Phase II ABT-888 With Cyclophosphamide

NCT01306032 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 11008011-C-0080
• Study Type: interventional
• Target: 124
• Locations: 2 countries
• Sites: 10

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.

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

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With an Overall 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. 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.

  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.

• Progression Free Survival

  Time to progression for each participant for the initial intervention.

  Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days.

Secondary Outcomes (4)

• Number of Participants With Adverse Events

  up to 30 days following the last dose of study drug.

• Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline

  At baseline (t=0h) and 4h post drug administration (t=4h)

• Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood

  At baseline (t=0h) and 24h post drug administration (t=24h)

• Number of Participants With Deleterious Mutations in DNA Repair Genes

  Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months

Study Arms (6)

Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide

EXPERIMENTAL

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

Drug: ABT-888; Drug: Cyclophosphamide

Triple-negative Breast Cancer: Cyclophosphamide Alone

EXPERIMENTAL

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.

Drug: Cyclophosphamide

BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide

EXPERIMENTAL

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

Drug: ABT-888; Drug: Cyclophosphamide

BRCA- positive Ovarian Cancer: Cyclophosphamide Alone

EXPERIMENTAL

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.

Drug: Cyclophosphamide

Non-Hodgkin's: ABT-888 + Cyclophosphamide

EXPERIMENTAL

Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.

Drug: ABT-888; Drug: Cyclophosphamide

Non-Hodgkin's: Cyclophosphamide Alone

EXPERIMENTAL

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.

Drug: Cyclophosphamide

Interventions

ABT-888 DRUG

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.

Also known as: Veliparib

BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide; Non-Hodgkin's: ABT-888 + Cyclophosphamide; Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide

Cyclophosphamide DRUG

Also known as: Cytoxan

BRCA- positive Ovarian Cancer: Cyclophosphamide Alone; BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide; Non-Hodgkin's: ABT-888 + Cyclophosphamide; Non-Hodgkin's: Cyclophosphamide Alone; Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide; Triple-negative Breast Cancer: Cyclophosphamide Alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically documented:
• BRCA-positive ovarian cancer (documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%)
• primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer (no requirement for BRCA status)
• triple-negative breast cancer (documented estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (Her2/neu) negative from the original pathology report if considered adequate, or per The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (47, 48)) with metastasis to distant sites
• Low-grade lymphoid malignancies (NHL), as described below, whose disease has progressed following at least one line of standard therapy:
• Follicle center lymphoma, follicular or diffuse-recurrent/refractory
• Marginal zone B-cell lymphoma: splenic, nodal, extranodal (this includes mucosa-associated lymphoid tissue (MALT)) - recurrent/refractory
• Lymphoplasmacytic lymphoma - recurrent/refractory
• Small lymphocytic lymphoma (SLL) (absolute lymphocytes count below 5,000)
• Pathology must be confirmed by the registering institution. For patients who are eligible for the study due to a history of BRCA1/2 mutation, documented evidence of their mutation status must be provided prior to enrolling on the study.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan.
• Any prior therapy or radiotherapy must have been completed greater than or equal to 4 weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study, and should have recovered to eligibility levels from any toxicities.
• Patients who have had prior treatment with any PARP inhibitors are eligible unless the PARP inhibitor was administered in combination with cyclophosphamide.
• Patients with bone metastases or hypercalcemia on bisphosphonate treatment are eligible to participate
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of ABT-888 in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I combination trials.

You may not qualify if:

• Women who are pregnant or breastfeeding.
• Patients with 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.
• Patients with germ cell and borderline ovarian epithelial tumors.
• Patients who have received prior cyclophosphamide should not be excluded solely because of receiving prior cyclophosphamide.
• Patients with history of central nervous system (CNS) metastases who have received treatment and who have been on stable doses of anti-seizure medicine and had no seizures x 3 months will be eligible.
• Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow the capsule whole. Capsules must not be crushed or chewed; nasogastric or gastrostomy tube (G-tube) administration is not allowed.
• Men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (10)

University of California, Davis

Davis, California, 95616, United States

Location

H. Lee Moffitt Cancer Center &amp; Research Institute

Tampa, Florida, 33612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Mayo Clinic, Rochester

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

Ohio State University

Columbus, Ohio, 43210-1240, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030-4096, United States

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (5)

• 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. doi: 10.1158/1078-0432.CCR-06-3039.

  PMID: 17473206 BACKGROUND

• 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. doi: 10.1046/j.1440-1746.2001.02378.x.

  PMID: 11339428 BACKGROUND

• 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. doi: 10.1002/ajh.2830370402.

  PMID: 1907096 BACKGROUND

• Kummar S, Oza AM, Fleming GF, Sullivan DM, Gandara DR, Naughton MJ, Villalona-Calero MA, Morgan RJ Jr, Szabo PM, Youn A, Chen AP, Ji J, Allen DE, Lih CJ, Mehaffey MG, Walsh WD, McGregor PM 3rd, Steinberg SM, Williams PM, Kinders RJ, Conley BA, Simon RM, Doroshow JH. Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer. Clin Cancer Res. 2015 Apr 1;21(7):1574-82. doi: 10.1158/1078-0432.CCR-14-2565. Epub 2015 Jan 14.

  PMID: 25589624 RESULT

• Tattersall A, Ryan N, Wiggans AJ, Rogozinska E, Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2022 Feb 16;2(2):CD007929. doi: 10.1002/14651858.CD007929.pub4.

  PMID: 35170751 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Ovarian Neoplasms; Triple Negative Breast Neoplasms; Fallopian Tube Neoplasms; Breast Neoplasms

Interventions

veliparib; Cyclophosphamide

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Fallopian Tube Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Alice Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

301-435-0517

Study Officials

• Alice Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 26, 2011
• First Posted: March 1, 2011
• Study Start: January 12, 2011
• Primary Completion: December 31, 2014
• Study Completion: December 15, 2016
• Last Updated: April 26, 2017
• Results First Posted: May 25, 2016

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (9); CA (1)