FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of HER-2 Expressing Gastric or GEJ Cancer
Condition: Stomach Cancer; Gastroesophageal Junction Cancer
MeSH terms: Stomach Neoplasms
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.

      Arm B (Herceptin/pertuzumab group) Patients randomized to Arm B will receive the FLOT regimen
      identical to Arm A as described above in conjunction with three-weekly Herceptin at 8mg/kg
      initial dose (Day 1, loading dose) followed by subsequent doses of Herceptin at 6mg/kg on d22
      and d43 and pertuzumab at 840mg on d1, d22, and d43. Surgery is recommended to occur 4 weeks
      after last FLOT/Herceptin/pertuzumab dose (4 weeks after d43 = day 71). Patients will receive
      3 additional doses of Herceptin and pertuzumab on d1, d22, and d43 of the post-operative
      treatment phase, together with the postoperative chemotherapy. Moreover, patients will
      receive 11 additional doses of Herceptin and pertuzumab after the end of post-operative FLOT.

      In both of the arms, tumor assessments (CT or MRI) are performed before randomization and
      prior to surgery and then every 3 months thereafter until progression/relapse, death or end
      of follow-up.

      During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to
      every treatment dose. Safety of FLOT/Herceptin/pertuzumab will be monitored continuously by
      careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.
    

Intervention name(s): FLOT alone; FLOT + Herceptin/Pertuzumab
Intervention type(s): Drug; Biological
Intervention description(s): Pre-operative therapy:
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43
Surgery is recommended to be scheduled 4 weeks after d43.
Post-operative therapy (start 6 to 8 weeks after surgery):
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43; Pre-operative therapy:
Herceptin 8/6 mg/kg, d1, d22, d43
Pertuzumab 840 mg, d1, d22, d43
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43
Surgery is recommended to be scheduled 4 weeks after d43.
Post-operative therapy (start 6 to 8 weeks after surgery):
Herceptin 8/6 mg/kg, d1, d22, d43
Pertuzumab 840 mg, d1, d22, d43
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43.
Intervention MeSH terms: Trastuzumab; Pertuzumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment