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A Phase 1 Dose-Escalation Study of ABT-888 (Veliparib) in Combination With Carboplatin in HER2 Negative Metastatic Breast Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Both
BRCA1 Mutation Carrier, BRCA2 Mutation Carrier, Estrogen Receptor-negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Male Breast Cancer, Progesterone Receptor-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Triple-negative Breast Cancer

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Trial Information

A Phase 1 Dose-Escalation Study of ABT-888 (Veliparib) in Combination With Carboplatin in HER2 Negative Metastatic Breast Cancer


PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of veliparib along with carboplatin on a
14-day and 21- day schedule in patients with Her2 negative metastatic breast cancer that are
estrogen receptor (ER)/progesterone receptor(PR) negative or ER and/or PR positive with
defects in Fanconi Anemia (FA) pathway repair genes.

II. To determine the safety and tolerability of combining veliparib on a 14-day and 21-day
schedule with carboplatin in this patient population.

III. To determine the preliminary efficacy of this combination in this patient population.

SECONDARY OBJECTIVES:

I. To determine the pharmacodynamic endpoints of PARP inhibition in the tumor by using, A)
3'-[F-18]Fluoro-3'-deoxythymidine Positron Emission Tomography (FLT-PET) of the target
lesions, B) circulating tumor cells to detect the induction of the histone variant
gammaH2AX, and C) peripheral blood mononuclear cells to assess poly ADP-Ribose (PAR) levels.

II. To determine biomarkers in the primary tumor that may predict antitumor responses to
PARP inhibition such as BRCA1/2 protein, FANCD2 nuclear foci formation and expression of miR
155.

OUTLINE: This is a multicenter, dose-escalation study of veliparib.

Patients receive carboplatin intravenously (IV) over 1 hour on day 1 and veliparib orally
(PO) twice daily on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity. Patients may undergo fluorothymidine PET scan and
peripheral blood cell and tumor tissue collection periodically for correlative studies.

After completion of study treatment, patients are followed up for 12 weeks.


Inclusion Criteria:



- Patients must have histologically or cytologically proven metastatic or locally
advanced inoperable breast cancer that fulfills one of the following two criteria:

- Triple-negative breast cancer

- ER and/or PR positive, HER2 negative if their tumors have been shown to be
deficient for the FA pathway, based on FATSI immunofluorescence screening

- HER negative with a known germline BRCA1/2 mutation

- Patients with ER- and/or PR-positive breast cancer will be consented to
have their existing, or to be obtained, paraffin-embedded tumor tissue
screened for FA deficiency

- Patients with treated brain metastases and life expectancy of greater than 3 months
allowed

- Patients with uncontrolled CNS metastasis are not eligible

- Recovered from adverse events due to agents administered more than 4 weeks earlier

- Menopausal status not specified

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min

- Patients with known Gilbert syndrome with abnormal unconjugated bilirubin will be
eligible

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation

- Able to swallow pills

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Known HIV-infected patients on protease inhibitors are ineligible

- HIV-infected patients with adequate CD4 counts (> 500) and not on protease
inhibitors are eligible

- Patients with a recent history of seizure (6 months to 1 year) are not eligible

- Patients with a long-term history of seizures and stable on anti-seizure
medications may be eligible

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to veliparib or other agents used in study

- Patients may not be receiving any other investigational agents

- No more than 3 prior chemotherapy regimens for metastatic disease

- No prior therapy with veliparib for metastatic disease

- Any number of prior hormone therapies will be allowed

- At least 4 weeks should have elapsed since prior chemotherapy (6 weeks for mitomycin
C and nitrosoureas and 2 weeks for hormone therapy) or radiation therapy (2 weeks for
limited-field palliative radiation to the bone)

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number and severity of toxicity incidents to measure the safety and tolerability of this treatment combination for the treatment of Her2 negative metastatic breast cancer

Outcome Description:

Non-hematologic toxicities will be evaluated via the ordinal CTCAE version 4.0 standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTCAE standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Outcome Time Frame:

Up to 12 weeks post-treatment

Safety Issue:

Yes

Principal Investigator

Bhuvaneswari Ramaswamy

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02552

NCT ID:

NCT01251874

Start Date:

November 2010

Completion Date:

Related Keywords:

  • brca1 Mutation Carrier
  • brca2 Mutation Carrier
  • Estrogen Receptor-negative Breast Cancer
  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male

Name

Location
Ohio State University Medical Center Columbus, Ohio  43210
Lombardi Comprehensive Cancer Center at Georgetown University Washington, District of Columbia  20057