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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)


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adenocarcinoma of the Pancreas, BRCA1 Mutation Carrier, BRCA2 Mutation Carrier, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

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.


Inclusion Criteria:



- Male or female 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); 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)

- 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 (Part I [Arms A, B])

- 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

- Patients can have either locally advanced or metastatic pancreas adenocarcinoma and
received prior therapy (Part II [Arm C])

- 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 glutamic pyruvate transaminase (ALT/SGPT) <
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

- 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

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Optimal dose of veliparib with gemcitabine and cisplatin (non-randomized part I)

Outcome Time Frame:

21 days

Safety Issue:

No

Principal Investigator

Eileen O'Reilly

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00864

NCT ID:

NCT01585805

Start Date:

April 2012

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Pancreas
  • brca1 Mutation Carrier
  • brca2 Mutation Carrier
  • Recurrent Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
M D Anderson Cancer CenterHouston, Texas  77030
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins HospitalBaltimore, Maryland  21231