Kurzfassung

This is a multicencer, randomized, controlled, open-label study including patients with locally advanced adenocarcinoma of the stomach and GEJ scheduled to receive perioperative chemotherapy.
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 evaluate safety and tolerability. Patients with locally advanced esophagogastric adenocarcinoma (i.e. cT2 any N or any T N-positive) with exclusion of distant...This is a multicencer, randomized, controlled, open-label study including patients with locally advanced adenocarcinoma of the stomach and GEJ scheduled to receive perioperative chemotherapy.
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 evaluate 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 centrally reviewed and then stratified by tumor site (GEJ vs. gastric), histological type (intestinal vs. diffuse/mixed or unknown) and clinical stage (T1/2 vs. T3/4 and/or N+) and randomized 1:1 to receive either FLOT (Arm A) or FLOT/ramucirumab (Arm B).
Arm A (FLOT):
Patients randomized to Arm A will receive 4 per-operative cycles (8 weeks) of biweekly FLOT (docetaxel 50mg/m² in 250ml NaCl 0.9% iv over 1 h; oxaliplatin 85 mg/m² in 500 ml G5% iv over 2 h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9% iv over 30 min; 5-FU 2600 mg/m² over 24 h, q2wk) of the peroperative treatment phase. Surgery in Arm A is planned to occur 4-6 weeks after d1 of last FLOT. Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT in the post-operative treatment phase. Post-operative treatment should start 6-8 weeks, but at maximum 12 weeks after surgery.
Arm B (FLOT/ramucirumab):
Patients randomized to Arm B will receive ramucirumab 8mg/kg iv over 60 min in combination with the FLOT regimen, which is administered identical to Arm A as described above. Surgery in Arm B is planned to occur 4-6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after last d1 of FLOT/ramucirumab dose). Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT/ramucirumab in the post-operative treatment phase followed by a total of 16 cycles of ramucirumab as a monotherapy (q2wk), starting 2 weeks after d1 of the last cycle of FLOT/ramucirumab.
In both of the arms, tumor assessments (CT or MRT) are performed before randomization and prior to surgery, and then every 3 months thereafter until progression/relapse, death or end of follow-up. A change from CT into MRI in the follow-up period is possible at any time.
During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/ramucirumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.
When the recruitment of the phase II portion is completed, the primary end point of the phase II portion will be analyzed, along with all relevant safety outcome measures. A continuation to phase III will be recommended if the phase II portion observes  a positive efficacy signal in terms of pCR/pSR rates, and if FLOT/ramucirumab is shown to be feasible  and is not associated with relevant increase in postsurgical morbidity or mortality.
If decided to continue the trial into phase III and this is confirmed and accepted by Lilly Deutschland GmbH, further efficacy  endpoints will not be analyzed at this time. The transition into phase III will be performed via an amendment of the study protocol, considering a new sample size calculation taking into account the results of the FLOT4. For the phase III part, additional centers on representative parts of the world will be recruited. The phase II/III design is not alpha-spending. In case of continuation, only pathological response and safety will be analyzed at the end of the phase II portion. All other efficacy parameters such as OS, PFS etc. will not be analyzed. Therefore, alpha-level for the primary endpoint of phase III which is OS will not be affected by the phase II/III design and is at p=0.05.» weiterlesen» einklappen