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About
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.
Full 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.
Enrollment
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Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
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:
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
Adequate coagulation profile
Patients on oral anticoagulation are advised to change to low molecular weight heparin prior to study entry, to be eligible
ECOG performance status 0 or 1
Body Mass Index (BMI) ≤30
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.
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:
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:
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
Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis
Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the previous year
Cardiovascular diseases as follows:
Other severe acute or chronic medical conditions or psychiatric conditions including recent (within the past year) active suicidal ideation or behaviour
Current signs or symptoms of any other severe progressive or uncontrolled hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease other than directly related to gastrooesophageal adenocarcinoma, which in the opinion of the investigator,might impair the subject's tolerance of trial treatment or procedures.
Major surgery, major trauma or open biopsy within 28 days prior to registration (not including staging laparoscopy)
Evidence of bleeding diathesis or coagulopathy
Active infection requiring systemic therapy, non-healing wound, ulcer or bone fracture requiring therapy
Known positive tests for human immunodeficiency virus (HIV) infection
Active Hepatitis A, B or C infection. If there is a previous history of Hepatitis infection which has been treated and cleared, there must be evidence that disease is not currently active.
Known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)
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
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). Lactation- breast-feeding is contraindicated and must be discontinued for the duration of the trial and for at least 1 month afterward the last dose of Avelumab.
Any patient specific factors which are likely to interfere with compliance of trial specific procedures or treatment.
Primary purpose
Allocation
Interventional model
Masking
44 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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