A Randomized Phase II Study of Gemcitabine, Cisplatin +/- Veliparib in Patients With Pancreas Adenocarcinoma and a Known BRCA/ PALB2 Mutation (Part I) and a Phase II Single Arm Study of Single-Agent Veliparib in Previously Treated Pancreas Adenocarcinoma (Part II) (NCI #8993, Version Date 03/02/2012)
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 the study. (Part I)\ II.
To evaluate the response rate (Response Evaluation Criteria in Solid Tumors [RECIST]
criteria) to gemcitabine, cisplatin, and veliparib (Arm A) and gemcitabine and cisplatin
(Arm B) at 6 weeks in breast cancer (BRCA) and partner and localizer of BRCA2 (PALB2)
mutation carriers with advanced pancreas adenocarcinoma. (Part I) III. To evaluate the
response rate (RECIST criteria) to single-agent veliparib (Arm C) at 8 weeks 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 arms A and B. (Part
I) IV. To evaluate overall survival of patients in study arms A and B. (Part I) V. To
evaluate progression-free survival of BRCA and PALB2 mutation carriers with previously
treated pancreas adenocarcinoma (Arm C) treated with single-agent veliparib. (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.
VIII. To evaluate overall survival of patients treated in Arm C. (Part II)
TERTIARY OBJECTIVES:
I. To determine the genotype of BRCA1, BRCA2, and PALB2-mutated pancreas adenocarcinoma.
(Aim I) 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 Poly (ADP-ribosyl)ation (PAR) in peripheral blood mononuclear
cells (PBMCs), hair follicles, and tumor tissues at sequential time points before and
following therapy with veliparib.
IV. To quantify levels of yH2AX and RAD51 foci in PBMCs, hair follicles, and tumor tissue
(where available) at sequential time points to assess for formation of double-stranded
deoxyribonucleic acid (DNA) breaks and stalled/collapsed replication forks and to evaluate
homologous recombination competence.
V. To correlate the results of genotyping with gene expression to provide functional
information on mutations identified. (Exploratory) VI. To assess 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 multicenter, dose-escalation study of veliparib followed by a randomized,
open-label study. A total of 6-24 patients for the non-randomized portion, 32-50 patients
for Part I, and 15-33 patients for Part II will be accrued for this study.
Patients receive veliparib orally (PO) twice daily (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.
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.
Some patients undergo tumor tissue, normal tissue, eyebrow hair follicle, and blood sample
collection at baseline, during, and after completion of treatment for BRCA1, BRCA2, and
PALB2-mutation, PAR, yH2AX and RAD51 foci, and gene expression analysis by polymerase chain
reaction (PCR), mass spectrometry, immunohistochemistry-based staining assay, and
spectrophotometry.
After completion of study treatment, patients are followed up every 3 months.
Interventional
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Optimal dose of veliparib with gemcitabine and cisplatin (non-randomized part I)
21 days
No
Eileen O'Reilly
Principal Investigator
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
NCI-2012-00864
NCT01585805
April 2012
Name | Location |
---|---|
Memorial Sloan-Kettering Cancer Center | New York, New York 10021 |
Dana-Farber Cancer Institute | Boston, Massachusetts 02115 |
University of Chicago Comprehensive Cancer Center | Chicago, Illinois 60637-1470 |
M D Anderson Cancer Center | Houston, Texas 77030 |
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital | Baltimore, Maryland 21231 |