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ABT-888 as Monotherapy and in Combination With Mitomycin C in Patients With Solid Tumors With Deficiency in Homologous Recombination Repair

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

ABT-888 as Monotherapy and in Combination With Mitomycin C in Patients With Solid Tumors With Deficiency in Homologous Recombination Repair


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


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.

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Feasibility of screening for Fanconi anemia (FA) deficiency across different tumor types, and that patients deficient in this pathway (no FancD2 foci formation in their tumors) exist in adequate number to justify further trials

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Miguel Villalona-Calero

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms



Ohio State University Medical Center Columbus, Ohio  43210
Lombardi Comprehensive Cancer Center at Georgetown University Washington, District of Columbia  20057