A Randomized Phase II Study of Preoperative Cisplatin Versus Paclitaxel in Patients With Triple Negative Breast Cancer: Evaluating the Homologous Recombination Deficiency (HRD) Biomarker
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 147
- 试验地点
- 20
- 主要终点
- Number of Participants With Pathologic Response by HR-deficiency (HRD) Status
研究概览
简要总结
This is a phase II study randomizing patients with stage I with T1 > 1.5 cm, stage II or III triple negative breast cancer (TNBC) to preoperative cisplatin versus paclitaxel. The study is designed to evaluate the ability of the Homologous Recombination Deficiency (HRD) assay to predict pathologic response to preoperative chemotherapy.
详细描述
Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response (residual cancer burden (RCB)-0/1) to singleagent cisplatin or paclitaxel.
This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score >=33. Crossover to an alternative chemotherapy was offered if there was inadequate response.
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
- •Participants must meet the following criteria on screening examination to be eligible to participate in the study
- •Pathologic documentation of invasive breast cancer by biopsy (FNA alone is not adequate).
- •AJCC clinical stage I with T1 > 1.5 cm, stage II or III invasive breast cancer.
- •Participants with multicentric or bilateral disease are eligible if at least one lesion meets stage eligibility criteria for the study and no tumor is HER2-positive.
- •Tumors must be HER2 negative defined as HER2 0 or 1+ by immunohistochemistry (IHC) assays and /or lack of gene amplification by FISH defined as a ratio < 2 on invasive tumor by local review.
- •ER and PgR status by IHC must be known. Tumor must be ER and PR negative (≤5% staining) by local review.
- •Known BRCA1/2 (BReast CAncer) status is not required for study entry. However patients known to have a germline deleterious BRCA1/2 mutation should be encouraged to consider a preoperative trial specifically designed for BRCA1/2 carriers, if available.
- •Breast imaging should include imaging of the ipsilateral axilla. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to confirm the presence of metastatic disease in the lymph nodes.
- •For patients with a clinically negative axilla, baseline assessment of the axilla will be performed at the discretion of the treating investigator.
- •For patients with pathologically positive axillary lymph nodes prior to preoperative therapy, a level I and II lymph node dissection at the time of definitive surgery is recommended.
- •Patients with a prior history of contra-lateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer within the last 5 years.
- •Women ≥ 18 years of age.
- •ECOG performance status ≤1 (see Appendix A).
- •Laboratory Evaluation
- •Absolute neutrophil count (ANC) ≥ 1,500 / mm3
- •Platelet count ≥ 100,000/ mm3
- •Bilirubin ≤ 1.5x upper limit of normal (ULN), for patients with Gilbert syndrome, direct bilirubin will be measured instead of total bilirubin
- •ALT, AST ≤3.0 x ULN ALK Phos <2.5 x ULN
- •Creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min
- •Hemoglobin ≥ 9 mg/dl
- •Use of an effective means of contraception is required in subjects of childbearing potential since study agents are known to be teratogenic. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
- •Ability to understand and the willingness to sign a written informed consent document
- •Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy and did not receive prior chemotherapy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
- •Patient must be willing to undergo mandatory research biopsy and blood draw. Prior to biopsy procedures patients must be able to be off medications that could increase the risk of bleeding
排除标准
- •Participants with axillary adenopathy only are not eligible for this study.
- •Prior chemotherapy: Prior non-taxane or platinum containing chemotherapy will be allowed if the prior exposure was at least 5 years ago and the exposure is thought not to potentially interact with the primary outcome of the trial or put the patient at undue risk, and should be reviewed with study PI on a case by case basis.
- •Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.
- •Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for DCIS or breast conserving treatment and hormonal therapy for DCIS or invasive breast cancer.
- •Ongoing use of any other investigational or study agents.
- •Peripheral neuropathy of any etiology > grade 1 (NCI CTCAE Version 4.0- Appendix B)
- •Significant hearing loss that would prevent cisplatin administration.
- •Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin dose modification (i.e., Cre > 1.5 mg/dl or GFR < 60 cc/min).
研究组 & 干预措施
Arm A: Cisplatin
Cisplatin given by IV infusion at a dose of 75 mg/m2 every 3 weeks (1 cycle) for 4 cycles as preoperative chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to crossover to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy.
干预措施: Cisplatin (Drug)
Arm B: Paclitaxel
Paclitaxel given by IV infusion at a dose of 80 mg/m2 weekly for 12 weeks (4 cycles) as neoadjuvant chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to 'crossover' to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Number of Participants With Pathologic Response by HR-deficiency (HRD) Status
时间窗: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33.
次要结局
- Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status(Evaluated after definitive breast surgery, up to 4-5 months from enrollment.)
- Positive Predictive Value (PPV) of HRD Score(Evaluated after definitive breast surgery, up to 4-5 months from enrollment.)
- Number of Pathologic Response(Evaluated after definitive breast surgery, up to 4-5 months from enrollment.)
- Number With Pathologic Response(Evaluated after definitive breast surgery, up to 4-5 months from enrollment.)
研究者
Erica Mayer, MD, MPH
Principal Invesitigator
Dana-Farber Cancer Institute