Veliparib with or without Mitomycin C in Treating Patients with Metastatic, Unresectable, or Recurrent Solid Tumors

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IBiomarker/Laboratory analysis, Treatment18 and overOSU 09100
NCI-2012-01473, CDR0000656393, 8472, NCT01017640

Trial Description

Summary

This phase I trial studies the side effects and best dose of veliparib when given with or without mitomycin C in treating patients with solid tumors that have spread to other places in the body, cannot be removed by surgery or have come back. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitomycin C, 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. Giving veliparib together with mitomycin C may kill more tumor cells.

Further Study Information

PRIMARY OBJECTIVES:

I. To screen cancer patients across different histological sites to identify those with functional defects in the Fanconi anemia (FA) pathway in their tumors.

II. To establish the safety and practicality of treating patients with FA-deficient tumors with the poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor ABT-888 (veliparib) as protracted monotherapy.

III. To establish the safety and practicality of treating patients with FA-deficient tumors with the combination of mitomycin C (MMC) and ABT-888.

IV. To select a dose of ABT-888 protracted monotherapy and a dose-schedule of the combination of mitomycin C and ABT-888 in patients with FA deficient tumors for phase 2 trials.

SECONDARY OBJECTIVES:

I. To evaluate for germ-line FA repair deficiency and BRCA mutations in peripheral blood mononuclear (PBMC) in patients receiving ABT-888 treatment.

II. To evaluate in PBMC samples for foci produced by the histone variant gamma-H2A histone family, member X (H2AX) in patients receiving mitomycin C with or without ABT-888 in order to assess any possible effect of ABT-888 in the cellular sensing and processing of mitomycin C-induced deoxyribonucleic acid (DNA) double strand breaks.

III. Quantify the number of patients with antitumor responses.

OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive veliparib PO BID on days 1-7, 1-14, or 1-21. Patients also receive mitomycin C intravenously (IV) over 10-20 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Eligibility Criteria

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

Hemoglobin >= 9 g/dL

Platelets >= 100,000/mcL

Absolute neutrophil count (ANC) >= 1,500/mcL

Tumors have been shown to be deficient for the FA pathway, based on Fanconi anemia triple stain immunofluorescence (FATSI) screening

Life expectancy of greater than 3 months

Leukocytes >= 3,000/mcL

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

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

Up to two chemotherapy regimens for metastatic disease are allowed; in addition, prior adjuvant/neo-adjuvant chemotherapy, hormonal therapy, molecular targeted therapy or estrogen receptor B (Erb) inhibitor treatments (e.g., erlotinib, Herceptin, sorafenib, sunitinib) will be allowed and will not count towards eligibility; at least 4 weeks must elapse since prior chemotherapy or radiation therapy (two weeks for erlotinib, hormonal therapy, or limited field palliative radiation to bone, brain, or radiosurgery), 6 weeks if the last regimen included nitrosoureas or mitomycin C; previous use of mitomycin C would be restricted to topical applications (bladder cancer) or chemoembolization (e.g., liver tumors)

Patients should be able to swallow capsules

Creatinine within normal institutional limit OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

Total bilirubin within normal institutional limit

Patients must have a histologically confirmed solid malignancy that is metastatic, or unresectable, or recurrent, for which no curative or standard of care exist, or this standard of care is no longer effective

EXPANSION COHORT:

Diagnosis of colorectal malignancy

Absence of Fanconi anemia, complementation group D2 (FANCD2) foci by FATSI screening

Presence of biopsiable lesion by imaging

Consent to a baseline (prior to treatment) tumor biopsy and for a repeat biopsy at the time of progression on the event that an antitumor response is demonstrated on the MMC-ABT-888 regimen

Same eligibility as above, except that they will have no limitations related prior number of chemotherapy regimens given; patients could have received prior treatment with PARP inhibitors if used as single agent

Exclusion Criteria:

Patients with active seizure or a history of seizures

Pregnant women are excluded from this study; breastfeeding should be discontinued

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Patients previously treated with PARP inhibitors; with the exception of patients enrolled on Arm 2 who may have had prior treatment with PARP inhibitors as monotherapy

History of allergic reactions attributed to compounds of similar chemical or biologic composition as ABT-888 or Mitomycin C

Patients may not be receiving any other investigational agents

Patients with known central nervous system (CNS) metastases (unless previously resected or irradiated and not clinically active); patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Miguel Angel Villalona-Calero, Principal Investigator

Trial Sites

U.S.A.

District of Columbia
Washington

MedStar Georgetown University Hospital

John Lindsay Marshall
Ph: 202-444-7064
Email: marshalj@georgetown.edu

John Lindsay Marshall
Principal Investigator

Kentucky
Georgetown

Georgetown Cancer Treatment Center

John Lindsay Marshall
Ph: 202-444-7064
Email: marshalj@georgetown.edu

John Lindsay Marshall
Principal Investigator

Ohio
Columbus

Ohio State University Comprehensive Cancer Center

Miguel Angel Villalona-Calero
Ph: 614-293-9424
Email: miguel.villalona@osumc.edu

Miguel Angel Villalona-Calero
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01017640

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.