Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

ABT-888 (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, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving ABT-888 together with mitomycin may kill more tumor cells. This phase I trial is studying the side effects and best dose of ABT-888 when given with or without mitomycin in treating patients with metastatic, unresectable, or recurrent solid tumors.

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 PARP inhibitor ABT-888 as protracted monotherapy.

III. To establish the safety and practicality of treating patients with FA-deficient tumors with the combination of mitomycin C 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 cell (PBMC) in patients receiving ABT-888 treatment.

II. To evaluate in PBMC samples for foci produced by the histone variant gamma-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 DNA double strand breaks.

III. Quantify the number of patients with antitumor responses.

OUTLINE: This is a dose-escalation study of ABT-888. Patients are assigned to 1 of 2 treatment groups.

GROUP I: Patients receive ABT-888 orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive ABT-888 PO BID on days 1-7, 1-14, 1-21, or 1-28. 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. Blood and tissue samples are collected periodically for further laboratory analysis, including BRCA mutation analysis and H2AX and FancD2 activation analysis.

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

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed solid tumor malignancy for which no curative or standard therapy exists or for which standard therapy is no longer effective

• Metastatic, unresectable, or recurrent disease

• Tumor demonstrates deficiency for the Fanconi anemia pathway, based on FATSI immunofluorescence screening

• Up to two chemotherapy regimens for metastatic disease are allowed; in addition, prior adjuvant/neo- adjuvant chemotherapy, hormonal therapy, molecular targeted therapy or 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 nitrosureas or Mitomycin C

• Given the association of cumulative doses of Mitomycin C with toxicity, previous use of Mitomycin C would be restricted to topical applications (bladder cancer) or chemoembolization (e.g., liver tumors)

• Eastern Cooperation Oncology Group (ECOG) performance status (PS) =< 2 OR Karnofsky >= 60%

• Life expectancy > 3 months

• Leukocytes >= 3,000/mcL

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

• Hemoglobin >= 9 g/dL

• Platelet count >= 100,000/mcL

• Total bilirubin within normal institutional limit

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal

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

• The effects of ABT-888 on the developing human fetus are unknown, and Mitomycin C could be harmful to the fetus; for this reason, 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

• Fertile patients must use effective contraception

• Able to swallow capsules

• Ten additional evaluable patients will be accrued to the Arm 2 (MMC + ABT-888) therapeutic portion of the study, once the MTD and recommended phase 2 of the study has been defined; eligibility for these patients includes the following:

• Diagnosis of colorectal malignancy

• Absence of 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 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) should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment

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

• 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 because ABT-888 and Mitomycin C are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ABT-888 and Mitomycin, breastfeeding should be discontinued

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

• Patients with active seizure or a history of seizures

• Patients previously treated with poly ADP-ribose polymerase (PARP) inhibitors; with the exception of patients enrolled on Arm 2 who may have had prior treatment with PARP inhibitors as monotherapy

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Miguel Villalona-Calero

Principal Investigator

U.S.A.
District of Columbia
	Washington
	Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
		John L. Marshall	Ph: 202-687-6459
			Email: Mc183@georgetown.edu
Ohio
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		Miguel A. Villalona-Calero	Ph: 614-293-9424
			Email: miguel.villalona@osumc.edu

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01017640
Information obtained from ClinicalTrials.gov on May 06, 2013