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

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.

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

- Patients will be consented to have their existing, or about to be obtained, paraffin
embedded tumor tissue screened for FA deficiency; screening will be performed on an
ongoing basis on the breast, thoracic, gastrointestinal (GI), Georgetown University
(GU), and gynecologic (GYN) Ohio State University (OSU) clinics, anteceding and
concurrently with the clinical trial; it will continue until the numbers of patients
required for the clinical trial are identified and enrolled; based on the estimation
from our preliminary data of 15 to 30% of patients, depending on the primary organ
site, having tumors deficient for the FA pathway we will need to screen around 300
patients' samples to identify 40-50 patients; none of the eligibility criteria
defined above or below will need to be met for the screening portion, since FA
deficient patients identified by screening may meet eligibility criteria for the
clinical trial at a later time; (e.g., patient is undergoing standard of care
treatment at the time of the screening); separate written consents for screening and
for the clinical trial will be obtained from patients

- 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 (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 limits 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