Estrogen Receptor-negative Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-negative Breast Cancer
Conditions
Brief summary
This randomized phase II trial studies how well carboplatin and combination chemotherapy with or without veliparib works in treating patients with stage IIB-IIIC breast cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and combination chemotherapy are more effective with or without veliparib is more effective in treating breast cancer.
Detailed description
PRIMARY OBJECTIVE: 1\) To compare the pathologic complete response (path CR) in patients with stage IIB or stage III triple negative breast cancer treated with neoadjuvant paclitaxel and carboplatin to the path CR of patients treated with paclitaxel, carboplatin, and veliparib. SECONDARY OBJECTIVES: 1. Relapse free survival (follow-up period of 36 months). 2. Overall clinical response to neoadjuvant therapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 36 months.
Interventions
DRUGPaclitaxel
Given IV
DRUGCarboplatin
Given IV
DRUGDoxorubicin
Given IV
DRUGCyclophosphamide
Given IV
DRUGVeliparib
Given PO
Sponsors
Susan G. Komen Breast Cancer Foundation
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be obtained prior to any study-related procedures. 2. Histologically confirmed adenocarcinoma of the breast with the following markers: Estrogen receptor negative (\<1%), progesterone receptor negative (\<1%), and Her-2/neu negative (Her-2/neu 0-1+ IHC or FISH ratio \<1.8 or average HER2 gene copy number of \<four signal/nucleus for test systems without internal control probe). 3. Female ≥ 18 years old. 4. Clinical stage IIA (T2N0), IIB (T2N1, T3N0) or stage IIIA (T1N2, T2N2, T3N1, T3N2), IIIB, or IIIC breast cancer with no prior treatment. 5. Complete radiology or tumor assessment within 28 days prior to enrollment 1. Breast MRI 2. Unilateral Breast Ultrasound 3. Distant metastatic work-up completed with PET/CT. 4. If enlarged axillary lymph nodes are found during staging scans, FNA must be performed to determine whether the node is involved with cancer. 5. If axillary lymph nodes are clinically negative during initial work-up, sentinel node biopsy will be performed prior to initiation of chemotherapy. 6. ECOG Performance Status of 0 or 1 7. Adequate organ and hematologic function as evidenced by the following laboratory studies within 4 weeks of study enrollment: 1. Cardiac Ejection Fraction \>/= lower limit of normal as determined by 2-D echo or MUGA scan according to institutional standards. 2. Hematologic function, as follows: Absolute neutrophil count ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L, Hemoglobin ≥ 9 g/dL, PTT and INR \< 1.5 x ULN. 3. Renal function, as follows: Serum creatinine \</= 1.4 mg/dL). 4. Hepatic function, as follows:Aspartate aminotransferase (AST) ≤ 2.5 x ULN, Alanine aminotransferase (ALT) ≤ 2.5 x ULN , Total bilirubin ≤ 2 x ULN (except for patients with UGT1A1 promoter polymorphism, i.e. Gilbert syndrome, confirmed by genotyping or Invader UGT1A1 molecular assay prior to study enrollment. Patients enrolled with Gilbert syndrome must have total bilirubin \< 3 ULN). 8. Patient must be willing and able to undergo MRI as outlined in protocol.
Exclusion criteria
1. Known hypersensitivity to doxorubicin, cyclophosphamide, paclitaxel, cremophor or medications containing cremophor(miconazole, docetaxel, sandimmune, nelfinavir mesylate, propofol, diazepam injection, vitamin K injection, ixabepilone, aci-jel) or carboplatin. 2. Known HIV or active Hepatitis B or C infection. 3. Prior treatment for the currently diagnosed breast cancer. 4. Prior treatment with doxorubicin up to 400 mg/m2. 5. Pre-existing Grade 3 or 4 sensory neuropathy. 6. History of bleeding diathesis or extensive bleeding requiring blood transfusion within 14 days of enrollment. 7. Major surgical procedure within 4 weeks (28 days) prior to enrollment (port placement is not considered a major surgical procedure). 8. Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, congestive heart failure, or ongoing arrhythmias requiring medication or pacemaker. 9. Non-healing wound, ulcer or fracture. 10. Ongoing or active infection. 11. Pregnant (i.e., positive beta-human chorionic gonadotropin test) or lactating 12. Not willing to use a highly effective method of birth control (i.e. those which result in low failure rates, less than 1% per year), defined as intrauterine devices, barrier methods (condoms, contraceptive sponges, diaphragms, vaginal rings used with spermicidal jellies or creams), oral contraceptive pills, or sexual abstinence. Contraception must be used during the study. 13. T0 tumors 14. Active dental infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants That Achieve Pathologic Complete Response (PCR) | 36 months following surgery | PCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin (H&E) evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Clinical Response | Up to 3 years | The count and percentage of subjects with each category of overall clinical response will be summarized by presence of baseline measureable disease (i.e., complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\], unable to evaluate \[UE\], neurogenerative disease \[ND\]). Evaluated per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) as assessed b MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Beta will be used as priors for combination regimens in calculating the posterior distribution of the pathologic complete response \[pCR\] for each respective treatment group. Among subjects with measurable disease, a 95% credible region will be calculated for the odds ratio for each treatment combination relative to each other. |
| Relapse Free Survival | Up to 3 years | Analyzed using Kaplan-Meier methods, stratified by study group, and the log rank test will be completed. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (Paclitaxel, Carboplatin) Patients receive paclitaxel IV and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Paclitaxel: Given IV
Carboplatin: Given IV
Doxorubicin: Given IV
Cyclophosphamide: Given IV | 5 |
| Arm 2 (Veliparib, Paclitaxel, Carboplatin) Patients receive veliparib PO BID on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Paclitaxel: Given IV
Carboplatin: Given IV
Doxorubicin: Given IV
Cyclophosphamide: Given IV
Veliparib: Given PO | 4 |
| Total | 9 |
Baseline characteristics
| Characteristic | Total | Arm 1 (Paclitaxel, Carboplatin) | Arm 2 (Veliparib, Paclitaxel, Carboplatin) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 2 Participants |
| Region of Enrollment United States | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 3 / 5 | 1 / 4 |
| serious Total, serious adverse events | 1 / 5 | 0 / 4 |
Outcome results
Primary
Count of Participants That Achieve Pathologic Complete Response (PCR)
PCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin (H&E) evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes.
Time frame: 36 months following surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Paclitaxel, Carboplatin) | Count of Participants That Achieve Pathologic Complete Response (PCR) | 3 Participants |
| Arm 2 (Veliparib, Paclitaxel, Carboplatin) | Count of Participants That Achieve Pathologic Complete Response (PCR) | 3 Participants |
Secondary
Overall Clinical Response
The count and percentage of subjects with each category of overall clinical response will be summarized by presence of baseline measureable disease (i.e., complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\], unable to evaluate \[UE\], neurogenerative disease \[ND\]). Evaluated per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) as assessed b MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Beta will be used as priors for combination regimens in calculating the posterior distribution of the pathologic complete response \[pCR\] for each respective treatment group. Among subjects with measurable disease, a 95% credible region will be calculated for the odds ratio for each treatment combination relative to each other.
Time frame: Up to 3 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 (Paclitaxel, Carboplatin) | Overall Clinical Response | Partial Response | 2 Participants |
| Arm 1 (Paclitaxel, Carboplatin) | Overall Clinical Response | Progressive Disease | 1 Participants |
| Arm 1 (Paclitaxel, Carboplatin) | Overall Clinical Response | Pathological Complete Response | 2 Participants |
| Arm 2 (Veliparib, Paclitaxel, Carboplatin) | Overall Clinical Response | Progressive Disease | 1 Participants |
| Arm 2 (Veliparib, Paclitaxel, Carboplatin) | Overall Clinical Response | Partial Response | 1 Participants |
| Arm 2 (Veliparib, Paclitaxel, Carboplatin) | Overall Clinical Response | Pathological Complete Response | 2 Participants |
Secondary
Relapse Free Survival
Analyzed using Kaplan-Meier methods, stratified by study group, and the log rank test will be completed.
Time frame: Up to 3 years
Population: Sincere efforts have been made to gather and report the data, however, no data is available for this outcome measure.