Phase II ABT-888 With Cyclophosphamide
- Conditions
- Ovarian CancerPrimary Peritoneal CancerSerous Carcinoma CancerTriple-Negative Breast CancerFallopian Tube Cancer
- Interventions
- Registration Number
- NCT01306032
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
- The experimental cancer treatment drug ABT-888 (Veliparib) works by preventing deoxyribonucleic acid (DNA) repair in tumor cells. Cyclophosphamide is a cancer treatment drug that works by causing DNA damage in cells, including cancer cells, resulting in cell death. However, because cyclophosphamide has strong and unpleasant side effects, researchers are interested in finding drugs that can be given in combination with cyclophosphamide that will allow a lower dose of cyclophosphamide to be given with similar effects. The combination of ABT-88 and cyclophosphamide may be an effective treatment for some types of cancer, such as certain kinds of breast or ovarian cancer and non-Hodgkin's lymphoma that often do not respond to standard therapies.
Objectives:
- To evaluate the safety and effectiveness of ABT-888 and cyclophosphamide in ovarian and breast cancer and in non-Hodgkin's lymphoma that have not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have been diagnosed with (1) (Breast cancer 1/2) BRCA1/2 ovarian cancer, primary peritoneal or ovarian high-grade carcinoma, or fallopian tube cancer; (2) triple-negative breast cancer (not responsive to hormone-related therapy); or (3) low grade non-Hodgkin's lymphoma.
Design:
* Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will be divided into two groups with different treatment subgroups.
* Group 1: Participants who have BRCA-positive ovarian cancer, primary peritoneal or ovarian high-grade serous carcinoma, or fallopian tube cancer
* Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
* Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
* Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
* Group 2: Participants who have triple-negative breast cancer or non-Hodgkin's lymphoma
* Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
* Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
* Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
* Participants receiving only cyclophosphamide who show signs of disease progression after tumor imaging studies can receive the combination of ABT-888 with cyclophosphamide.
* Treatment will continue as long as participants tolerate the drugs and the disease does not progress.
- Detailed Description
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 (complete response (CR) + partial response (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/protein 53 (p53)), perform exploratory gene expression profiling to correlate PARP messenger ribonucleic acid (mRNA) levels or BRCA mutation status with response to therapy, count circulating tumor cells (CTCs), and determine H2AX levels in CTCs and tumor biopsies (National Cancer Institute (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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 124
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide ABT-888 Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide ABT-888 Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. Non-Hodgkin's: ABT-888 + Cyclophosphamide ABT-888 Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. Non-Hodgkin's: Cyclophosphamide Alone Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression. Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. Triple-negative Breast Cancer: Cyclophosphamide Alone Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression. BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. BRCA- positive Ovarian Cancer: Cyclophosphamide Alone Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression. Non-Hodgkin's: ABT-888 + Cyclophosphamide Cyclophosphamide Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
- Primary Outcome Measures
Name Time Method Percentage of Participants With an Overall Response Rate an average of 126 days for ovarian; 71 days for TNBC; for crossover intervention, pts stayed on study for an avg of 134 days for ovarian; 50 days for TNBC. Complete response (CR) + partial response (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. CR + PR was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Progression Free Survival Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days. Time to progression for each participant for the initial intervention.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events up to 30 days following the last dose of study drug. Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline At baseline (t=0h) and 4h post drug administration (t=4h) PAR levels (in pg/μg protein) were assessed in peripheral blood mononuclear cells (PBMCs) by immunoassay to assess poly (ADP-ribose) polymerase (PARP) activity. Significant inhibition of PARP activity is associated with 50% or greater reduction in PAR levels.
Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood At baseline (t=0h) and 24h post drug administration (t=24h) Number of CTCs (evaluable defined as ≥ 6 CTCs) were measured in whole blood during the course of treatment to determine drug-induced deoxyribonucleic acid damage in tumor cells.
Number of Participants With Deleterious Mutations in DNA Repair Genes Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months Gene expression profiling was performed in archival tumor tissue for a panel of 211 genes using deoxyribonucleic acid (DNA) array to determine deleterious mutations (i.e. nonsynonymous mutations at coding regions) of genes. Sequences were mapped to human genome reference hg19. Variants were identified with VarScan, annotated with AVIA, and masked to the exonic or exonic:splicing regions of the 211 interrogated DNA repair genes, with nonsynonymous/frameshift/stop-gain/stop-loss variants that have a population frequency of 1% or less in either 1000G (2014_04) or the ExomeSequencingProject (ESP6500si_all) with a minimum variant frequency of 10% and at least 20 reads. Lastly, variants were manually inspected for known platform and mapping errors.
Trial Locations
- Locations (10)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
H. Lee Moffitt Cancer Center & Research Institute
🇺🇸Tampa, Florida, United States
Mayo Clinic, Rochester
🇺🇸Rochester, Minnesota, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
University of California, Davis
🇺🇸Davis, California, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States