Cyclophosphamide With or Without Veliparib in Patients With Locally Advanced or Metastatic Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 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: September 16, 2014
Last verified: July 2014

May 10, 2011
September 16, 2014
May 2011
May 2015   (final data collection date for primary outcome measure)
  • Recommended phase II dose of veliparib that may be used with metronomic cyclophosphamide [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events version 4.0 will be utilized for adverse events reporting.
  • Progression-free survival (PFS) according to RECIST version 1.1 [ Time Frame: From first treatment day until objective or disease progression or death from any cause, assessed up to 6 months ] [ Designated as safety issue: No ]
    The PFS distributions of the two treatment arms will be estimated by the Kaplan-Meier method. Ninety-five percent confidence intervals for the Kaplan-Meier estimates will be calculated using Greenwood's approach. The log-rank test will be applied to compare the PFS distributions between the two treatment arms and the Cox Proportional hazards model will be fit to the data to estimate the hazard ratio.
Progression-free survival (PFS) of patients treated with cyclophosphamide with vs without veliparib [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01351909 on ClinicalTrials.gov Archive Site
  • 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.
  • Overall survival [ Time Frame: Time from treatment initiation to death, assessed up to 4 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.
  • MacroH2A1.1 expression levels (Phase II) [ Time Frame: Up to 4 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.
  • PARP1 expression status (Phase II) [ Time Frame: Up to 4 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.
  • Clinical response (complete or partial response) of patients treated with cyclophosphamide with vs without veliparib [ Designated as safety issue: No ]
  • Clinical benefit rate defined as objective response plus stable disease for at least 24 weeks from day +1 [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Adverse event profile of these regimens in these patients [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Cyclophosphamide With or Without Veliparib in Patients With Locally Advanced or Metastatic Breast Cancer
Sequential Phase I - Randomized Phase II, Double-Blind, Placebo-Controlled Trial of Cyclophosphamide Alone or in Combination With Veliparib (ABT-888) in ER and/or PR-Positive and HER2/Neu-Negative Metastatic Breast Cancer.

This randomized phase I/II trial studies cyclophosphamide with or without veliparib in treating patients with locally advanced or metastatic breast cancer. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cyclophosphamide works better with or without veliparib in treating breast cancer.

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. (Phase I) II. To determine if the addition of veliparib (ABT-888) to metronomic dose cyclophosphamide improves median progression free survival (PFS) compared with cyclophosphamide alone in patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (Her2)-negative metastatic breast cancer who progressed on at least two lines of prior chemotherapy and one line of prior endocrine therapy. (Phase II)

SECONDARY OBJECTIVES:

I. To determine if the addition veliparib (ABT-888) to cyclophosphamide chemotherapy improves the response rate.

II. To determine if the addition veliparib (ABT-888) to cyclophosphamide chemotherapy improves the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day +1).

III. To determine the survival in patients treated with cyclophosphamide alone and cyclophosphamide plus veliparib (ABT-888).

IV. To determine the adverse event profile in patients treated with cyclophosphamide alone and cyclophosphamide plus veliparib (ABT-888).

TERTIARY OBJECTIVES:

I. To determine whether the macroH2A1.1 and poly (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 phase I, dose-escalation study of veliparib, followed by a phase II study.

PART I:

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

PART II: Patients are randomized to 1 of 2 treatment arms.

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

ARM II: Patients receive placebo PO BID on days 1-21 and cyclophosphamide as in Arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Drug: veliparib
    Given PO
    Other Name: ABT-888
  • Drug: cyclophosphamide
    Given PO
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Other: placebo
    Given PO
    Other Name: PLCB
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (veliparib, cyclophosphamide)
    Patients receive veliparib PO BID and cyclophosphamide PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: veliparib
    • Drug: cyclophosphamide
    • Other: laboratory biomarker analysis
  • Active Comparator: Arm II (cyclophosphamide, placebo)
    Patients receive placebo PO BID on days 1-21 and cyclophosphamide as in Arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: cyclophosphamide
    • Other: placebo
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
92
Not Provided
May 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Phase I: Patients must have histologically confirmed breast cancer (metastatic breast cancer [MBC]) that is 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) Phase II: Patients must have histologically confirmed breast cancer (MBC) that is ER positive and/or PR positive, and 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
  • ER/PR expression (by standard immunohistochemical assay) on primary tumor and/or metastatic lesion known, and classified as ER and/or PR-positive according to ASCO/CAP guidelines (including 1-9% expression)
  • National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic breast cancer "…biopsy documentation of first recurrence, if possible, and determination of hormone receptor status (ER and 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 Phase II: Patients must have received two or more prior chemotherapy regimens for metastatic disease, which must have included an antitubulin agent (eg, paclitaxel, docetaxel, vinorelbine, ixabepilone) and capecitabine; there should be at least a 4 week interval between the last chemotherapy dose and registration (one week for capecitabine, 2 weeks for weekly paclitaxel in the presence of disease progression), and the patient should have recovered from acute toxicity related to prior therapy; no prior treatment with veliparib or other PARP inhibitors (eg, BSI 201)
  • 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)
Both
18 Years and older
No
United States
 
NCT01351909
NCI-2011-02590, NCI-2011-02590, CDR0000700033, 11-02-068, 8853, P30CA013330, N01CM62204
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Eleni Andreopoulou Montefiore Medical Center - Moses Campus
National Cancer Institute (NCI)
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP