This randomized phase II trial studies how well veliparib together with gemcitabine hydrochloride and cisplatin works compared to gemcitabine hydrochloride and cisplatin alone in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or spread from the primary site (place where it started) to other places in the body (metastatic). Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving veliparib together with gemcitabine hydrochloride and cisplatin is an effective treatment for 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 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) CORRELATIVE SCIENCE 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. EXPLORATORY OBJECTIVES: I. To correlate the results of genotyping with gene expression to provide functional information on mutations identified. II. 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. 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 of each cycle. Patients also receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and cisplatin IV over 30 minutes on days 3 and 10 of each cycle. Cycles 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 of each cycle and gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 30 minutes on days 3 and 10 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial and undergo tumor biopsy during screening and on study. ARM B (no prior therapy or \>= 6 months since adjuvant therapy): Patients receive gemcitabine hydrochloride IV and cisplatin IV as patients in arm A. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial and undergo tumor biopsy during screening and on study. PART II: Patients who are eligible receive treatment in Arm C. ARM C (prior therapy): Patients receive veliparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial. After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
88
Undergo biopsy
Undergo tumor tissue and blood sample collection
Given IV
Undergo CT
Given IV
Given IV
Undergo MRI
Given PO
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
Ingalls Memorial Hospital
Harvey, Illinois, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Mercy Hospital Saint Louis
St Louis, Missouri, United States
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Commack
Commack, New York, United States
Memorial Sloan Kettering Westchester
Harrison, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Memorial Sloan Kettering Nassau
Uniondale, New York, United States
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
...and 2 more locations
Optimal dose of veliparib with gemcitabine hydrochloride and cisplatin (non-randomized part I)
Time frame: 21 days
Response rate to gemcitabine hydrochloride and cisplatin with versus without veliparib (randomized Part I)
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Simon's two-stage minimax design will be employed separately in each arm A and B.
Time frame: Up to 5 years
Response rate of single-agent veliparib (Part II)
Will be assessed by RECIST criteria. Simon's two-stage optimal design will be employed.
Time frame: Up to 5 years
Progression-free survival (Parts I and II)
Kaplan-Meier method will be used.
Time frame: From the date of study enrollment to documentation of clear-cut progression of disease or last follow-up, assessed up to 5 years
Incidence of adverse events (Parts I and II)
Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 will be utilized for adverse event reporting beginning April 1, 2018). Toxicity and tolerability of all three study arms will be assessed and summarized using descriptive statistics.
Time frame: Up to 5 years
Disease control rate (complete response + partial response + stable disease) and duration of response (Parts I and II)
The disease control rate will be recorded for all three study arms.
Time frame: Up to 5 years
Overall survival (Parts I and II)
Kaplan-Meier method will be used.
Time frame: From the time of study enrollment to the date of death or last follow-up, assessed up to 5 years
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