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.
SECONDARY OBJECTIVES:
I. For patients with gBRCA mutation associated breast cancer or triple-negative breast
cancer (TNBC) with or without BRCAness phenotype, compare the efficacy of cisplatin with or
without ABT-888 on overall survival (OS), response rate, and clinical benefit rate.
II. Compare the differential benefit of ABT-888 across the three groups using both PFS and
OS as outcomes.
III. Compare toxicities of ABT-888 to placebo in each of the three groups separately.
TERTIARY 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 impact of prediction analysis of microarray 50 (PAM50) basal signature
(independent of gBRCA status and other BRCAness markers) on RR and PFS in patients treated
with chemotherapy versus chemotherapy plus ABT-888.
IV. To evaluate the impact of BRCA1 mRNA expression (independent of gBRCA status and other
BRCAness markers) on response rate (RR) and PFS in patients treated with chemotherapy versus
chemotherapy plus 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 breast cancer (stage IV disease) and be human epidermal
growth factor receptor 2 (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])
- 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 (documentation
required)
- Patients must have measurable or non-measurable disease; patients must have a
chest/abdominal computed tomography (CT) scan (or positron emission tomography
[PET]/CT of diagnostic quality, conventional or spiral) and bone scan 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
- Patients must have =< 1 prior cytotoxic regimens for metastatic disease
- 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 6 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
provided it has been 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
- Patients must have a performance status of 0-2 by Zubrod criteria
- Peripheral granulocyte count of >= 1,500/mL within 21 days prior to registration
- Hemoglobin >= 9 g/dL within 21 days prior to registration
- Platelet count >= 100,000/ mL within 21 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)
- 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)
- 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 known brain metastases must 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 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 must not be pregnant or nursing; men and women of reproductive potential
must have agreed to use an effective contraceptive method; 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 agree to have specimens submitted for germline deoxyribonucleic acid
(DNA) sequencing and other correlative studies
- 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
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
