A Randomized Phase II Biomarker Neoadjuvant Study of Sequential AC Followed by Ixabepilone Compared to Sequential AC Followed by Paclitaxel in Women With Early Stage Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 384
- 试验地点
- 11
- 主要终点
- Percentage of Participants Achieving Pathologic Complete Response (pCR) in 20- and 26-Gene Model Subgroups
研究概览
简要总结
The study will evaluate the effectiveness of ixabepilone when given after doxorubicin plus cyclophosphamide (AC) compared to standard treatment of paclitaxel given after doxorubicin plus cyclophosphamide in patients with early stage breast cancer. In addition the study will verify predefined biomarkers as well as discover new biomarkers that could identify patients who are more likely to respond to ixabepilone than standard paclitaxel based therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
A
干预措施: Ixabepilone (Drug)
A
干预措施: Cyclophosphamide (Drug)
A
干预措施: Doxorubicin (Drug)
B
干预措施: Paclitaxel (Drug)
B
干预措施: Cyclophosphamide (Drug)
B
干预措施: Doxorubicin (Drug)
结局指标
主要结局
Percentage of Participants Achieving Pathologic Complete Response (pCR) in 20- and 26-Gene Model Subgroups
时间窗: pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.
For each of the 2 biomarker sets (20-gene or 26-gene), a multi-gene model was built using penalized logistic regression on all pharmacogenomic evaluable subjects for each treatment arm separately. Receiver Operating Characteristic (ROC) plots for separate arm using 5 fold cross validation were generated. ROC for separate arms using cross over were also added. Further analysis on the multiple gene models (as mentioned in the SAP) was planned only based on the initial findings from the 2 ROC plots. For 20- and 26-gene models, ROC curves generated for each study arm did not indicate that these multi-gene models differentially predicted for pCR between the treatment arms, so further analyses to estimate the optimal cut-off and the pCR rates were not conducted.
Percentage of Participants Achieving Pathologic Complete Response (pCR) in Biomarker-Defined Populations
时间窗: pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.
Beta III tubulin positivity determined by cross-validation method. Optimal cutoff: ≥46% tumor cells staining at 2 plus or 3 plus intensity (corresponding Beta III tubulin positivity=39.4%). Pre-specified cutoff of Beta III tubulin positivity: ≥50% 2plus or 3plus cells (corresponding prevalence=38.5%). Optimal cutoffs for TACC3 and CAPG positivity determined by cross-validation method: 6.889 and 6.844 \[log2 normalized intensity units\], respectively (corresponding to prevalence rates of 43.3% and 44.3%).
Percentage of Participants Achieving Pathologic Complete Response (pCR)
时间窗: at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy)
The pCR was defined as no histologic evidence of residual invasive adenocarcinoma in the breast and axillary lymph nodes, with or without the presence of ductal carcinoma in situ (DCIS) in the breast.
次要结局
- Percentage of Participants Achieving Clinical Objective Response(after the last dose of either ixabepilone or paclitaxel (at 12 weeks) but before surgery (4-6 weeks after the last dose of 12 weeks of therapy))
- Percentage of Participants With pCR/RCB1 and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-specified Thresholds(pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.)
- Number of Participants by Dose for AC(12 weeks (4 3-week cycles))
- Reason for First Dose Reduction of AC(12 weeks (4 3-week cycles))
- Percentage of Participants Requiring Breast Conservation Surgery(at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy))
- On-Study Hematology: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase(prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy during ixabepilone or paclitaxel treatment phase)
- Percentage of Participants Achieving Combined pCR and Minimal Residual Cancer Burden (RCB) 1(at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy))
- Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]), to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of β-tubulin, Kallikreins 5, 6, 10 Are Differentially Predictive of pCR(pCR evaluated at time of surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.)
- Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]) to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of β-tubulin, Kallikreins 5, 6, 10 Are Differentially Predictive of pCR/RCB1(pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.)
- Percentage of Participants With pCR and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-specified Thresholds, Estrogen-Receptor (ER) Negative Participants(pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.)
- Percentage of Participants With pCR and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-Specified Thresholds(: pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.)
- Overall Safety Summary: Deaths, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Drug-Related AEs, and Most Common Treatment-Related Non-Hematologic Adverse Events (TNAEs) Occuring in >=10% of Participants(prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy)
- Severity of Any Drug-Related AEs and Gastrointestinal AEs by System Organ Class(prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy)
- Prevalence of Biomarker Based on Optimal Threshold (Biomarker Positive Participants)(pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy and mRNA samples obtained prior to treatment)
- On-Study Liver Function: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase(prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of study therapy during ixabepilone or paclitaxel treatment phase)
- Number of Participants With Dose Delay and Reason for Dose Delay for Ixabepilone/Paclitaxel(12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel))
- On-Study Renal Function: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase(prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy during ixabepilone or paclitaxel treatment phase)
- Number of Participants by Dose for Ixabepilone/Paclitaxel(12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel))
- Number of Participants With Course Delay and Reason for Delay for AC(12 weeks (4 3-week cycles))
- Reason for First Dose Reduction of Ixabepilone/Paclitaxel(12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel))