Veliparib With or Without Mitomycin C in Treating Patients With Metastatic, Unresectable, or Recurrent Solid Tumors

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:
NCT01017640
First received: November 19, 2009
Last updated: August 15, 2014
Last verified: June 2014
  Purpose

This phase I trial studies the side effects and best dose of veliparib when given with or without mitomycin C in treating patients with metastatic, unresectable, or recurrent 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 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.


Condition Intervention Phase
Unspecified Adult Solid Tumor, Protocol Specific
Drug: veliparib
Drug: mitomycin C
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: ABT-888 as Monotherapy and in Combination With Mitomycin C in Patients With Solid Tumors With Deficiency in Homologous Recombination Repair

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Feasibility of screening for FA deficiency across different tumor types, defined as adequate number of patients deficient on this pathway [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: No ]
  • Ability to safely deliver veliparib in a continuous dose as monotherapy [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]
  • Ability to safely deliver the combination of mitomycin C and veliparib [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]
  • Selection of a dose schedule of veliparib monotherapy for phase II trials [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]
  • Selection of a dose schedule of the combination of mitomycin C and veliparib for phase II trials [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • FancD2 foci formation in peripheral blood mononuclear cells [ Time Frame: Up to week 5 ] [ Designated as safety issue: No ]
    Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.

  • BRCA mutations [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.

  • Foci produced by the histone variant gamma-H2AX [ Time Frame: Up to week 5 ] [ Designated as safety issue: No ]
    Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.

  • Tumor shrinkage as assessed by radiological means [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 75
Study Start Date: October 2009
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (veliparib)
Patients receive veliparib PO BID in the absence of disease progression or unacceptable toxicity.
Drug: veliparib
Given PO
Other Name: ABT-888
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (veliparib and mitomycin C)
Patients receive veliparib PO BID on days 1-7, 1-14, or 1-21. Patients also receive mitomycin C IV over 10-20 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: veliparib
Given PO
Other Name: ABT-888
Drug: mitomycin C
Given IV
Other Names:
  • MITC
  • MITO
  • MITO-C
  • Mitocin-C
  • MTC
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • Tumors have been shown to be deficient for the FA pathway, based on Fanconi anemia triple stain immunofluorescence (FATSI) screening
  • 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)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 OR Karnofsky >= 60%
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limit
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 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
  • 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
  • Patients should be able to swallow capsules
  • 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 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
  • 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; breastfeeding should be discontinued
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients with active seizure or a history of seizures
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01017640

Locations
United States, District of Columbia
Lombardi Comprehensive Cancer Center at Georgetown University Recruiting
Washington, District of Columbia, United States, 20057
Contact: John L. Marshall    202-687-6459    Mc183@georgetown.edu   
Principal Investigator: John L. Marshall         
United States, Kentucky
Georgetown Cancer Treatment Center Recruiting
Georgetown, Kentucky, United States, 40324
Contact: John L. Marshall    202-687-6459    Mc183@georgetown.edu   
Principal Investigator: John L. Marshall         
United States, Ohio
Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Miguel A. Villalona-Calero    614-293-9424    miguel.villalona@osumc.edu   
Principal Investigator: Miguel A. Villalona-Calero         
Sponsors and Collaborators
Investigators
Principal Investigator: Miguel Villalona-Calero Ohio State University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01017640     History of Changes
Other Study ID Numbers: NCI-2012-01473, NCI-2012-01473, OSU-09100, CDR0000656393, OSU 09100, 8472, N01CM00070, N01CM62207, P30CA016058
Study First Received: November 19, 2009
Last Updated: August 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Mitomycins
Mitomycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014