Gastric Adenocarcinoma, Oesophageal Adenocarcinoma
Conditions
Keywords
Gastric cancer, Oesophageal cancer, Gastro-oesophageal cancer, Perioperative, Immunotherapy, Anti PDL1, Avelumab, FLOT
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.
Detailed description
Patients will receive chemo-immunotherapy consisting of FLOT chemotherapy (Folinic acid 200mg/m2 iv infusion day 1, Oxaliplatin 85mg/m2 iv infusion day 1, Docetaxel 50mg/m2 iv day 1, Fluorouracil 2600mg/m2 over 24 hours iv) and the PD-L1 inhibiting monoclonal antibody Avelumab. The safe dose of Avelumab in combination with FLOT will be established in a safety run-in phase with a standard 3+3 design, starting with the recommended dose of 10mg/kg iv Avelumab (dose level 0) in which a dose reduction to 7mg/kg iv (dose level -1) may occur. 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 Objectives: To evaluate the safety, efficacy and toxicities and to explore biomarkers of peri-operative chemo-immunotherapy with Avelumab and FLOT.
Interventions
DRUGFLOT-A
This is a single-arm study with all patients receiving combination FLOT-A
Sponsors
Merck KGaA, Darmstadt, Germany
Royal Marsden NHS Foundation Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male/female patients aged ≥18 years 2. Histologically confirmed gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as gastro-oesophageal adenocarcinoma (GOA) in this protocol). 3. 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. 4. Absence of distant metastases on CT scan and PET scan and staging laparoscopy (where indicated) prior to study entry 5. No prior therapy for GOA 6. Considered fit for surgery by surgical/anaesthetic team 7. 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) 8. 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. 9. Adequate liver function * Serum bilirubin \<22 umol/L * ALT/AST ≤2.5x ULN 10. Adequate coagulation profile * International Normalised Ratio (INR) \< 1.5 * Activated Prothrombin Time (APTT) \< 1.5xULN 11. Patients on oral anticoagulation are advised to change to low molecular weight heparin prior to study entry, to be eligible 12. ECOG performance status 0 or 1 13. Body Mass Index (BMI) ≤30 14. Patient is fit to undergo all protocol investigations and receive all protocol treatment based on the assessment in the surgical and oncology clinics. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrolment. 15. Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans
Exclusion criteria
Patients are not eligible for the trial if any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response rate of combination FLOT-A | Within 2 years of study opening | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with grade 3 or 4 treatment-related adverse events as assessed by CTCAE v4.0 | Within 2 years | Safety of peri-operative FLOT-A will be assessed by summarising grade 3-4 toxicity and DLT rates as proportions. |
| Radiological response rate using RECIST 1.1 criteria | Within 3 years | Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria. Radiological tumour response before surgery will be defined as partial response or complete response. |
| Median progression free survival by Kaplan Meir method | Within 5 years | PFS will be summarised using Kaplan Meier methods, presenting median survival with 95% confidence intervals. PFS is defined as time from registration to clinical/radiological progression or death from any cause. Patients event free at time of analysis will be censored at last follow-up date. |
| Median overall survival by Kaplan Meir method | Within 5 years | OS will be summarised using Kaplan Meier method, presenting median survival with 95% confidence intervals. OS is defined as time from registration to date of death of any cause. Patients event free at time of analysis will be censored at last follow-up date. |
Countries
United Kingdom
Outcome results
None listed