Trial record 1 of 1 for:    NCT01585805
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Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Patients With Locally Advanced or Metastatic Pancreatic Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01585805
First received: April 25, 2012
Last updated: June 17, 2014
Last verified: June 2014

April 25, 2012
June 17, 2014
April 2012
July 2017   (final data collection date for primary outcome measure)
  • Optimal dose of veliparib with gemcitabine hydrochloride and cisplatin (non-randomized part I) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
  • Response rate to gemcitabine hydrochloride and cisplatin with versus without veliparib as assessed by RECIST (randomized Part I) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Simon's two-stage minimax design will be employed .
  • Response rate of single-agent veliparib using RECIST criteria (Part II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Simon's two-stage optimal design will be employed.
  • Optimal dose of veliparib (non-randomized Part I) [ Designated as safety issue: No ]
  • Response rate to gemcitabine and cisplatin with versus without veliparib as assessed by RECIST (randomized portion) and analyzed by Simon's two-stage minimax design in each arm (randomized Part I) [ Designated as safety issue: No ]
  • Efficacy of single-agent veliparib using Simon's two-stage optimal design (Part II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01585805 on ClinicalTrials.gov Archive Site
  • Progression-free survival [ 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 ] [ Designated as safety issue: No ]
    Kaplan-Meier method will be used.
  • Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicity and tolerability of all three study arms will be assessed and summarized using descriptive statistics.
  • Disease control rate (CR + PR + SD) and duration of response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From the time of study enrollment to the date of death or last follow-up, assessed up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier method will be used.
  • Progression-free survival of patients in study Arm A compared to Arm B using the Kaplan-Meier method (Part I) [ Designated as safety issue: No ]
  • Safety and tolerability of Arm A vs Arm B vs Arm C [ Designated as safety issue: Yes ]
  • Disease control rate (CR + PR + SD) and duration of response [ Designated as safety issue: No ]
  • Overall survival of patients in Arm A vs Arm B vs Arm C using the Kaplan-Meier method [ Designated as safety issue: No ]
  • Progression-free survival of patients in Arm C [ Designated as safety issue: No ]
  • Adverse events as assessed by the National Cancer Institute Common Terminology Criteria version 4.0 [ Designated as safety issue: Yes ]
  • Molecular and genetic phenotype correlation with clinical and epidemiologic characteristics of these patients using descriptive statistics [ Designated as safety issue: No ]
  • Identification of BRCA-reversion mutations [ Designated as safety issue: No ]
  • Correlation between baseline PAR inhibition and response using a multivariate logistic regression [ Designated as safety issue: No ]
  • Molecular and genetic phenotype of tumors [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Descriptive statistics will be utilized. An exploratory analysis will be undertaken to correlate the molecular profiling with outcome (e.g., response, progression-free survival time, overall survival time). Kaplan-Meier plots and Cox regression will be used for exploratory analysis of the survival endpoints and logistic regression will be used for response endpoints.
  • Proportion of genetic reversions of BRCA gene mutations [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    The evaluation will be a descriptive and exploratory one. The proportion of genetic reversions of BRCA gene mutations to wild type will be summarized using binomial proportions.
  • Change in PAR levels [ Time Frame: Baseline up to day 84 ] [ Designated as safety issue: No ]
    Summarized by percent of baseline. In each arm, a paired t-test will be employed to compared baseline to after treatment PAR levels. Standard descriptive methods will be used to summarize baseline levels and the changes from baseline (following treatment). Changes in PAR levels from baseline to after treatment will be associated with response using Wilcoxon rank sum test.
  • Transcriptome analyses by ribonucleic acid (RNA) sequencing [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Descriptive statistics will be employed to describe the observed effects.
  • Differentially expressed genes found using the limma package, and standard cut-offs [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Descriptive statistics will be employed to describe the observed effects.
Not Provided
 
Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Patients With Locally Advanced or Metastatic Pancreatic Cancer
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)

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 locally advanced or metastatic pancreatic cancer. 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 or by stopping them from dividing. 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 (gemcitabine hydrochloride) 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 single-agent gemcitabine, cisplatin, and veliparib (Arm A) and gemcitabine, cisplatin (Arm B) in breast cancer, early onset (BRCA) and partner and localizer of BRCA2 (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 B. (Part I) IV. To evaluate overall survival of patients in study arm A and 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) 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 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.

III. To quantify levels of poly(adenosine diphosphate [ADP]-ribose) (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 gamma H2A histone family, member X (yH2AX) and RAD51 recombinase (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 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.

After completion of study treatment, patients are followed up every 3 months.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adenocarcinoma of the Pancreas
  • BRCA1 Mutation Carrier
  • BRCA2 Mutation Carrier
  • Recurrent Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Drug: veliparib
    Given PO
    Other Name: ABT-888
  • Drug: gemcitabine hydrochloride
    Given IV
    Other Names:
    • dFdC
    • difluorodeoxycytidine hydrochloride
    • gemcitabine
    • Gemzar
  • Drug: cisplatin
    Given IV
    Other Names:
    • CACP
    • CDDP
    • CPDD
    • DDP
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm A (veliparib, gemcitabine hydrochloride, cisplatin)
    Patients receive veliparib PO BID on days 1-12 or 1-21. Patients also receive 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.
    Interventions:
    • Drug: veliparib
    • Drug: gemcitabine hydrochloride
    • Drug: cisplatin
    • Other: laboratory biomarker analysis
  • Active Comparator: Arm B (gemcitabine hydrochloride, cisplatin)
    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.
    Interventions:
    • Drug: gemcitabine hydrochloride
    • Drug: cisplatin
    • Other: laboratory biomarker analysis
  • Experimental: Arm C (veliparib)
    Patients receive veliparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: veliparib
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
107
Not Provided
July 2017   (final data collection date for primary outcome measure)

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 (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 g/dL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 2 times institutional upper limit of normal (ULN)
  • Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT) =< 2.5 x institutional ULN unless there is evidence of liver metastases in which case the AST (SGOT)/ALT (SGPT) must be =< 5 times institutional ULN
  • Creatinine =< 1.5 x 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 serum 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 an 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
Both
19 Years and older
No
United States,   Canada,   Israel
 
NCT01585805
NCI-2012-00864, NCI-2012-00864, CDR0000732189, MSKCC-12-045, 12-045, 8993, N01CM00032, P30CA008748, U01CA069856, N01CM00071
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Eileen O'Reilly Memorial Sloan-Kettering Cancer Center
National Cancer Institute (NCI)
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP