Combination Chemotherapy, Cetuximab and Radiation for Patients With Localized Gastric Cancer

Integration of Cetuximab, in Combination With Local Radiotherapy, in Perioperative Chemotherapy of Resectable and Locally Advanced Gastric Cancer. A Pilot Phase Ib-trial

Outcome of EXPAND study (no benefit from adding cetuximab to the first-line chemotherapy in advanced gastric cancer in the overall patient population)

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.

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 OUTLINE: Prospective, multicenter, open-label dose escalating phase Ib trial During induction chemo-immuno-therapy, patients receive cetuximab IV over 1-2 hours on days 1, cisplatin IV over 1 hour on day 1 and capecitabine twice daily per os from the evening of day 1 to the morning of day 15. Treatment repeats every 3 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Radiotherapy will start after the end of the third cycle of chemotherapy and be performed concomitantly with weekly cetuximab and cisplatin. Cohorts of 3-6 patients receive escalating doses of radiotherapy (levels of 36/39.6/45 Gy) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which maximum 3 of 12 patients experience dose-limiting toxicity. Gastric resection should be performed within 4-6 weeks after completion of neoadjuvant treatment. 4-6 weeks after surgery, a further 3 cycles of chemo-immuno-therapy will be administered if the patient has recovered from surgery and the treatment is considered as feasible by the investigator. For note: Cisplatin may be replaced by oxaliplatin during induction chemotherapy and postoperative chemotherapy. In case if oxaliplatin is used to replace cisplatin during induction chemotherapy, replacement of cisplatin by oxaliplatin during radio-chemo-immunotherapy may also be considered by the investigator. Capecitabine may be replaced by infusional 5-FU on day 1-5 every 21 days in case of contraindications to capecitabine. In case if both cisplatin and capecitabine are to be replaced, 4 cycles of FOLFOX-6 (d-l leucovorin, followed by 5-FU bolus and a continuous infusion of over 46 hours every 2 weeks should be administered in combination with cetuximab). Patients undergo tumor tissue and blood sample collection periodically for biological studies. Samples are analyzed for major histopathological response. After completion of study treatment, patients are followed periodically for at least 5 years.

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.

Induction chemotherapy: Cetuximab 400mg/m2 (loading dose) on day 1 Cetuximab 250mg/m2 weekly thereafter Followed by: Cetuximab 250mg/m2 weekly on day 1 during chemoradiation Postoperative treatment: 3 cycles of Cetuximab 250mg/m2 weekly on day 1

Induction chemotherapy: Capecitabine 1000mg/m2 twice daily from the evening of day 1 to the morning of day 15 within each 3 weeks cycle Postoperative treatment: Capecitabine 1000mg/m2 twice daily from the evening of day 1 to the morning of day 15 within each 3 weeks cycle

Induction chemotherapy: Cisplatin 80mg/m2 on day 1 of each 21 day cycle Followed by: Cisplatin 30mg/m2 weekly on day 1 during chemoradiation Postoperative treatment: Cisplatin 80mg/m2 on day 1 of each 21 day cycle

Patients will be evaluated for dose limiting toxicities until four weeks after combined radio-chemo-immunotherapy

Defined as completion of preoperative therapy (including surgery in patients with initially resectable tumors) and being alive 30 days postoperatively.

Inclusion Criteria: 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 Exclusion Criteria: 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