Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer
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Purpose
This phase I trial studies the side effects and best dose of veliparib when given together with carboplatin and to see how well they work in treating patients with human epidermal growth factor 2 (HER2)-negative breast cancer that has spread to other parts of the body. Carboplatin kills cancer cells by damaging the deoxyribonucleic acid (DNA) that lets the cancer cell survive and reproduce. The body has proteins that try to repair the damaged DNA. Veliparib may prevent these proteins from repairing the DNA so that carboplatin may be able to kill more tumor cells. Giving veliparib with carboplatin may kill more tumor cells than carboplatin alone.
| Condition | Intervention | Phase |
|---|---|---|
|
BRCA1 Mutation Carrier BRCA2 Mutation Carrier Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Male Breast Carcinoma Progesterone Receptor Negative Progesterone Receptor Positive Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Triple-Negative Breast Carcinoma |
Drug: Veliparib Drug: Carboplatin Other: Fluorothymidine F-18 Procedure: Positron Emission Tomography Other: Laboratory Biomarker Analysis Other: Pharmacological Study |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase 1 Dose-Escalation Study of ABT-888 (Veliparib) in Combination With Carboplatin in HER2 Negative Metastatic Breast Cancer |
- Incidence of adverse events to measure the safety and tolerability of this treatment combination [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]Number and severity of toxicity incidents will be tabulated. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria for Adverse Events (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.
- Clinical response (complete and partial response as well as stable and progressive disease) [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: No ]Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1).
- PARP-1 activity [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
- Thymidine kinase uptake on FLT-PET scans [ Time Frame: Up to 18 weeks (after course 3) ] [ Designated as safety issue: No ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
- Circulating tumor cell markers [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
| Estimated Enrollment: | 42 |
| Study Start Date: | November 2010 |
| Estimated Primary Completion Date: | January 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (veliparib, F 18 fluorothymidine, carboplatin)
Patients receive carboplatin IV over 1 hour on day 1 and veliparib 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.
|
Drug: Veliparib
Given PO
Other Name: ABT-888
Drug: Carboplatin
Given IV
Other: Fluorothymidine F-18
Correlative studies
Other Names:
Procedure: Positron Emission Tomography
Correlative studies
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies
|
Detailed Description:
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 poly(ADP-ribose) polymerase (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 gamma H2AX, 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 breast cancer 1/2, early onset (BRCA)1/2 protein, Fanconi anemia, complementation group D2 (FANCD2) nuclear foci formation and expression of micro-ribonucleic acid (RNA) 155 (miR 155).
OUTLINE: This is a dose-escalation study of veliparib.
Patients receive carboplatin intravenously (IV) over 1 hour on day 1 and veliparib orally (PO) twice daily (BID) on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 weeks.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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 FA triple stain immunofluorescence (FATSI) 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
- No more than 3 prior chemotherapy regimens for metastatic disease will be allowed; any number of prior hormone therapies will be allowed; however, 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)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
-
Patients with treated brain metastases and life expectancy of greater than 3 months allowed
- Patients with uncontrolled central nervous system (CNS) metastasis are not eligible
- Patients with known Gilbert syndrome with abnormal unconjugated bilirubin will be eligible
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic acid transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X 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
- No prior therapy with veliparib for metastatic disease will be allowed
- 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
- Ability to understand and the willingness to sign a written informed consent document
- Patients must be able to swallow pills
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Patients may not be receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
- 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 women are excluded from this study; breastfeeding should be discontinued if the mother is treated with veliparib
- Known human immunodeficiency virus (HIV)-infected patients on protease inhibitors (HIV-infected patients with adequate cluster of differentiation [CD]4 counts [> 500] and not on protease inhibitors are eligible)
- Patients with active seizure or a history of seizures are not eligible
- Patients with uncontrolled CNS metastasis are not eligible; patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01251874
| United States, New York | |
| Montefiore Medical Center - Moses Campus | |
| Bronx, New York, United States, 10467-2490 | |
| United States, Ohio | |
| Ohio State University Comprehensive Cancer Center | |
| Columbus, Ohio, United States, 43210 | |
| Principal Investigator: | Bhuvaneswari Ramaswamy | Ohio State University Comprehensive Cancer Center |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01251874 History of Changes |
| Other Study ID Numbers: | NCI-2011-02552, NCI-2011-02552, CDR0000688990, OSU 10080, 8609, U01CA076576, P30CA016058 |
| Study First Received: | December 1, 2010 |
| Last Updated: | January 19, 2015 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms Breast Neoplasms, Male Carcinoma Breast Diseases Neoplasms Neoplasms by Histologic Type Neoplasms by Site |
Neoplasms, Glandular and Epithelial Skin Diseases Carboplatin Antineoplastic Agents Pharmacologic Actions Therapeutic Uses |
ClinicalTrials.gov processed this record on February 27, 2015