Integration of Cetuximab, in Combination With Local Radiotherapy, in Perioperative Chemotherapy of Resectable and Locally Advanced Gastric Cancer. A Pilot Phase Ib-trial
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Dose limiting toxicity
研究概览
简要总结
RATIONALE: Radiotherapy is currently the most efficient way to induce pathologic responses, which are associated with a favorable prognosis in localized tumors. Novel radiotherapy techniques are associated with significantly less toxicity than traditional radiation protocols and permit to avoid the toxicity to adjacent organs. Established chemotherapy regimens, such as cisplatin and capecitabine, and monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Giving radiation therapy together with cisplatin and cetuximab before surgery aims to induce a pathological response and improve the prognosis after surgery.
PURPOSE: This phase I trial is studying the side effects and best dose of radiation therapy when given together with cisplatin and cetuximab in treating patients who are undergoing surgery for locally advanced gastric cancer.
详细描述
OBJECTIVES:
Primary
• To determine the maximum tolerated dose of radio-chemo-immunotherapy - in patients with localized or locally advanced gastric cancer
Secondary
- To determine the efficacy, as measured by major histopathological response rates (tumor regression grade 1 and 2)
- Metabolic response
- Secondary resectability
- R-0 resection rate
- Surgical morbidity
- Toxicity
- Overall survival
- Time to local and systemic progression after R0-resection
- Feasibility
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically proven, localized (UICC stage I-II, T1-2, N1-2 or T3N0) or locally advanced (UICC stage III, T3-4, N+) gastric or Siewert Type II and III GE-junction adenocarcinoma. Tumor stage is determined by thoraco-abdominal CT-scan, EUS, as well as mandatory laparoscopy to rule out peritoneal carcinomatosis within 28 days prior to registration.
- •ECOG-status 0-1
- •Hematologic, liver, and renal function normal
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during and for 12 months after completion of study treatment
排除标准
- •Peritoneal carcinomatosis, as diagnosed by mandatory laparoscopy or distant metastasis
- •Concurrent treatment with other experimental drugs or other anti-cancer therapy, or treatment within a clinical trial within 30 days prior to trial entry
- •Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, no myocardial infarction within the last 12 months, unstable angina pectoris, or significant arrhythmia)
- •Active or uncontrolled infection.
- •Definitive contraindications for the use of corticosteroids as premedication
- •Prior systemic (chemo- or targeted) treatment. Prior radiotherapy to the upper abdomen
- •Any contraindication to treatment with cetuximab, capecitabine or cisplatin
- •Any concomitant medication which is contraindicated for use with the trial drugs, such as sorivudin or brivudin
- •HER-2 over expression, as determined by immunohistochemistry (IHC 3+) or the combination of IHC and FISH (IHC 2+/FISH+)
- •Previous malignancy within 5 years, with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
- •Known hypersensitivity against any of the study drugs (cetuximab, cisplatin or capecitabine) or any component of the trial drugs
- •Known deficit of dihydropyrimidine dehydrogenase
- •Pre-existing peripheral neuropathy > grade I
- •Due to known interactions of coumarin antagonists (e.g. warfarin) and capecitabine patients requiring oral anticoagulation should be included in the study only after a switch from oral anticoagulation to low molecular weight heparin
研究组 & 干预措施
Cetuximab, capecitabine, cisplatin based chemoradiation
Induction chemotherapy:
3 cycles (of 3 weeks) with capecitabine, cisplatin and weekly cetuximab: Cetuximab 400mg/m2 (loading dose)on day 1 and 250mg/m2 weekly thereafter, Cisplatin 80mg/m2 on day 1 every three weeks, Capecitabine 1000mg/m2 twice daily from the evening of day 1 to the morning of day 15 within each 3 weeks cycle.
Followed by:
Radio-chemo-immunotherapy:
Cetuximab 250mg/m2 weekly on day 1, Cisplatin 30mg/m2 weekly on day 1, Radiotherapy (dose escalation levels) 36/39.6/45 Gy(according to dose level) in 5 fractions of 1.8 Gy per week
Surgery:
Will be performed 4-6 weeks after neoadjuvant radiochemotherapy
Postoperative treatment:
3 cycles of Chemo-immunotherapy with cetuximab, cisplatin and capecitabine -as described above- will be administered postoperatively if the patient has recovered adequately from surgery and the treatment is considered as feasible by the investigator.
干预措施: Cetuximab (Biological)
Cetuximab, capecitabine, cisplatin based chemoradiation
Induction chemotherapy:
3 cycles (of 3 weeks) with capecitabine, cisplatin and weekly cetuximab: Cetuximab 400mg/m2 (loading dose)on day 1 and 250mg/m2 weekly thereafter, Cisplatin 80mg/m2 on day 1 every three weeks, Capecitabine 1000mg/m2 twice daily from the evening of day 1 to the morning of day 15 within each 3 weeks cycle.
Followed by:
Radio-chemo-immunotherapy:
Cetuximab 250mg/m2 weekly on day 1, Cisplatin 30mg/m2 weekly on day 1, Radiotherapy (dose escalation levels) 36/39.6/45 Gy(according to dose level) in 5 fractions of 1.8 Gy per week
Surgery:
Will be performed 4-6 weeks after neoadjuvant radiochemotherapy
Postoperative treatment:
3 cycles of Chemo-immunotherapy with cetuximab, cisplatin and capecitabine -as described above- will be administered postoperatively if the patient has recovered adequately from surgery and the treatment is considered as feasible by the investigator.
干预措施: Capecitabine (Drug)
Cetuximab, capecitabine, cisplatin based chemoradiation
Induction chemotherapy:
3 cycles (of 3 weeks) with capecitabine, cisplatin and weekly cetuximab: Cetuximab 400mg/m2 (loading dose)on day 1 and 250mg/m2 weekly thereafter, Cisplatin 80mg/m2 on day 1 every three weeks, Capecitabine 1000mg/m2 twice daily from the evening of day 1 to the morning of day 15 within each 3 weeks cycle.
Followed by:
Radio-chemo-immunotherapy:
Cetuximab 250mg/m2 weekly on day 1, Cisplatin 30mg/m2 weekly on day 1, Radiotherapy (dose escalation levels) 36/39.6/45 Gy(according to dose level) in 5 fractions of 1.8 Gy per week
Surgery:
Will be performed 4-6 weeks after neoadjuvant radiochemotherapy
Postoperative treatment:
3 cycles of Chemo-immunotherapy with cetuximab, cisplatin and capecitabine -as described above- will be administered postoperatively if the patient has recovered adequately from surgery and the treatment is considered as feasible by the investigator.
干预措施: Cisplatin (Drug)
结局指标
主要结局
Dose limiting toxicity
时间窗: Patients will be evaluated for dose limiting toxicities until four weeks after combined radio-chemo-immunotherapy
次要结局
- Metabolic response(After 6 weeks of chemo-immunotherapy)
- Secondary resectability(Decided by a multidisciplinary team 3-5 weeks after the end of neoadjuvant treatment)
- Major histopathological response rate(at surgery 4-6 weeks after end of neoadjuvant therapy)
- R-0 resection rate(at surgery 4-6 weeks after the end of neoadjuvant therapy)
- Surgical morbidity(within 30 days after surgery)
- Overall survival(Measured by median, 1-, 2-, and 3- year survival rates)
- Time to local and systemic progression after R0-resection(5 years after completion of the trial treatement)
- Feasibility(Defined as completion of preoperative therapy (including surgery in patients with initially resectable tumors) and being alive 30 days postoperatively.)
- Toxicity (according to NCI-CTCAE, Version 4.0)(Within 30 days after completion of the trial treatement)
研究者
Dr Anna Dorothea Wagner
Médecin associée
Centre Hospitalier Universitaire Vaudois