Clinical trial NCT01306032
Conditions: Ovarian Cancer Primary Peritoneal Cancer Serous Carcinoma Cancer Triple-Negative Breast Cancer Fallopian Tube Cancer
Keywords: PARP Inhibitor BRCA Mutations DNA Damage Repair Pharmacodynamics Metronomic Cyclophosphamide Ovarian Cancer Breast Cancer Fallopian Tube Cancer Peritoneal Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2011-01-12; Completion date: 2016-12-15
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. arm 2: 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. arm 3: Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. arm 4: 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. arm 5: Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule. arm 6: 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.
Interventions: intervention 1: ABT-888 intervention 2: Cyclophosphamide
Intervention descriptions: intervention 1: PARP enzymes are 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. intervention 2: None

Protocol documents: