Clinical Trials /

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

NCT01351909

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cyclophosphamide and Veliparib in Treating Patients With Locally Advanced or Metastatic Breast Cancer
  • Official Title: Phase I Trial of Low-Dose Cyclophosphamide in Combination With Veliparib (ABT-888) in HER2/Neu-Negative Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2011-02590
  • SECONDARY ID: NCI-2011-02590
  • SECONDARY ID: CDR0000700033
  • SECONDARY ID: 11-02-068
  • SECONDARY ID: 11-01501
  • SECONDARY ID: P8853_A18PAMDREVW01
  • SECONDARY ID: 8853
  • SECONDARY ID: 8853
  • SECONDARY ID: N01CM62204
  • SECONDARY ID: P30CA013330
  • NCT ID: NCT01351909

Conditions

  • HER2/Neu Negative
  • Recurrent Breast Carcinoma
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IV Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (veliparib, cyclophosphamide)
VeliparibABT-888, PARP-1 inhibitor ABT-888Treatment (veliparib, cyclophosphamide)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (veliparib, cyclophosphamide)ExperimentalPatients 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.
  • Cyclophosphamide
  • Veliparib

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose of veliparib and cyclophosphamide
Time Frame:21 days
Safety Issue:
Description: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

Measure:Clinical response (complete or partial response) according to RECIST version 1.1
Time Frame:Up to 24 weeks
Safety Issue:
Description: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.
Measure:MacroH2A1.1 expression levels
Time Frame:Up to 6 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Time from treatment initiation to death, assessed up to 6 years
Safety Issue:
Description:Overall survival will be analyzed using standard survival analytic approaches including the Kaplan-Meier method and the log-rank test.
Measure:PARP1 expression status
Time Frame:Up to 6 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 11, 2017