Cyclophosphamide and Veliparib in Treating Patients With Locally Advanced or Metastatic Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01351909
First received: May 10, 2011
Last updated: June 12, 2015
Last verified: June 2015
  Purpose

This phase I trial studies the side effects and best dose of cyclophosphamide and veliparib when given together in treating patients with breast cancer that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide together with veliparib may work better in treating breast cancer.


Condition Intervention Phase
HER2/Neu Negative
Recurrent Breast Carcinoma
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: Cyclophosphamide
Other: Laboratory Biomarker Analysis
Drug: Veliparib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Low-Dose Cyclophosphamide in Combination With Veliparib (ABT-888) in HER2/Neu-Negative Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose of veliparib and cyclophosphamide [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 will be utilized for adverse events reporting.


Secondary Outcome Measures:
  • Clinical response (complete or partial response) according to RECIST version 1.1 [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
    Clinical response and benefit rates in each group will be estimated by computing proportions and corresponding 95% confidence intervals. Rates will be compared between groups using the Fisher's exact test.

  • MacroH2A1.1 expression levels [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    Expression levels of macroH2A1.1 will be compared between patients with and without clinical benefit using the two-sample T-test or Wilcoxon rank sum test, depending on the distribution of the data. Logistic regression models will also be fit to the data to adjust for potential confounders in the analysis.

  • Overall survival [ Time Frame: Time from treatment initiation to death, assessed up to 6 years ] [ Designated as safety issue: No ]
    Overall survival will be analyzed using standard survival analytic approaches including the Kaplan-Meier method and the log-rank test.

  • PARP1 expression status [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    Expression levels of PARP1 will be compared between patients with and without clinical benefit using the two-sample T-test or Wilcoxon rank sum test, depending on the distribution of the data. Logistic regression models will also be fit to the data to adjust for potential confounders in the analysis.


Estimated Enrollment: 55
Study Start Date: May 2011
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (veliparib, cyclophosphamide)
Patients receive veliparib orally PO QD and cyclophosphamide PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given PO
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • CYCLOPHOSPHAMIDE
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888
  • VELIPARIB

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of veliparib (ABT-888) that can be combined with metronomic dose cyclophosphamide in patients with metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the macroH2A1.1 and poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) expression status in archival paraffin embedded tumor specimens from either the primary tumor or metastatic disease is predictive of clinical benefit with veliparib (ABT-888) plus cyclophosphamide.

OUTLINE: This is a dose-escalation study.

Patients receive veliparib orally (PO) once daily (QD) and cyclophosphamide PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase I: Patients must have histologically confirmed breast cancer (metastatic breast cancer [MBC]) that is human epidermal growth factor receptor 2 (HER2/neu) negative (as determined by local pathology or reference laboratory), and have disease that is metastatic (stage IV [TxNxM1]) or locally advanced and not amenable to potentially curative surgical resection (eg, clinical stage IIIB-C)
  • HER2/neu negative disease (performed on primary tumor and/or metastatic lesion using commercially available/approved assay in local institutional or reference laboratory), according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
  • National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic breast cancer "…biopsy documentation of first recurrence, if possible, and determination of hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status…."; therefore, histologic and/or cytologic confirmation of metastatic disease is encouraged whenever feasible, but not required; in some circumstances, histologic confirmation may not be feasible (eg, bone metastases not amenable to biopsy and elevated cancer antigen [CA]27-29 tumor marker); for patients who have had histologic confirmation of metastatic disease, it is required that the biopsy confirm that the metastatic tumor is ER and/or PR positive, and HER2/neu negative; for patients in whom biopsy confirmation of metastatic disease is not feasible, it is required that the primary tumor be ER and/or PR-positive and HER2/neu negative
  • Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or non-measurable disease, with measurement obtained within 4 weeks of registration
  • Phase I: Patients must have received at least one prior chemotherapy regimen for metastatic disease; patients with deleterious germ line mutations in breast cancer (BRCA)1 or BRCA2 are not required to have received prior chemotherapy for metastatic disease
  • Patients must have had progressive disease after at least one line of endocrine therapy for metastatic disease (includes relapse while receiving endocrine therapy); there should be at least 1 week interval between the last endocrine treatment for an aromatase inhibitor and at least 2 weeks for tamoxifen or fulvestrant
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dl (per manufacturer recommendation)
  • Total bilirubin within normal institutional limits (unless isolated indirect hyperbilirubinemia due to Gilbert's disease)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Patients with a history of brain metastases are eligible if they have been treated with radiation and have stable brain metastases at least 3 months after radiation and must also be off steroids
  • Patients must be able to swallow whole capsules and tolerate oral medications
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; being not of childbearing potential is defined as: (1) prior hysterectomy, or (2) no menstrual period for at least 24 months; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have radiotherapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to systemic agents administered more than 3 weeks earlier
  • Patients may not be receiving any other investigational agents
  • Patients with known brain metastases with active symptoms or requiring anticonvulsive medications, or steroids should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib (ABT-888) or cyclophosphamide used in the study
  • Evidence of complete or partial bowel obstruction or other unable to take oral medications
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
  • Patients unable to swallow whole capsules
  • 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
  • Pregnant (positive pregnancy test) or lactating women will be excluded from the study; also, unwillingness to use effective means of contraception in subjects with child-bearing potential will be excluded from the study; women of child-bearing potential must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation
  • Patients with active severe infection; known infection with human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, or severe concurrent illness will be excluded from the study; HIV-positive patients on combination antiretroviral therapy are ineligible
  • Patients with a history of seizure disorder requiring antiepileptics who have had a seizure episode within the last 6 months
  • Prior treatment with veliparib (ABT-888) or other PARP inhibitors (e.g., olaparib)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01351909

Locations
United States, New York
Albert Einstein College of Medicine Recruiting
Bronx, New York, United States, 10461
Contact: Joseph A. Sparano    718-405-8404    jsparano@montefiore.org   
Principal Investigator: Joseph A. Sparano         
Montefiore Medical Center - Moses Campus Recruiting
Bronx, New York, United States, 10467-2490
Contact: Joseph A. Sparano    718-405-8404    jsparano@montefiore.org   
Principal Investigator: Joseph A. Sparano         
Montefiore Medical Center-Einstein Campus Recruiting
Bronx, New York, United States, 10461
Contact: Joseph A. Sparano    718-405-8404    jsparano@montefiore.org   
Principal Investigator: Joseph A. Sparano         
Sponsors and Collaborators
Investigators
Principal Investigator: Joseph Sparano Montefiore Medical Center - Moses Campus
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01351909     History of Changes
Other Study ID Numbers: NCI-2011-02590, NCI-2011-02590, CDR0000700033, P8853_A18PAMDREVW01, 11-02-068, 8853, N01CM62204, P30CA013330
Study First Received: May 10, 2011
Last Updated: June 12, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on July 27, 2015