A Randomized Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination with Temozolomide or Veliparib in Combination with Carboplatin and Paclitaxel Versus Placebo plus Carboplatin and Paclitaxel in Subjects with BRCA 1 or BRCA 2 Mutation and Metastatic Breast Cancer (M12-895)

Summary

This is a Phase 2 randomized, partially blinded, multinational, multicenter study to evaluate the efficacy and tolerability of veliparib in combination with TMZ or veliparib in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in approximately 255 subjects with BRCa1 or BRCa2 mutation as
documented by the Sponsor core laboratory and metastatic breast cancer who have received no more than one prior line of cytotoxic therapy for metastatic disease.
approximately 85 research sites will participate.
Subjects will be randomized in a 1:1:1 ratio to one of the three treatment groups .
Subject randomization will be stratified by eR-positive and/or PgR-positive versus eR-negative and PgR-negative status, prior cytotoxic therapy versus no prior cytotoxic therapy, and eCoG 0-1 versus 2.

There will be approximately 80 subjects per arm. The three study treatment arms are the following:
* Veliparib at a dose of 120 mg BiD + TMZ;
* Veliparib + Carboplatin/Paclitaxel; or
* Placebo + Carboplatin/Paclitaxel.
Veliparib is an oral capsule administered 120 mg BiD on Days 1 to 7.

Veliparib + Temozolomide Dosing arm
Subjects randomized to receive veliparib 120 mg BiD + TMZ will self-administer the morning dose of veliparib and TMZ at the same time and the evening dose of veliparib approximately 12 hours after the morning dose in the same calendar day on Days 1 to 7 of each 28-day cycle
For Cycle 1, the TMZ dose will start at 150 mg/m2 QD on Days 1 to 5 of each 28-day cycle as per Table 1.

Subjects randomized to receive veliparib + carboplatin/paclitaxel or placebo + carboplatin/paclitaxel will self-administer veliparib or placebo on Days 1 to 7 of each 21-day cycle as per Table 3. The evening dose of veliparib or placebo should be administered approximately 12 hours after the morning dose. Carboplatin and paclitaxel will be administered on Day 3 of each 21-day cycle. Paclitaxel will be infused before carboplatin. The dose of carboplatin and paclitaxel will be based upon the baseline weight (C1D1) for all cycles; however, the dose should be recalculated on the basis of new weight, if there is a weight change of [Greater Than] 10% from baseline. The morning dosing of veliparib or placebo on Day 3 of every cycle should be taken before the carboplatin/paclitaxel infusion

Paclitaxel
Subjects should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists according to local institutional standard guidelines, the locally approved product label, local practice, or the applicable summary of product characteristics (SPC). The medications used for the pretreatment of paclitaxel will be recorded in the eCRF.Paclitaxel will be administered intravenously over 3 hours at a dose of 175 mg/m2.

Carboplatin
Carboplatin46 will be administered intravenously over approximately 15 to 30 minutes at auC6, immediately following paclitaxel infusion. The duration of carboplatin infusion may be lengthened according to institutional guidelines. When glomerular filtration rate (GFR) is estimated by serum creatinine using the isotope Dilution Mass Spectroscopy
(iDMS) method, the maximum dose of carboplatin should be limited to 900 mg.Similarly, when the GFR is estimated using isotopic/edetic acid (eDTa) clearance, maximum carboplatin dosing should be based upon standard guidelines and institutional

Participant Eligibility

Patients must meet the following criteria to be eligible:
1. >= 18 years of age.
2.Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic. Locally recurrent disease must not be amenable to surgical
resection or radiation with curative intent.
3. Must have a documented deleterious BRCA1 or BRCA2 germline mutation. The investigator
should ensure that the testing is consistent with local guidelines, and clinical practice, and that the
test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe amplification
(MLPA) or 2) a well-characterized methodology previously validated by sequencing, such as that
used to assess founder mutations. If testing has been performed by a laboratory other than Sponsor
core laboratory, subjects may be enrolled and must be re-tested by Sponsor core laboratory for
confirmation of BRCA1 or BRCA2 germline mutations.
4. If HER2 positive (HER2 3+ by immunohistochemistry or amplification by fluorescence in situ
hybridization [FISH > 2]), subjects must have progressed on at least one prior standard
HER2-directed therapy or the subject must have a contraindication to anti-HER2 therapy
5. Measurable or non-measurable (but radiologically evaluable) disease per RECIST version 1.1 on CT scan (within 28 days of C1D1) with at least one lesion outside previously irradiated areas.
6. ECOG Performance status of 0 to 2.
7. Adequate hematologic, renal, and hepatic function as follows:

* Bone Marrow: Absolute neutrophil count (ANC) >= 1500/mm3 (1.5 x 109/L); Platelets
>= 100,000/mm3 (100 x 109/L); Hemoglobin >= 9.5 g/dL (1.4 mmol/L); Leukocytes
> 3,000/mm3;

* Renal Function: Serum creaMeasurable lesion by RECIST (version 1.1)tinine <= 1.5 x upper limit of normal (ULN) range OR creatinine
clearance >= 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal;

* Hepatic Function: Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) <= 2.5
x institutional upper limit of normal. For subjects with liver metastases, AST and/or ALT < 5 x
ULN range; bilirubin <= 1.5 x the ULN range. Subjects with Gilbert's Syndrome may have a
bilirubin >= 1.5 x the ULN range if no evidence of biliary obstruction exists;

* Activated Partial Thromboplastin Time (APTT) must be <= 1.5 x the ULN range and
international normalized ratio (INR) < 1.5. Subjects on anticoagulant therapy will have an
appropriate partial thromboplastin time (PTT) and INR as determined by the investigator.
8. Women of childbearing potential and men must agree to use adequate contraception (one of the
following listed below) prior to study entry, for the duration of study participation and for 90 days
following completion of therapy. Women of childbearing potential must have a negative serum
pregnancy test within 7 days prior to initiation. To be considered of non-child bearing potential,
postmenopausal women must be amenorrheic for at least 12 months or subjects must be surgically
sterile.

* Total abstinence from sexual intercourse (for a minimum of one complete menstrual cycle prior
to study drug administration);

* Vasectomized male subjects or vasectomized partner of female subjects;

* Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with
spermicidal jellies or cream);

* Intra-Uterine Device (IUD);

* Additionally, male subjects (including those who are vasectomized) whose partners are
pregnant or might be pregnant must agree to use condoms for the duration of the study and for
90 days following completion of therapy.
9. Capable of understanding and complying with parameters as outlined in the protocol and able to
sign and date the informed consent, approved by an Independent Ethics Committee
(IEC)/Institutional Review Board (IRB), prior to initiation of any screening or study-specific
procedures.