A Randomized, Double-blind, Placebo-controlled, Phase III Study of Neoadjuvant-Adjuvant Durvalumab and FLOT Chemotherapy Followed by Adjuvant Durvalumab or Placebo in Patients with Resectable Gastric and Gastroesophageal Cancer (GC/GEJC) (MATTERHORN)

Neoadjuvant-adjuvant or adjuvant alone chemotherapy are a standard component of
resectable gastric cancer and gastroesophageal junction cancer (GC/GEJC)
treatment. The currently recommended chemotherapies have had a positive impact
on the survival of patients with resectable GC/GEJC; however, the recurrence
rate within 5 years after surgery remains high and the 5-year overall survival
(OS) rate remains poor, especially in Western countries. Therefore, there is a
significant unmet medical need in resectable GC/GEJC and a novel therapy is
globally required.

The combination of immune checkpoint inhibitors (PD-L1/PD-1) and platinum-based
chemotherapy has shown significant anti-tumor activity in multiple tumor types
and has become a standard of care in first-line NSCLC. Durvalumab is a human
monoclonal antibody (mAb) of the IgG immunoglobulin G (IgG) 1* subclass that
inhibits binding of PD-L1 to PD-1 and cluster of differentiation (CD)80. It is
considered that the combination of durvalumab with neoadjuvant-adjuvant FLOT
chemotherapy (fluorouracil [5-FU] + leucovorin + oxaliplatin + docetaxel),
commonly used in Western countries, may result in a significant improvement in
clinical outcomes in patients with resectable GC/GEJC.

Therefore, this study will evaluate neoadjuvant-adjuvant treatment with
durvalumab in combination with FLOT (Arm A) compared to placebo in combination
with FLOT (Arm B) in patients with resectable GC/GEJC.

This study has been transitioned to CTIS with ID 2023-507338-26-00 check the CTIS register for the current data.

Primary objective:
To compare Arm A relative to Arm B on event-free survival (EFS)

Key secondary objectives:
- To compare Arm A relative to Arm B on overall survival (OS)
- To compare Arm A relative to Arm B on pathological complete response (pCR)
rate

This is a randomized, double-blind, placebo-controlled, multicenter, global
Phase III study to assess the efficacy and safety of neoadjuvant-adjuvant
durvalumab in combination with FLOT chemotherapy followed by adjuvant
durvalumab monotherapy in patients with resectable GC/GEJC (ie, radical-surgery
eligible; >T2 N0-3 M0 or T0-4 N1-3 M0, per AJCC 8th edition).

Patients will be randomized in a 1:1 ratio to each of the following treatment
arms:
- Treatment Arm A: durvalumab 1500 mg on Day 1 + FLOT on Days 1 and 15 Q4W for
4 cycles (2 cycles neoadjuvant + 2 cycles adjuvant) followed by durvalumab 1500
mg on Day 1 Q4W for 10 additional cycles
- Treatment Arm B: placebo on Day 1 + FLOT on Days 1 and 15 Q4W for 4 cycles
(2 cycles neoadjuvant + 2 cycles adjuvant) followed by placebo on Day 1 Q4W for
10 additional cycles

Patients will be randomized in a 1:1 ratio to each of the following treatment
arms:

- Treatment Arm A: durvalumab 1500 mg on Day 1 + FLOT on Days 1 and 15 Q4W for
4 cycles (2 cycles neoadjuvant + 2 cycles adjuvant) followed by durvalumab 1500
mg on Day 1 Q4W for 10 additional cycles
- Treatment Arm B: placebo on Day 1 + FLOT on Days 1 and 15 Q4W for 4 cycles
(2 cycles neoadjuvant + 2 cycles adjuvant) followed by placebo on Day 1 Q4W for
10 additional cycles


Patients will be stratified according to:
- geographic region (Asia vs non-Asia)
- clinical lymph node status (positive vs negative)
- PD-L1 expression status (TIP >=1% vs TIP <1%)

Tumor sample should be collected during screening to determine the PD-L1
expression status.

Patients are subject to the following assessments throughout the study:
- Anamnesis (at screening, including medical history)
- Physical examination
- ECOG performance status
- Vital functions (blood pressure, heart rate, body temperature and respiratory
rhythm)
- Body weight measurement
- CT/MRI scan
- ECG
- blood - and urine examination
- questionnaires (in hospital using a tablet) (EORTC QLQ-C30, EORTC QLQ-STO22,
EORTC IL38, EQ-5D-5L, PRO-CTCAE, PGIC, PGIS,
PGI-TT).
- pregnancy test when applicable
- AE/SAE assessment
- IP administration
- biopsy (new biopsy or <3 months old)

The side effects of durvalumab can range from mild to severe or in some cases
even life-threatening. Conditions have been built into the study to identify as
early as possible the side effects that can be serious.

Very common (seen in more than 1 in 10 people):
Fatigue/tiredness, diarrhea, rash/dry itchy skin, liver problems, nausea,
vomiting and abdominal pain, oedema, upper respiratory tract infections,
decreased appetite, shortness of breath, cough, pain in muscles and joints,
fever.

Common (seen in more than 1 in 100 people):
Pneumonitis, colitis, low or high thyroid (hypothyroidism or hyperthyroidism),
kidney injury, nervous system problems, infusion related reactions and allergic
reactions, pneumonia, influenza, hoarse voice, painful urination, night sweats,
oral thrush, dental infections, soft tissue infections.

Moreover, the study procedures could also have risks:
- pain or bruises through collection of blood/tumor biopsy
- rash through ECG stickers
- health risks through radiation of CT-scan/MRI