A Multi-Institutional Double-Blind Phase II Study Evaluating Response and Surrogate Biomarkers to Carboplatin and Nab-Paclitaxel (CP) With or Without Vorinostat as Preoperative Chemotherapy in HER2-negative Primary Operable Breast Cancer

简要总结

详细描述

OBJECTIVES: Primary * To determine pathological complete response (pCR) rates in patients with HER2-negative primary operable breast cancer treated with neoadjuvant therapy comprising carboplatin and paclitaxel albumin-stabilized nanoparticle formulation (CP) with vs without vorinostat. Secondary * To evaluate the safety of these regimens in these patients. * To estimate clinical complete response (cCR) rates in patients treated with these regimens. * To correlate baseline and change (day 15) in surrogate uptake values (SUV) on FDG-PET with pathological and clinical response in patients treated with these regimens, and to determine what percent of women with ≥ 25% or ≥ 50% reduction in SUV on day 15 achieve a pCR and a cCR to CP with vs without vorinostat. * To correlate baseline and change in markers of proliferation with pathological and clinical response in patients treated with these regimens. * To evaluate long term outcomes (e.g., recurrence of the breast cancer, development of a new cancer, or death) for patients treated with these regimens. Tertiary * To evaluate baseline and change in candidate gene methylation and expression profiles. * To evaluate baseline and change in tissue and peripheral blood mononuclear cell histone acetylation. * To compare cCR and pCR in women with basal-like features versus other subtypes. OUTLINE: This is a multicenter, randomized, double-blind, phase II study (primary study portion) with a 6-12 patient run-in portion. * Run-in portion: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Once safety of the combination of chemotherapy and vorinostat is confirmed, subsequently enrolled patients are entered to the primary study portion. * Primary study portion: Patients are stratified by hormone receptor status (estrogen receptor \[ER\]-negative and progesterone receptor \[PR\]-negative vs ER-positive and/or PR-positive). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after completion of neoadjuvant chemotherapy, patients undergo breast conserving surgery or mastectomy at the discretion of the treating physician. Patients undergo tumor tissue biopsy at baseline, day 15, and at the time of definitive surgery. Samples are analyzed by immunohistochemistry (IHC), RNA extraction, and gene expression analysis using RT-PCR to identify candidate markers for response and molecular profiles that may be relevant to an understanding of drug mechanisms. Methylation of relevant genes (e.g., ERalpha, APC-1, RARbeta, cyclin D2, Twist, RASSF1A, and HIN-1) are evaluated by quantitative multiplex methylation-specific PCR. Changes in gene expression as a result of treatment are determined by IHC or quantitative RT-PCR. Blood samples are collected at baseline, day 15, at the time of definitive surgery, and 4 weeks after surgery for DNA methylation studies, pharmacogenomic studies, and histone acetylation assays. Patients also undergo fludeoxyglucose F 18-positron emission tomography (FDG-PET) or PET/CT at baseline and day 15 to assess treatment response as measured by standardized uptake values. After completion of study treatment, patients are followed every 6 months.

主要结局

次要结局

• Safety as Measured by Number of Participants Who Experience Adverse Events(up to 30 days post-treatment)
• Number of Participants With Clinical Complete Response (cCR)(12 weeks)
• Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET(Baseline and day 15)
• Absolute Change From Baseline in Ki-67(Change from baseline to Cycle 1-Day 15)
• Change in Cumulative Methylation Index (CMI)(Change from baseline to Day 15)
• Cumulative Methylation Index (CMI) at Day 15(Day 15)
• Number of Participants Who Experience Death During Treatment(Up to 12 weeks)
• Number of Participants Who Develop New Cancer(Up to death of last participant (duration unknown))
• Number of Participants With Recurrence of Breast Cancer(Up to death of last participant (duration unknown))
• Overall Survival(Up to death of last participant (duration unknown))