FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of Adenocarcinoma of the Stomach and Gastroesophageal Junction Expressing HER-2. A Phase II/III Trial of the AIO.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 81
- 试验地点
- 1
- 主要终点
- PhaseII: Rate of pathological complete response
研究概览
简要总结
Previous studies provide a strong theoretical rationale for the conduct of a randomized study evaluating the efficacy and safety of Herceptin and pertuzumab in combination with FLOT in the perioperative treatment of resectable HER-2 positive adenocarcinoma of the stomach or GEJ.
详细描述
This is a multicenter, randomized, controlled, open-label study including patients with locally advanced adenocarcinoma of the stomach and GEJ scheduled to receive perioperative chemotherapy. According to centrally assessed HER-2 status: Patients with HER-2 positive tumors will receive FLOT +/- Herceptin / pertuzumab.
The scope of the phase II portion of the trial is to evaluate pathological response rates of either regimen assessed by a centralized pathology and define safety and tolerability.
Patients with locally advanced esophagogastric adenocarcinoma (i.e. cT2 any N or any T N-positive) with exclusion of distant metastases will be included in this trial.
Patients will be stratified by age (18-69 vs. ≥ 70), tumor site (GEJ vs. gastric) and clinical stage (T1/2 vs. 3/4 and N- vs. N+) and randomized 1:1 to receive either FLOT (Arm A) or FLOT/Herceptin/pertuzumab (Arm B).
Arm A (control group) Patients randomized to Arm A will receive 4 pre-operative treatments of FLOT (Docetaxel 50 mg/m², iv over 2 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9 %, iv over 1 h; 5-FU 2600 mg/m², iv over 24 h) on d1, d15, d29, d43 of the preoperative treatment phase. Surgery is recommended to occur 4 weeks after last FLOT (4 weeks after d43 = day 71). Patients will receive 4 additional post-operative treatments of FLOT on d1, d15, d29, and d43 of the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed adenocarcinoma of the GEJ (type I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:
- •Medical and technical operability
- •Centralized detection of either an adenocarcinoma with HER-2 3+ (IHC) or HER-2 2+ (IHC) with amplification proven by FISH, SISH or CISH
- •No preceding cytotoxic or targeted therapy
- •No prior partial or complete tumor resection
- •Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
- •Exclusion of distant metastasis by CT or MRI of thorax and abdomen, and bone scan (if osseous lesions are suspected due to clinical signs)
- •Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of pertuzumab and Herceptin treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
- •Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
- •Adequate haematological, hepatic and renal function parameters:
- •Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3
- •Serum creatinine ≤ 1.5 x upper limit of normal, or GFR > 40 ml/min
- •Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.5 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
- •LVEF value > 55 %, as assessed by echocardiography
- •Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
排除标准
- •Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
- •Known hypersensitivity against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
- •Other known contraindications against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
- •Documented history of congestive heart failure of any NYHA, myocardial infarction within the past 6 months before the first dose of study treatment
- •Clinically significant valvular defect , history of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHG or diastolic blood pressure > 100 mmHg) or uncontrollable high-risk cardiac arrhythmia (i.e tachycardia with a heart rate > 100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher grade atrioventricular-block (second degree AV-block Type 2 (Mobitz2) or third degree AV-block)
- •Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
- •Known brain metastases
- •Other severe internal disease or acute infection
- •Peripheral polyneuropathy ≥ NCI Grade II
- •Chronic inflammatory bowel disease
- •Clinically significant active GI bleeding
- •On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
- •Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
- •Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
- •Any other concurrent antineoplastic treatment including irradiation
研究组 & 干预措施
FLOT alone
Pre-operative therapy with FLOT followed by surgical resection followed by post-operative therapy with FLOT
干预措施: FLOT alone (Drug)
FLOT + Herceptin/Pertuzumab
Pre-operative therapy with FLOT + Herceptin/Pertuzumab followed by surgical resection followed by post-operative therapy with FLOT + Herceptin/Pertuzumab
干预措施: FLOT + Herceptin/Pertuzumab (Biological)
结局指标
主要结局
PhaseII: Rate of pathological complete response
时间窗: 3 years
Phase III: Median Progression Free Survival
时间窗: 5 years
次要结局
- Phase II/III: Median Overall Survival(3/5 years)
- Phase III: Median OS(5 years)
- Phase II/III: R0 resection rate(75 days)
- Phase II: PK Analysis(3 years)
- Phase II/III: Subgroup analyses: pathological response according to HER-2 status HER-2 IHC 3+ vs. other cases(3/5 years)
- Phase III: Pathological Response Rates(5 years)
- Phase III: PFS rates(3 and 5 years)
- Phase III: OS rates(3 and 5 years)
- Phase II: Median Progression Free Survival (PFS)(3 years)
- Phase II/III: Subgroup analyses: PFS according to HER-2 status HER-2 IHC 3+ vs. other cases(3/5 years)
- Phase II/III: Subgroup analyses: OS according to HER-2 status HER-2 IHC 3+ vs. other cases(3/5 years)