Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To optimize the dose of veliparib combined with fixed doses of gemcitabine hydrochloride
(gemcitabine) and cisplatin in a (non-randomized, lead-in portion of Part I).

II. To evaluate the response rate (Response Evaluation Criteria in Solid Tumors [RECIST]
criteria) of gemcitabine, cisplatin, and veliparib (Arm A) and gemcitabine, cisplatin (Arm B)
in BRCA and PALB2 mutation carriers with advanced pancreas adenocarcinoma. (Part I) III. To
evaluate the response rate (RECIST criteria) of single-agent veliparib (Arm C) in BRCA and
PALB2 carriers with previously treated pancreas adenocarcinoma. (Part II)

SECONDARY OBJECTIVES:

I. To evaluate the progression-free survival of patients in study Arm A and Arm B. (Part I)
II. To describe the safety and tolerability of gemcitabine, cisplatin, and veliparib and
gemcitabine and cisplatin in BRCA and PALB2 carriers with advanced pancreas adenocarcinoma.
(Part I) III. To determine the disease control rate (complete response [CR] + partial
response [PR] + stable disease [SD]) and duration of response in study Arm A and Arm B. (Part
I) IV. To evaluate overall survival in study Arm A and Arm B. (Part I) V. To evaluate
progression-free survival for single-agent veliparib in BRCA and PALB2 mutation carriers with
previously treated pancreas adenocarcinoma (Arm C). (Part II) VI. To describe the safety and
tolerability of single-agent veliparib in BRCA and PALB2 mutation carriers with previously
treated pancreas adenocarcinoma. (Part II) VII. To determine the disease control rate (CR +
PR + SD) and duration of response in Arm C. (Part II) VIII. To evaluate overall survival in
Arm C. (Part II)

TERTIARY OBJECTIVES:

I. To determine the genotype of BRCA1, BRCA2 and PALB2-mutated pancreas adenocarcinoma.

II. To assess pre and post therapy biopsies for novel or persistent genetic alterations in
genes identified in aim I.

III. To quantify levels of PAR in peripheral blood mononuclear cells (PBMCs) and tumor
tissues at sequential time points before and following therapy with veliparib.

IV. To quantify levels of gammaH2AX and RAD51 foci in PBMCs and tumor tissue (where
available) at sequential time points to assess for formation of double-stranded
deoxyribonucleic acid (DNA) breaks, stalled/collapsed replication forks and evaluate
homologous recombination competence.

V. To correlate the results of genotyping with gene expression to provide functional
information on mutations identified. (Exploratory) VI. An exploratory assessment of
differential expression of genes involved in DNA repair pathways pre and post treatment to
identify candidate genes predictive of response or resistance to therapy for further study in
preclinical models of disease. (Exploratory)

OUTLINE: This is a dose-escalation study of veliparib followed by a randomized, open-label
study.

Patients receive veliparib orally (PO) twice daily (BID) on days 1-12 or 1-21. Patients also
receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and cisplatin IV over 30
minutes on days 3 and 10. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity. (CLOSED AS OF 12/13/13)

PART I: Once the maximum-tolerated dose of veliparib has been established, patients are
randomized to 1 of 2 treatment arms.

ARM A (no prior therapy or >= 6 months since adjuvant therapy): Patients receive veliparib PO
BID on days 1-12 and gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 30
minutes on days 3 and 10. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity.

ARM B (no prior therapy or >= 6 months since adjuvant therapy): Patients receive gemcitabine
hydrochloride IV and cisplatin IV as patients in arm A. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

PART II: Patients who are eligible receive treatment in Arm C.

ARM C (prior therapy): Patients receive veliparib PO BID on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months thereafter.

Inclusion Criteria:

- Patients with cytologically or histologically confirmed locally advanced or metastatic
pancreas adenocarcinoma with a BRCA1 or 2 or PALB2 mutation confirmed by report from
Myriad Genetics (United States of America [USA]); reports from other molecular
diagnostic companies can be used to confirm mutations as well; BRCA 1 or 2 or PALB2
mutation can be confirmed locally for all international sites

- For Part I, non-randomized, lead-in portion, patients with a known BRCA 1 or 2 or
PALB2 mutation are eligible along with patients who potentially may have a
likelihood of having a BRCA mutation (e.g., personal or family history of breast,
pancreas, ovary, endometrial, prostate or other likely related malignancy); for
Part I, randomized portion, a known BRCA 1 or 2 or PALB2 mutation is required

- For Part I (Arms A, B): Patients can have either locally advanced or metastatic
pancreas adenocarcinoma for which no prior therapy has been administered for either
locally advanced or metastatic disease; prior adjuvant therapy is permissible if
gemcitabine or a fluoropyrimidine was administered with or without radiation and if
disease recurrence has been documented at least 6 months after completion of adjuvant
therapy

- For Part II (Arm C): Patients can have either locally advanced or metastatic pancreas
adenocarcinoma; up to two prior treatment regimens are permissible (excluding a prior
PARP inhibitor) for either localized or metastatic pancreas adenocarcinoma; prior
combined chemotherapy and radiotherapy is permissible provided the patient has
measurable disease outside the radiation port; prior therapy must have been completed
at least 3 weeks prior to starting study therapy

- Eastern Cooperative Oncology Group (ECOG) performance status:

- For Part I (Arm A, B): 0-1 (Karnofsky > 70%)

- For Part II (Arm C): 0-2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9.0 mg/dl

- Platelets >= 100,000/mcL

- Total bilirubin =< 2 x institutional upper limit of normal

- Aspartate aminotransferase(AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase(ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
institutional upper limit of normal unless there is evidence of liver metastases in
which case the AST (SGOT)/ALT (SGPT) must be =< 5 x institutional upper limit of
normal

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Measurable disease by RECIST criteria

- For the lead-in, non-randomized portion of Part I, either measurable or evaluable
disease is acceptable

- For Part I, randomized portion, measurable disease is required

- If a woman is of child-bearing potential a negative blood or urine pregnancy test is
required; women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 3 weeks earlier

- For Part I, prior adjuvant therapy with gemcitabine or a fluoropyrimidine therapy
is permitted if completed > 6 months prior to recurrence; no prior PARP inhibitor
therapy is allowed

- For Part II, no prior PARP inhibitor therapy is permitted; up to two prior
treatment regimens are permitted as follows: 1 adjuvant and 1 metastatic; 1
locally advanced and 1 metastatic; or 2 metastatic, or a variation thereof

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib or other agents used in study

- For Part I: patients with known contraindications to platinum agents are excluded

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with veliparib; this may also apply to other agents used in this
study

- Patients with a known active infection, e.g., hepatitis B virus or hepatitis C virus;
human immunodeficiency virus (HIV)-positive patients who are otherwise well and who do
not have evidence of significant immune compromise are eligible

- Patients with active seizure or history of seizure are not eligible

- Patients with uncontrolled central nervous system (CNS) metastasis are not eligible;
patients with CNS metastases are to be stable for > 3 months after treatment and off
steroid treatment prior to study enrollment

- Patients with prior malignancy successfully treated who are currently stable and on no
active treatment are eligible

- Patients who are unable to swallow pills/capsules are ineligible