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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT01306032
Other study ID # 110080
Secondary ID 11-C-0080
Status Active, not recruiting
Phase Phase 2
First received February 26, 2011
Last updated January 23, 2015
Start date January 2011
Est. completion date May 2015

Study information

Verified date July 2014
Source National Institutes of Health Clinical Center (CC)
Contact n/a
Is FDA regulated No
Health authority United States: Federal Government
Study type Interventional

Clinical Trial Summary

Background:

- The experimental cancer treatment drug ABT-888 works by preventing 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) 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.


Description:

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Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment


Intervention

Drug:
ABT-888 + Cyclophospharmide
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.

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Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (3)

Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37. — View Citation

Shiobara M, Miyazaki M, Ito H, Togawa A, Nakajima N, Nomura F, Morinaga N, Noda M. Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2001 Mar;16(3):338-44. — View Citation

Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T. Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol. 1991 Aug;37(4):223-7. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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 p... Cycle 1 No
Primary Compare the response rate (CR+PR) of the combination of ABT-888with metronomic oral cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in patients with triple-negative metastatic breast cancer, stratified for ... Cycle 1 No
Secondary Determine PAR levels in tumor biopsies, evaluate in archival tissuewhether patients tumors have mutations in genes involved in DNAdamage repair (e.g., BRCA/Fanconi anemia/p53), perform exploratorygene expression profiling to correlate... Cycles 1 and 2 No
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