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Adenocarcinoma

Stomach Neoplasms

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Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

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Docetaxel

Oxaliplatin

Atezolizumab

Leucovorin

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Folic Acid

Vitamin B Complex

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Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Folate

Vitamin B9

Patients randomized to treatment Arm A will receive atezolizumab (840 mg IV over 1 hour) + FLOT in four 2-week treatment cycles prior to undergoing surgery. Following surgery, patients will receive four further 2-week cycles of atezolizumab + FLOT followed by 8 additional 3-week treatment cycles with atezolizumab alone (maintenance setting: 1,200 mg q3w). FLOT can be deescalated to FLO, FLT or FL in case of chemorelated toxicity at any time and at the discretion of investigator.

Patients randomized to Arm B will receive FLOT alone for four 2-week treatment cycles prior to surgery. Following surgery, patients will receive four further 2-week cycles of chemotherapy alone. FLOT can be deescalated to FLO, FLT or FL in case of chemo-related toxicity at any time and at the discretion of investigator. Docetaxel 50 mg/m², d1 Oxaliplatin 85 mg/m², d1 Calciumfolinat 200 mg/m², d1 5-Fluorouracil 2600 mg/m², d1

Day 1 q2w: 840 mg IV over 1 hour (4 cycles perioperative with FLOT) + Day 1 q3w: 1200 mg IV over 1 hour (8 additional cycles monotherapy)

5-Fluorouracil

Calciumfolinat

Thorsten Goetze, Prof.

Christina Kopp

Thorsten Goetze, Prof

Salah-Eddin Al-Batran, Prof

Mara Kern

Salah-Eddin Al-Batran, Prof.

This is a multicenter, randomized, controlled, open-label study comparing perioperative atezolizumab with FLOT chemotherapy versus FLOT alone in patients with locally advanced, operable adenocarcinoma of the stomach or GEJ with high immune responsiveness.

The study will evaluate the safety and efficacy of the study treatment regimens. Potential study participants will be assessed for eligibility during a 28-day screening period that includes central verification of clinical stage and eligibility. Only immune-competent patients with either of the following MSI-high, PD-L1 CPS≥1, TMB ≥10/MB or EBV+ will be enrolled. Eligible patients will be randomized to perioperative treatment with either atezolizumab with FLOT (Arm A) or FLOT alone (Arm B). Randomization will occur in a 1:1 ratio with stratification by clinical nodal stage (N+ vs. N-), location of the primary (GEJ type I vs. GEJ type II/III vs. stomach), and PD-L1-status (CPS≥5 vs. CPS\<5). MSI testing will also be performed but not used as stratification factor.

Following randomization, study patients will enter the study treatment period which will last approximately 22 to 52 weeks depending on treatment arm and timing of surgery.

Arm A: FLOT with Atezolizumab:

Patients randomized to treatment Arm A will receive atezolizumab + FLOT in four 2-week treatment cycles as described below prior to undergoing surgery. Following surgery, patients will receive four further 2-week cycles of atezolizumab + FLOT followed by 8 additional 3-week treatment cycles with atezolizumab alone.

Arm B: FLOT alone:

Patients randomized to Arm B will receive FLOT alone for four 2-week treatment cycles prior to surgery. Following surgery, patients will receive four further 2-week cycles of chemotherapy alone.

Study of Atezolizumab + FLOT vs. FLOT Alone in Patients With GC/GEJ and High Immune Responsiveness

A Randomized, Open-label Phase II/III Efficacy and Safety Study of Atezolizumab in Combination With FLOT Versus FLOT Alone in Patients With Gastric Cancer and Adenocarcinoma of the Oesophago-gastric Junction and High Immune Responsiveness (MO30039/MO43340) - The DANTE Trial

Prevalence of detectable ctDNA in patients after curative surgery

Cumulative incidence of ctDNA clearance (on treatment) compared between arms

to compare Event free survival (EFS) in patients with locally advanced, operable esophagogastric adenocarcinoma receiving perioperative FLOT with atezolizumab versus FLOT alone in the intent to treat population (ITT) and where EFS is defined as the time from randomization to disease progression or relapse after surgery or death from any cause

Pathological complete regression (pCR, TRG 1a by Becker) rate where pCR is defined as the absence of residual tumor based on evaluation of the resected esophagogastric specimen in the primary by a central reference pathologist

Pathological complete and subtotal regression (TRG1a/b by Becker). TRG1a/b is defined as \< 10% residual tumor per tumor bed based on evaluation of the resected esophagogastric specimen in the primary by a central reference pathologist.

R0 resection rate where R0 resection is defined as a microscopically margin negative resection with no gross or microscopic tumor remains in the areas of the primary tumor and/or sampled regional lymph nodes based on evaluation by the local pathologist.

Overall survival (OS) where OS is defined as the time from randomization to death from any cause

Overall survival (OS) where OS is defined as the time from randomization to death from any cause and EFS, where EFS is defined as the time from randomization to disease progression or relapse after surgery or death from any cause, both compared between the specific subgroups

Roche Pharma AG

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Ramucirumab

Angiogenesis Inhibitors

Growth Inhibitors

Pre-operative therapy with FLOT followed by surgical resection followed by post-operative therapy with FLOT

* Docetaxel 50 mg/m², d1
* Oxaliplatin 85 mg/m², d1
* Calciumfolinat 200 mg/m², d1
* 5-Fluorouracil 2600 mg/m², d1

Pre-operative therapy with FLOT + ramucirumab followed by surgical resection followed by post-operative therapy with FLOT + ramucirumab

* Ramucirumab 8mg/kg, d1
* Docetaxel 50 mg/m², d1
* Oxaliplatin 85 mg/m², d1
* Calciumfolinat 200 mg/m², d1
* 5-Fluorouracil 2600 mg/m², d1

Salah-Eddin Al-Batran, Prof. Dr.

Previous studies provide a strong theoretical rationale for the conduct of a randomized study evaluating the efficacy and safety of ramucirumab in combination with FLOT in the perioperative treatment of resectable adenocarcinoma of the stomach or GEJ.

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.

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 pre-operative cycles (8 weeks) of biweekly FLOT (Docetaxel 50 mg/m² in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m², iv over 24 h, q2wk) of the preoperative treatment phase. Surgery in Arm A is planned to occur 4 to 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 to 8 weeks, but at maximum 12 weeks after surgery.

Arm B (FLOT/ramucirumab) Patients randomized to Arm B will receive ramucirumab 8mg/kg i.v. 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 to 6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after d1 of last 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 MRI) 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.

FLOT vs. FLOT/Ramucirumab for Perioperative Therapy of Gastric or GEJ Cancer (RAMSES)

Perioperative RAMucirumab in Combination With FLOT Versus FLOT Alone for reSEctable eSophagogastric Adenocarcinoma - RAMSES - a Phase II/III Trial of the AIO

Survival rates for the different time points will be determined using the Kaplan-Meier analysis of OS.

Survival rates for the different time points will be determined using the Kaplan-Meier analysis of PFS

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Atezolizumab + FLOT vs. FLOT Alone in Patients With GC/GEJ and High Immune Responsiveness	NCT03421288	Gastric Cancer Gastroesophagea...	Atezolizumab 5-Fluorouracil Calciumfolinat Oxaliplatin Docetaxel	18 Years -	Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
FLOT vs. FLOT/Ramucirumab for Perioperative Therapy of Gastric or GEJ Cancer (RAMSES)	NCT02661971	Stomach Cancer Gastroesophagea...	Docetaxel Oxaliplatin Calciumfolinat 5-Fluorouracil Ramucirumab	18 Years - 70 Years	Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
FLOT vs. FLOT/Ramucirumab for Perioperative Therapy of Gastric or GEJ Cancer (RAMSES)	NCT02661971	Stomach Cancer Gastroesophagea...	Docetaxel Oxaliplatin Calciumfolinat 5-Fluorouracil Ramucirumab	18 Years - 70 Years	Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

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