Cisplatin With or Without Veliparib in Treating Patients With Recurrent or Metastatic Triple-Negative and/or BRCA Mutation-Associated Breast Cancer With or Without Brain Metastases

PRIMARY OBJECTIVES:

I. To compare the efficacy of cisplatin with or without ABT-888 (veliparib) on
progression-free survival (PFS) in each of the following groups: patients with germline BRCA
(gBRCA) mutation-associated breast cancer, patients with germline BRCA wild-type breast
cancer who have evidence of BRCAness phenotype, and patients with germline BRCA wild-type
breast cancer who do not have evidence of BRCAness phenotype.

II. To compare the efficacy of cisplatin with or without ABT-888 on PFS in patients with
triple negative and/or gBRCA mutation-associated breast cancer and brain metastases. (Brain
Metastases Cohort)

SECONDARY OBJECTIVES:

I. For patients with gBRCA mutation associated breast cancer or triple-negative breast cancer
(TNBC) with or without BRCAness phenotype, to compare the efficacy of cisplatin with or
without ABT-888 on overall survival (OS), response rate, and clinical benefit rate.

II. To compare the differential benefit of ABT-888 across the three groups using both PFS and
OS as outcomes.

III. For patients in the brain metastases cohort, to compare the efficacy of cisplatin with
or without ABT-888 on OS.

IV. For patients in the brain metastases cohort, to compare the efficacy of cisplatin with or
without ABT-888 on intracranial and extracranial response rates (intracranial by Response
Assessment Neuro-Oncology Criteria [RANO] and extracranial by Response Evaluation Criteria in
Solid Tumors version 1.1 [RECIST 1.1]).

V. To compare toxicities of ABT-888 to placebo in each of the four groups separately.

TRANSLATIONAL OBJECTIVES:

I. To evaluate the impact of homologous recombination deficiency score (independent of other
BRCAness markers) on response rate (RR) and PFS in patients treated with chemotherapy versus
chemotherapy plus ABT-888.

II. To evaluate the overlap among various markers utilized to define the BRCAness phenotype.

III. To evaluate the combined impact of PAM50 basal subtype and BRCAness phenotype on RR and
PFS in patients treated with chemotherapy versus chemotherapy plus ABT-888.

IV. To evaluate the impact of BRCA1 mRNA expression (independent other BRCAness markers) on
response rate (RR) and PFS in patients treated with chemotherapy versus chemotherapy plus
ABT-888.

V. Application of somatic BRCAness phenotype markers on metastatic tumor tissue to identify
patients likely to benefit from platinum-based therapy and ABT-888.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and placebo orally
(PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive cisplatin IV over 1 hour on day 1 and veliparib PO BID on days 1-14.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 9 weeks for 54 weeks,
every 18 weeks until progression, and then every 6 months for up to 5 years after
progression.

Inclusion Criteria:

- Patients must have metastatic and/or recurrent (distant or locoregionally recurrent)
breast cancer and be HER2 non-over expressing per 2013 American Society of Clinical
Oncology (ASCO)-College of American Pathologists (CAP) HER testing guidelines (0 or 1+
by immunohistochemistry [IHC]; and/or HER2 ratio < 2.0 and HER2 copy number < 4
signals/cell by in-situ hybridization [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:

- Triple negative: histologically confirmed primary and/or metastatic site that is
estrogen receptor (ER)-negative (=< 1%), progesterone receptor (PR)-negative (=<
1%), and HER2-negative

- BRCA mutation: previously confirmed deleterious breast cancer 1, early onset
(BRCA1) or breast cancer 2, early onset (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 computed tomography (CT) scan (or positron emission tomography
[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 non-contrast 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; all
disease must be assessed and documented on the Baseline Tumor Assessment Form

- Patients must have adequate tissue available and must agree to have specimens
submitted for germline BRCA deoxyribonucleic acid (DNA) sequencing and other
correlative studies

- NOTE: 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 poly (adenosine diphosphate
[ADP]-ribose) polymerase (PARP) inhibitors; prior carboplatin in the
adjuvant/neoadjuvant setting and prior treatment with iniparib 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

- Absolute neutrophil count (ANC) of >= 1,500/mL (within 21 days prior to registration);
patients must not have had a blood transfusion within 28 days prior to registration

- Hemoglobin >= 10 g/dL (within 21 days prior to registration); patients must not have
had a blood transfusion within 28 days prior to registration

- Platelet count >= 100,000/ mL (within 21 days prior to registration); patients must
not have had a blood transfusion within 28 days prior to registration

- Bilirubin =< 1.5 mg/dL (or =< 3.0 mg/dL if due to Gilbert's syndrome or if liver
metastases are present) (within 21 days prior to registration)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
institutional upper limit of normal (IULN) (or =< 5 x IULN if liver metastases are
present) (within 21 days prior to registration)

- 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) 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 the additional criteria 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
previously incidentally discovered or asymptomatic brain metastasis(es) must receive
surgical excision and/or radiation therapy prior to registration; 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 must not have treatment-related acute myeloid leukemia (AML)
(t-AML)/myelodysplastic syndrome (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 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 baseline peripheral neuropathy that exceeds grade 1

- Patients must have a complete history and physical examination within 28 days prior to
registration

- Patients of childbearing potential must not be pregnant (negative pregnancy test) or
nursing; 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

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines

- As part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study had been
entered in the system

- Progressive Brain Metastases Cohort

- S1416 is one study with two cohorts; patients who have progressive brain
metastases after surgical excision and/or intracranial radiation will be in the
Progressive Brain Metastases Cohort and will require a baseline magnetic
resonance imaging (MRI); patients with previously treated brain metastases,
stable disease and stable neurologic function for 14 days prior to trial
registration will be in the Standard Cohort and may obtain MRI of the brain at
the physician's discretion; randomization and treatment is the same for both
cohorts

- In addition to all of the previous eligibility criteria, patients with
progressive brain metastases who do not satisfy the conditions to enroll in the
standard cohort (neurologic stability for 14 days following surgery and/or
radiation therapy) must also meet the following criteria to enroll as part of the
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., whole brain radiation therapy
[WBRT], stereotactic radiosurgery [SRS], gamma knife [GK] or local
equivalent); patients must not have evidence of diffuse leptomeningeal
disease on brain MRI or by previously documented cerebrospinal fluid (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 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