocol.
  • Patients must not have treatment-related AML/MDS or features suggestive of AML/MDS.
  • Patients must not have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation.
  • Patients must not have baseline peripheral neuropathy that exceeds Grade 1.
  • Patients of childbearing potential must not be pregnant (negative pregnancy test) or nursing due to the possibility of harm to a fetus or nursing infant from this treatment regimen. Men and women of reproductive potential must have agreed to use an effective contraceptive method for 6 months after completion of study treatment. A woman is considered to be of “reproductive potential” if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.

Treatment Plan

All patients will have BRCA 1/2 testing completed by a central lab. Results of BRCA1, BRCA2 and ten other actionable genes will be provided to the treating physician with 4-8 weeks.

Patients will be randomized to one of the tollowing arms:
Arm 1: Cisplatin 75 mg/m2 IV q21days + Placebo
Arm 2: Cisplatin 75 mg/m2 IV q21days + ABT-888 300 mg po BID Day 1-14 q21days

Treatment will continue until disease progression, symptomatic deterioration, unacceptable toxicity, treatment delay for any reason > 3 weeks, start of alternative anti-cancer agent during the study period (palliative radiotherapy and surgery may be acceptable), patient becomes pregnant or begins breastfeeding during treatment, or patient withdrawal from study for any reason.

ABT-888 and matched placebo are provided for the study free of charge.