Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Unresectable Breast Carcinoma
Conditions
Brief summary
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
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.
Interventions
PROCEDUREBiopsy
Undergo biopsy
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGCarboplatin
Given IV
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
DRUGVeliparib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subject With Overall Response | Up to 8 weeks post-treatment | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \<10 mm; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR |
| Progression-free Survival | From start of treatment to time of progression or death from any cause, whichever occurs first, assessed up to at least 1 year | Progression-free survival will be summarized as time from first protocol treatment until progression or death from any cause, using the product-limit Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 21 days from start of treatment, up to 2 years | The maximum tolerated dose of veliparib in combination with AUC 5 of Carboplatin is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design. |
| Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | During the first cycle of treatment, up to 21 days | Dose-limiting toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Pre-specified DLT criteria included the following adverse events (AE), judged to be at least possibly related to study therapy: any grade III non-hematological toxicity not reversible to grade II or less within 96 hours, or any grade IV toxicity (excluding alopecia or controllable nausea and vomiting). Additionally, patients unable to take 80% of the planned ABT-888 due to toxicity/tolerability will be considered to have had a DLT. |
| Overall Survival | From start of treatment to time of death from any cause, assessed up to at least 3 years | Overall survival will be summarized as time from first protocol treatment until death from any cause, using the product-limit Kaplan-Meier estimator. |
Countries
Canada, United States
Participant flow
Pre-assignment details
28 patients were enrolled in the Phase I trial and 49 patients in the Phase II trial. However, 5 were either inevaluable or did not start treatment, resulting in 44 patients included in the final sample. Of those 5 patients, 3 did not get any drug due to consent withdrawal or choosing other therapy. The remaining 2 were treated but were deemed inevaluable due to not receiving enough drug per protocol. Hence there is data sent to the NCI on those 2 patients who were not part of the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm A, Dose Level 1 - 50 mg Veliparib, AUC 6 Carboplatin (Phase I) Patients receive veliparib 50 mg PO BID on days 1-21 of each cycle and carboplatin AUC 6 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. | 7 |
| Arm A, Dose Level -1 - 50 mg Veliparib, AUC 5 Carboplatin (Phase I) Patients receive veliparib 50 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 6 |
| Arm A, Dose Level A - 100 mg Veliparib, AUC 5 Carboplatin (Phase I) Patients receive veliparib 100 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 3 |
| Arm A, Dose Level B - 150 mg Veliparib, AUC 5 Carboplatin (Phase I) Patients receive veliparib 150 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 6 |
| Arm A, Dose Level C - 200 mg Veliparib, AUC 5 Carboplatin (Phase I) Patients receive veliparib 200 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 6 |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) Patients receive veliparib 150 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 22 |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) Patients receive veliparib 150 mg PO BID on days 1-21 of each cycle and carboplatin AUC 5 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. | 22 |
| Total | 72 |
Baseline characteristics
| Characteristic | Arm A, Dose Level 1 - 50 mg Veliparib, AUC 6 Carboplatin (Phase I) | Arm A, Dose Level -1 - 50 mg Veliparib, AUC 5 Carboplatin (Phase I) | Arm A, Dose Level A - 100 mg Veliparib, AUC 5 Carboplatin (Phase I) | Arm A, Dose Level B - 150 mg Veliparib, AUC 5 Carboplatin (Phase I) | Arm A, Dose Level C - 200 mg Veliparib, AUC 5 Carboplatin (Phase I) | Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) | Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 47 Years | 53 Years | 44 Years | 52 Years | 44 Years | 42 Years | 44 Years | 43 Years |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 6 Participants | 6 Participants | 2 Participants | 5 Participants | 6 Participants | 11 Participants | 5 Participants | 41 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 15 Participants | 22 Participants |
| Region of Enrollment United States | 7 participants | 6 participants | 3 participants | 6 participants | 6 participants | 22 participants | 22 participants | 72 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 6 Participants | 22 Participants | 22 Participants | 72 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 7 | 6 / 6 | 2 / 3 | 4 / 6 | 4 / 6 | 11 / 22 | 12 / 22 |
| other Total, other adverse events | 7 / 7 | 6 / 6 | 3 / 3 | 6 / 6 | 6 / 6 | 22 / 22 | 22 / 22 |
| serious Total, serious adverse events | 6 / 7 | 3 / 6 | 2 / 3 | 3 / 6 | 2 / 6 | 8 / 22 | 6 / 22 |
Outcome results
Primary
Number of Subject With Overall Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \<10 mm; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR
Time frame: Up to 8 weeks post-treatment
Population: Arm A includes all patients across dose levels (DL1-DL5) in the safety lead-in Phase I portion of the study, while Arm B comprises only BRCA1 and BRCA2 mutation carriers in the Phase II portion. The protocol pre-specified that the response rate for Phase I would be collected and reported as a single arm/group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Safety Lead-in (Phase I) | Number of Subject With Overall Response | 15 Participants |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) | Number of Subject With Overall Response | 3 Participants |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) | Number of Subject With Overall Response | 8 Participants |
Primary
Progression-free Survival
Progression-free survival will be summarized as time from first protocol treatment until progression or death from any cause, using the product-limit Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: From start of treatment to time of progression or death from any cause, whichever occurs first, assessed up to at least 1 year
Population: Arm A includes all patients across dose levels (DL1-DL5) in the safety lead-in Phase I portion of the study, while Arm B comprises only BRCA1 and BRCA2 mutation carriers in the Phase II portion. The protocol pre-specified that progression-free survival for Phase I would be summarized and reported as a single arm/group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Safety Lead-in (Phase I) | Progression-free Survival | 8.7 Months |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) | Progression-free Survival | 3.6 Months |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) | Progression-free Survival | 6.6 Months |
Secondary
Maximum Tolerated Dose (MTD)
The maximum tolerated dose of veliparib in combination with AUC 5 of Carboplatin is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design.
Time frame: 21 days from start of treatment, up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Safety Lead-in (Phase I) | Maximum Tolerated Dose (MTD) | 150 mg |
Secondary
Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I
Dose-limiting toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Pre-specified DLT criteria included the following adverse events (AE), judged to be at least possibly related to study therapy: any grade III non-hematological toxicity not reversible to grade II or less within 96 hours, or any grade IV toxicity (excluding alopecia or controllable nausea and vomiting). Additionally, patients unable to take 80% of the planned ABT-888 due to toxicity/tolerability will be considered to have had a DLT.
Time frame: During the first cycle of treatment, up to 21 days
Population: This is a Phase I/II trial with the Phase I portion designed to determine the maximum tolerated dose of veliparib in combination with carboplatin. Arm A is separated into 5 different dose levels to adequately evaluate DLTs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Safety Lead-in (Phase I) | Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | 2 Participants |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) | Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | 1 Participants |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) | Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | 0 Participants |
| Arm A, Dose Level B - 150 mg Veliparib, AUC 5 Carboplatin (Phase I) | Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | 0 Participants |
| Arm A, Dose Level C - 200 mg Veliparib, AUC 5 Carboplatin (Phase I) | Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I | 3 Participants |
Secondary
Overall Survival
Overall survival will be summarized as time from first protocol treatment until death from any cause, using the product-limit Kaplan-Meier estimator.
Time frame: From start of treatment to time of death from any cause, assessed up to at least 3 years
Population: Arm A includes all patients across dose levels (DL1-DL5) in the safety lead-in Phase I portion of the study, while Arm B comprises only BRCA1 and BRCA2 mutation carriers in the Phase II portion. The protocol pre-specified that outcomes for Phase I would be summarized and reported as a single arm/group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Safety Lead-in (Phase I) | Overall Survival | 18.8 Months |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA I Carriers (Phase II) | Overall Survival | 11.9 Months |
| Arm B - 150 mg Veliparib, AUC 5 Carboplatin BRCA II Carriers (Phase II) | Overall Survival | 14.7 Months |