Veliparib With or Without Carboplatin in Treating Patients With Stage III or IV Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well veliparib with or without carboplatin works in treating patients with stage III or IV breast cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, 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. It is not yet known whether veliparib is more effective with or without carboplatin in treating breast cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the efficacy of single agent veliparib (ABT-888) (NSC 737664) in breast cancer (BRCA) carriers with metastatic breast cancer based on response rate (Response Evaluation Criteria In Solid Tumors [RECIST] criteria). SECONDARY OBJECTIVES: I. To conduct subset analysis on BRCA1 versus (vs.) BRCA2 and hormone receptor status. II. To evaluate progression-free survival of patients on single-agent ABT-888. III. To further describe the safety and tolerability of ABT-888 (NSC 737664) as a single agent and in combination with carboplatin for BRCA-associated breast cancer. IV. To evaluate the pharmacokinetics of ABT-888 (NSC 737664) alone and in combination with carboplatin. V. To assess the relationship between the level of poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibition by ABT-888 and biomarkers of deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear cell (PBMC's) and in tumor. VI. To explore the relationship between biomarkers of drug effect and progression-free survival. VII. To evaluate the efficacy and safety of the combination of carboplatin and ABT-888 in patients who have failed single agent ABT-888. VIII. To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status. OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 2 phases. SAFETY LEAD-IN PHASE: Patients receive veliparib orally (PO) twice daily (BID) on days 1-21 of each cycle and carboplatin intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study. PHASE II: Patients receive veliparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, patients are taken off treatment for 1 week and may then continue to recieve veliparib along with carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study. * As of the November 9, 2023 amendment, the pharmaceutical collaborator has discontinued the ABT-888 development program with the National Cancer Institute Cancer Therapy Evaluation Program (CTEP). Clinical supply will no longer be available after December 31, 2024. Patients will discontinue treatment by December 31, 2024, or earlier. After completion of study treatment, patients are followed up every 6 months.

Official Title
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Phase II Trial of Single Agent ABT-888 With Post-Progression Therapy of ABT-888 in Combination With Carboplatin in Patients With Stage IV BRCA-Associated Breast Cancer

Conditions
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Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Unresectable Breast Carcinoma

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be female, and must have histologically confirmed breast cancer that is metastatic or locally advanced, unresectable and for which standard curative measures do not exist or are no longer effective Patients must have a known deleterious BRCA mutation confirmed by report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (generally Myriad Genetics Laboratory). It is expected that BRCA testing will be covered as medically necessary care by the patient's insurance carrier Measurable disease by RECIST criteria; (evaluable disease is allowed only for the safety lead-in phase) Prior chemotherapy regimens for metastatic disease are completed, at least 3 weeks prior to starting therapy; prior radiation and hormonal treatment must be completed at least 1 week prior to starting therapy Female, age >= 18 years. Because no dosing or adverse event data are currently available on the use of ABT-888 in patients < 18 years of age, children are excluded from this study Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy of greater than four months Absolute neutrophil count (ANC) >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin =< 1.5 times institutional upper limit of normal Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 times institutional upper limit of normal unless there is evidence of liver metastasis, in which case the AST (SGOT)/ALT (SGPT) must be =< 5 times 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 If a woman is of child-bearing potential, a negative serum or urine pregnancy test is required; (The effects of ABT-888 [NSC 737664] on the developing human fetus are unknown; for this reason and because PARP Inhibitor agents are known to be teratogenic, 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; participants should agree to use contraception for at least 3 months after the completion of study therapy; 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: Prior therapy with platinum agents (adjuvant therapy with platinum agents is allowed, if completed >= 12 months prior to relapse), or PARP inhibitors (prior iniparib, since it is no longer considered a PARP inhibitor, is allowed) Patients may not be receiving any other investigational agents Patients with known central nervous system (CNS) metastases requiring anticonvulsive medications, or steroids or with active symptomatology; patients on anticonvulsant medications prescribed for reasons other than CNS metastases, not on steroids and without active symptomatology are eligible; patients must be off anti-seizure medications and steroids for 3 months or more before enrollment Patients with active seizure or a history of seizure; patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment History of allergic reactions attributed to compounds of similar chemical or biological composition to ABT-888 (NSC 737664) or PARP inhibitors Patients with contraindications to platinum agents are excluded Prior or current non-breast malignancy within 5 years except non-melanoma skin cancer or resected stage I ovarian cancer Patients with any non-malignant intercurrent illness (e.g., cardiovascular, pulmonary, or central nervous system disease) which is either poorly controlled with currently available treatment or which is of such severity that the investigators deem it unwise to enter the patient on protocol Pregnant women are excluded from this study because ABT-888 (NSC 737664) has the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ABT-888 (NSC 737664), breastfeeding should be discontinued Patients unable to swallow the ABT-888 tablets whole are ineligible; (the tablets cannot be crushed or broken) Patients with an active severe infection; known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus; HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ABT-888 (NSC 737664); in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II (veliparib, carboplatin)<br>Patients receive veliparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, patients are taken off treatment for 1 week and may then continue to recieve veliparib along with carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|
| Experimental: Safety Lead-In Phase (veliparib, carboplatin)<br>Patients receive veliparib PO BID twice daily on days 1-21 of each cycle and carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Measured by Response Evaluation Criteria in Solid Tumors version 1.1. | Up to 13 years | 
| Post-progression response rate (Phase II) | Measured by Response Evaluation Criteria in Solid Tumors version 1.1. Post-progression response (when patients receive the combination) will also be summarized. | Up to 13 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (Phase II) | Compared between arms using the log-rank test. Analyzed using Kaplan-Meier plots and multivariate Cox regression. | From start of treatment to time of progression or death, whichever occurs first, assessed up to 13 years | 
| Second progression-free survival (Phase II) | Compared between arms using the log-rank test. Analyzed using Kaplan-Meier plots and multivariate Cox regression. Second progression-free survival data (when patients receive the combination) will also be summarized. | From start of treatment to time of progression or death, whichever occurs first, assessed up to 13 years | 
| Incidence of adverse events | Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and 5.0. Assessed and summarized with descriptive statistics. | Up to 13 years |