Veliparib, Oxaliplatin, and Capecitabine in Treating Patients With Advanced Solid Tumors

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT01233505

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and the best dose of veliparib when given together with capecitabine and oxaliplatin in treating patients with advanced solid tumors. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving veliparib together with capecitabine and oxaliplatin may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Pancreas Adenocarcinoma of the Stomach BRCA1 Mutation Carrier BRCA2 Mutation Carrier Ovarian Mucinous Cystadenocarcinoma Recurrent Breast Cancer Recurrent Colon Cancer Recurrent Gastric Cancer Recurrent Ovarian Epithelial Cancer Recurrent Ovarian Germ Cell Tumor Recurrent Pancreatic Cancer Recurrent Rectal Cancer Stage IA Breast Cancer Stage IB Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Stage IV Colon Cancer Stage IV Gastric Cancer Stage IV Ovarian Epithelial Cancer Stage IV Ovarian Germ Cell Tumor Stage IV Pancreatic Cancer Stage IV Rectal Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: veliparib Drug: capecitabine Drug: oxaliplatin Other: pharmacological study Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To determine the dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of ABT-888 (veliparib) in combination with oxaliplatin and capecitabine in advanced solid tumors.

SECONDARY OBJECTIVES:

To evaluate the pharmacokinetics of ABT-888, oxaliplatin, and capecitabine when administered concomitantly.
To evaluate the safety and tolerability of the ABT-888 in combination with capecitabine and oxaliplatin.
To assess for evidence of anti-tumor activity with this combination, per tumor measurements using RECIST criteria, in these patients.

TERTIARY OBJECTIVES:

To assess the inhibition of poly(ADP-ribose) polymerase (PARP) in peripheral blood mononuclear cells secondary to treatment with ABT-888.
To determine the pharmacokinetics of ABT-888 in combination with oxaliplatin and capecitabine and the relation to treatment side effects.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib orally (PO) twice daily and capecitabine PO twice daily on 1-7 and 15-21, and oxaliplatin intravenously (IV) over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and urine sample collection at baseline and periodically during study for pharmacokinetic and poly (ADP-ribose) polymerase (PARP) inhibition studies.

After completion of study therapy, patients are followed up for 30 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of ABT-888 in Combination With Oxaliplatin and Capecitabine in Advanced Solid Tumors

Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (veliparib, capecitabine, oxaliplatin) Patients receive veliparib PO twice daily and capecitabine PO twice daily on 1-7 and 15-21, and oxaliplatin IV over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: veliparib Given PO Other Names: ABT-888 Drug: capecitabine Given PO Other Names: CAPE Ro 09-1978/000 Xeloda Drug: oxaliplatin Given IV Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (veliparib, capecitabine, oxaliplatin)

Patients receive veliparib PO twice daily and capecitabine PO twice daily on 1-7 and 15-21, and oxaliplatin IV over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: veliparib

Given PO

Other Names:

ABT-888

Drug: capecitabine

Given PO

Other Names:

CAPE

Ro 09-1978/000

Xeloda

Drug: oxaliplatin

Given IV

Other Names:

1-OHP

Dacotin

Dacplat

Eloxatin

L-OHP

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Maximum-tolerated (MTD) dose of veliparib in combination with oxaliplatin and capecitabine as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [28 days]
MTD defined as the dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT).
Dose-limiting toxicities of veliparib in combination with oxaliplatin and capecitabine as assessed by NCI CTCAE version 4.0 [28 days]

Secondary Outcome Measures

Pharmacokinetics of veliparib administered concomitantly with oxaliplatin and capecitabine [At baseline, at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours of days 1 and 7]
Graphical displays of individual, mean, and median plasma concentration over time will be presented at each ABT-888 dose level and overall in the entire group. Descriptive summaries for each pharmacokinetic endpoint will be presented by ABT-888 dose level.
Safety and tolerability as assessed by NCI CTCAE version 4.0 [Up to 30 days]
Reported in tabular format, both per dose level, as well as in the aggregate cohort.
Anti-tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) [Up to 30 days]
Anti-tumor responses will be summarized using descriptive statistics and will be presented in tables. In addition, two-sided 90% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be obtained.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed solid tumors that fulfill ≥ 1 of the following criteria:
BRCA1/2 mutation and a BRCA-related malignancy
Patients without a known BRCA mutation must have a probability of harboring a BRCA gene mutation as assessed by BRCAPRO computer program
Patients with a probability of having genetic mutation ≥ 20% or a BRCA mutation based on a non-Myriad test, must have a formal BRCA testing by Myriad Genetic Laboratories
Patients with known deleterious BRCA 1 or 2 mutation or a mutation of uncertain significance
Patients who refuse BRCA testing not allowed unless they have another acceptable histology
First- or second-line metastatic colorectal cancer
Any-line metastatic mucinous ovarian cancer
Any line of other metastatic gastrointestinal malignancies in which oxaliplatin has shown some activity (i.e., gastric or pancreatic adenocarcinoma)
Patients with uncontrolled CNS metastasis are not eligible; patients with CNS metastases who have had them treated and are stable for > 3 months will be eligible; patients must be off steroid treatment prior to study enrollment
Measurable disease
Patients with ovarian cancer who have a pre-treatment CA 125 level of at least twice the upper limit of normal allowed
ECOG performance status (PS) 0-2 (Karnofsky 60-100%)
Life expectancy > 3 months
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases)
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
Fertile patients must use adequate contraception (i.e., hormonal, barrier method of birth control, or abstinence)
Not pregnant or nursing
Negative pregnancy test
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
No uncontrolled intercurrent illness including, but not limited to, any of the following:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Psychiatric illness and/or social situations that would limit compliance with study requirements
No history of positive serology for hepatitis A, B, or C, liver disease, or other forms of hepatitis or cirrhosis
Patients who have active seizures or history of seizures are ineligible
No condition that impairs the ability to swallow and retain veliparib capsules, including any of the following:
Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation
Prior surgical procedures affecting absorption
Active peptic ulcer disease
No malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction
No peripheral neuropathy ≥ grade 2
No prolonged QTC > 450 msec (male) or QTC > 470 (female)
No concurrent combination antiretroviral therapy for HIV-positive patients
Recovered from adverse events of prior therapy or prior surgical procedures
Patients with chronic grade 1 or 2 adverse events that are not expected to improve are allowed at investigator's discretion
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
At least 4 weeks since prior radiotherapy with no > 35% of marrow irradiation
Prior fluoropyrimidine allowed
Prior veliparib allowed provided it was part of a single- or limited-dosing study, such as a phase 0 study
Prior capecitabine allowed provided patient tolerated 3500 mg/m² for 7 days out of 14 days
No other prior investigational agents
No prior oxaliplatin