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

• Status: Recruiting
• Trial end date: 2025-08-15
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Merck KGaA; Merck KGaA, Darmstadt, Germany

Criteria

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 T1-3 and N0-N2, with no evidence of distant metastases (M0) where the MDT believes that an R0 resection can be achieved at the outset. T4 tumours will be excluded due to the variable need to prolong pre-operative chemotherapy or chemo-radiotherapy as part of locally advanced protocol to reduce margin involvement and improve resectability.

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 exclusion criteria below are met:

1. Any contraindication or known hypersensitivity reaction to any of the study drugs, or components of Folinic acid, Oxaliplatin, 5FU or Docetaxel

2. 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)

3. Known dihydropyrimidine dehydrogenase (DPD) deficiency

4. Patients who have received chemotherapy, radiotherapy or immunotherapy for a previous malignancy

5. Any previous malignancy, with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer

6. Patients recommended to have radiotherapy as part of routine management for their GOA are ineligible

7. Any immunodeficiency disorder

8. Any active, known or suspected autoimmune disease that might deteriorate when receiving immunostimulatory agent, with the following exceptions:

• Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease 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 and at doses ≤10mg (or equivalent) of prednisolone per day

• Administration of steroids through a route known to result in minimal systemic exposure (topical, intranasal intra-ocular, or inhalation) are acceptable

9. Prior organ transplantation, including allogeneic stem-cell transplantation

10. History of inflammatory bowel disease

11. Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis

12. Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the previous year

13. Cardiovascular diseases as follows:

• Myocardial infarction within the previous year

• Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia, supraventricular tachycardia or atrial fibrillation with a resting heart rate > 110bpm)

• Unstable angina

• Congestive cardiac arrhythmia (New York Heart Association Classification Class II or above)

14. Current signs or symptoms of any other severe progressive or uncontrolled hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease other than directly related to gastro-oesophageal adenocarcinoma, which in the opinion of the investigator, might impair the subject's tolerance of trial treatment or procedures.

15. Major surgery, major trauma or open biopsy within 28 days prior to registration (not including staging laparoscopy)

16. Evidence of bleeding diathesis or coagulopathy

17. Active non-healing wound, ulcer or bone fracture requiring therapy

18. Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection

19. Known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)

20. Use of live attenuated vaccine within 28 days of initiation of study therapy, or anticipation that a live attenuated vaccine will be required during the study

21. Pregnancy/of child bearing potential. Pregnancy must be excluded with a negative serum pregnancy test, within 7 days before initiation of therapy, if the risk of conception exists. Sexually active female patients must be surgically sterile or be postmenopausal or must agree to use highly effective contraception. Sexually active male patients must be surgically sterile or must agree to use highly effective contraception, i.e. methods with a failure rate of <1% per year (see section 5.4 for full definition and examples of highly effective contraception).

22. Lactation- breast-feeding is contraindicated and must be discontinued for the duration of the trial and for up to 6 months afterwards.

23. Any patient specific factors which are likely to interfere with compliance of trial specific procedures or treatment.