Ph II Randomized Trial of the Combination of ABT-888 With Metronomic Oral Cyclophosphamide in Refractory BRCA-Pos Ovarian, Primary Peritoneal or Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, Triple-Neg Breast Cancer, and Low-Grade NHL
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining
genomic stability by regulating a variety of DNA repair mechanisms.
- Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes
have an increased risk of developing breast and ovarian cancers due to impaired or
defective DNA damage repair; these individuals have an increased susceptibility to
DNA-damaging agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA
damage caused by alkylating agents such as cyclophosphamide.
- Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP
inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in
xenograft models. This combination is well tolerated in a Phase I study and showing
promising activity.
Objectives:
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in
patients with deleterious BRCA mutations and refractory ovarian cancer or patients with
primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in
patients with triple-negative metastatic breast cancer, stratified for deleterious BRCA
mutation.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral
cyclophosphamide to the response rate (CR+PR) of single-agent metronomic oral
cyclophosphamide in patients with refractory low-grade lymphomas.
Secondary Objectives:
- Determine PAR levels in tumor biopsies, evaluate in archival tissue whether patients'
tumors have mutations in genes involved in DNA damage repair (e.g., BRCA/Fanconi
anemia/p53), perform exploratory gene expression profiling to correlate PARP mRNA levels or
BRCA mutation status with response to therapy, count CTCs, and determine ??H2AX levels in
CTCs and tumor biopsies (NCI clinical center only).
Eligibility:
-Adults with refractory BRCA-positive ovarian cancer, primary peritoneal or ovarian
high-grade serous carcinoma, fallopian tube cancer, triple-negative breast cancer, or
low-grade lymphoid malignancies (non-Hodgkin's lymphoma) whose disease has progressed
following at least one line of therapy.
Study Design:
- This is a randomized, multi-histology Phase II trial with patients enrolled into 3
cohorts: BRCA-positive ovarian cancer or primary peritoneal or ovarian high-grade
serous carcinoma or fallopian tube cancer (A); triple-negative breast cancer (B); or
low grade non-Hodgkin's lymphoma (C). Patients in cohort A will be randomized to the
combination of ABT-888 with metronomic oral cyclophosphamide or metronomic oral
cyclophosphamide alone. Patients in cohort B will be randomized to the combination of
ABT-888 with metronomic oral cyclophosphamide or metronomic oral cyclophosphamide
alone. Patients in cohort C will be randomized to the combination of ABT-888 with
metronomic oral cyclophosphamide or metronomic oral cyclophosphamide alone.
- Cyclophosphamide (50 mg) and ABT-888 (60 mg) will be administered orally once a day,
continuously in 21-day cycles.
Interventional
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Compare the CR+PR of ABT-888 with metronomic cyclophosphamide to the CR+PR of metronomic cyclophosphamide in patients with deleterious BRCA mutations/ ovarian cancer or patient's with peritoneal /ovarian high-grade serous cancer or fallopian tub...
2 years
Yes
Shivaani Kummar, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
110080
NCT01306032
January 2011
October 2013
Name | Location |
---|---|
National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
Memorial Sloan Kettering Cancer Center | New York, New York 10021 |
MD Anderson Cancer Center | Houston, Texas 77030-4096 |
Montefiore Medical Center | Bronx, New York 10467-2490 |
H. Lee Moffitt Cancer Center & Research Institute | Tampa, Florida 33612 |
Ohio State University | Columbus, Ohio 43210 |
University of Chicago | Chicago, Illinois 60637 |
Mayo Clinic, Rochester | Rochester, Minnesota 55905 |
University of California, Davis | Sacramento, California 95818 |