An Adaptive, Randomized Phase II Trial to Determine Pathologic Complete Response With the Addition of Carboplatin With and Without Veliparib to Standard Chemotherapy in the Neoadjuvant Treatment of Triple-Negative Breast Cancer
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.
1. Relapse free survival (follow-up period of 36 months).
2. Overall clinical response to neoadjuvant therapy.
3. To determine whether expression of 5 biomarkers (cytokeratin [CK]5, endothelial growth
factor receptor [EGFR], excision repair cross complementing 1 [ERCC1], Ki67,
poly[adenosine diphosphate (ADP)-ribosyl]transferase [Parp1]) correlate with a higher
pCR in response to a particular treatment combination. 4) To determine whether tumors
with biomarker signatures that are most like breast cancer (BRCA)-mutated tumors (high
expression of CK5 and high expression of EGFR), will correlate with a higher likelihood
of pCR with treatment with a PARP inhibitor in combination with chemotherapy.
5) To determine whether tumors with high expression of the markers ERCC1, Ki67, and Parp1
will correlate with a higher rate of pCR with platinum agents in combination with paclitaxel
or a PARP inhibitor.
6) To correlate response of tumor on imaging (magnetic resonance imaging [MRI], ultrasound
[US], and positron emission tomography [PET]/computed tomography [CT]) with path CR.
7) To correlate levels of circulating tumor cells (CTCs) with pathologic CR.
1. To evaluate additional exploratory biomarkers based on evidence of possible prognostic
or predictive value: BRCA1/BRCA2 complete mutational and rearrangement test. CK14,
CK17, cyclin B1, cluster of differentiation (CD)44, CD24, cyclin D1, vimentin,
thymidine phosphorylase, inhibitor of differentiation (ID)4, p53, p63, p73,
differentiated embryo-chondrocyte expressed gene (Dec)1, phospho-HistoneH3, thymidylate
synthase, p16, gammaH2AX, geminin, RAD51.
2. To determine which arms are best tolerated by patients with co-morbid conditions, such
as hypertension and diabetes.
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
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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. The posterior distribution of the odds ratio will be used to assess whether carboplatin and/or carboplatin +veliparib in combination with paclitaxel has a higher PCR compared to each other and simulations will be used to compare to paclitaxel alone. A 95% credible region will be calculated for the odds ratio comparing the two combination treatments, the odds ratio comparing each treatment to paclitaxel alone, the PCR for each treatment regimen, for the difference in the PCR between each combination regimen, and the difference of each combination regimen to paclitaxel alone.
At the time of surgery
Tiffany Avery, MD, MPH
Thomas Jefferson University
United States: Food and Drug Administration
|Anne Arundel Medical Center||Annapolis, Maryland 21401|
|University of Pittsburgh Medical Center||Pittsburgh, Pennsylvania 15213|
|Thomas Jefferson University||Philadelphia, Pennsylvania 19107-6541|
|Walter Reed National Military Medical Center||Bethesda, Maryland 20889|