Study Title: Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric Cancer

NCT03399071 | Unknown Phase 2 DMC

• 1 other identifier: 4557
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

A single centre phase II trial of peri-operative chemo-immunotherapy in operable gastro-oesophageal adenocarcinoma (GOA). This trial is designed to evaluate the safety and efficacy of administering Avelumab, an anti-PD-L1 monoclonal antibody, with cytotoxic FLOT chemotherapy for patients with operable GOA treated according to a peri-operative protocol. This trial is in 2 stages: the first stage will establish the safe and tolerated maximum administered dose (MAD) of Avelumab in combination with FLOT and the second stage will assess the efficacy of this combination therapy in achieving pathological complete response (pCR) and peri-operative safety.

Conditions

Gastric Adenocarcinoma; Oesophageal Adenocarcinoma

Keywords

Gastric cancer; Oesophageal cancer; Gastro-oesophageal cancer; Perioperative; Immunotherapy; Anti PDL1; Avelumab; FLOT

Outcome Measures

Primary Outcomes (1)

• Pathological complete response rate of combination FLOT-A

  The primary objective is to assess the efficacy of FLOT-A in the peri-operative setting in patients with operable GOAs. We aim to increase the pCR rate after peri-operative treatment from 10% (minimum expected path CR rate for peri-operative FLOT chemotherapy), to a superior pCR rate of \>25%, by adding Avelumab to FLOT. Complete histopathologic response is defined by no vital tumour cells neither in the oesophagus, the stomach nor in the regional lymph nodes. In cases of residual tumour, the response assessment will follow criteria described by Mandard et al.

  Within 2 years of study opening

Secondary Outcomes (4)

• Number of participants with grade 3 or 4 treatment-related adverse events as assessed by CTCAE v4.0

  Within 2 years

• Radiological response rate using RECIST 1.1 criteria

  Within 3 years

• Median progression free survival by Kaplan Meir method

  Within 5 years

• Median overall survival by Kaplan Meir method

  Within 5 years

Study Arms (1)

FLOT plus Avelumab (FLOT-A)

EXPERIMENTAL

Avelumab 10mg/kg (or Maximum Administered Dose established in safety run-in) iv infusion over 1 hour. Followed by FLOT: Oxaliplatin 85mg/m2 iv infusion day 1 over 2 hours, Folinic acid 200mg/m2 iv infusion day 1 over 2 hours, Docetaxel 50mg/m2 iv day 1 over 1 hour, Fluorouracil 2600mg/m2 over 24 hours iv

Drug: FLOT-A

Interventions

FLOT-A DRUG

This is a single-arm study with all patients receiving combination FLOT-A

FLOT plus Avelumab (FLOT-A)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male/female patients aged ≥18 years
• Histologically confirmed gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as gastro-oesophageal adenocarcinoma (GOA) in this protocol).
• Oesophageal and gastric tumours should be TNM7 stage T1-4 and N0-N2, with no evidence of distant metastases (M0) where the MDT believes that an R0 resection can be achieved after pre-operative chemotherapy.
• Absence of distant metastases on CT scan and PET scan and staging laparoscopy (where indicated) prior to study entry
• No prior therapy for GOA
• Considered fit for surgery by surgical/anaesthetic team
• Adequate bone marrow function:
• Absolute neutrophil count (ANC) \>1.5x10-9/L
• White blood count \>3x10-9/L
• Platelets ≥100x10-9/L
• Haemoglobin (Hb) \>9g/dL (can be post-transfusion)
• Adequate renal function: Creatinine Clearance of \>50ml/min or measured EDTA Clearance of ≥50ml/min. If the calculated Creatinine Clearance is \<60ml/min then a measured EDTA Clearance is required. If available, the EDTA Clearance should always take precedence over the Creatinine Clearance.
• Adequate liver function
• Serum bilirubin \<22 umol/L
• ALT/AST ≤2.5x ULN

You may not qualify if:

• Any contraindication or known hypersensitivity reaction to any of the study drugs, or components of Folinic acid, Oxaliplatin, 5FU or Docetaxel
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma)
• If known dihydropyrimidine dehydrogenase (DPD) deficiency, patients must be deemed safe to receive appropriate dose-adjusted 5-FU according to the identified mutation.
• Patients who have received anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Patients recommended to have radiotherapy as part of routine management for their GOA are ineligible
• Any immunodeficiency disorder
• Any active autoimmune disease that has required systemic treatment in the past 2 years (i.e, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or is expected to deteriorate when receiving avelumab, with the following exceptions:
• Patients only receiving hormone replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy (doses ≤10mg - or equivalent - of prednisolone per day) for adrenal or pituitary insufficiency) are eligible.
• Patients with vitiligo or psoriasis not requiring immunosuppressive treatment are eligible
• Patients requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement
• Administration of steroids through a route known to result in minimal systemic exposure (topical, intranasal intra-ocular, or inhalation) are acceptable. Steroids as pre-medication for hypersensitivity reactions e.g. CT contrast are also acceptable
• Prior organ transplantation, including allogeneic stem-cell transplantation
• History of inflammatory bowel disease with the following exception:
• Patients with a history of ulcerative colitis who have had a colectomy are eligible

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (1)

The Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Related Publications (1)

• Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore). 2022 May 27;101(21):e29304. doi: 10.1097/MD.0000000000029304.

  PMID: 35623069 DERIVED

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus; Stomach Neoplasms; Esophageal Neoplasms

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases

Study Officials

• Marco Gerlinger, MD, FRCP

  The Royal Marsden NHSFT

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All patients will receive chemo-immunotherapy consisting of FLOT chemotherapy and the PD-L1 inhibiting monoclonal antibody Avelumab. Four cycles of two-weekly chemo-immunotherapy will be administered before surgery and four further cycles post-operatively in patients who are fit enough to receive further chemo-immunotherapy after surgery. Resectional surgery will take place 4-8 weeks following the last dose of chemo-immunotherapy in patients who remain fit.

Study Record Dates

• First Submitted: November 16, 2017
• First Posted: January 16, 2018
• Study Start: July 31, 2017
• Primary Completion: November 1, 2022
• Study Completion: August 15, 2025
• Last Updated: February 21, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)