| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Operable oesophageal and gastric cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancers arising from the oesophagus or the stomach that the doctor thinks can be operated on |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
There are two parts to the trial: the first is the 'safety run-in' phase and the second is the 'main phase' or 'efficacy phase'. Each of these has different principal research objectives:
- The 'safety run-in' phase will establish the safe and tolerated dose of Avelumab in combination with FOLFOX in the first 6 to 12 patients entered into the trial. This so called 'maximum administered dose' will then be used for all subsequent patients entered into the main phase.
-The 'main phase' will assess the efficacy of FOLFOX-A in the peri-operative setting in patients with operable GOAs. We aim to increase the pathologic complete response rate from currently <5% with standard peri-operative chemotherapy to 20% with FOLFOX in combination with Avelumab. This would be an important achievement as patients who achieve a pathologic complete response with peri-operative therapy tend to have a better prognosis and are at much lower risk for subsequent distant disease recurrence. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of peri-operative FOLFOX-A
• To assess further efficacy measures including:
- pathological regression grading
- R0 resection rate (i.e. complete removal of the cancer at the time of surgery)
- Progression free survival
- Overall survival
- Radiological responses in the pre-operative phase
• To perform translational research analysis that may identify candidate predictive biomarkers, drug resistance mechanisms and biological rationals for more effective furture therapies |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
i. Histologically confirmed gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as gastro-oesophageal adenocarcinoma (GOA) in this protocol).
ii. 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.
iii. Absence of distant metastases on CT scan and PET scan and staging laparoscopy (where indicated) prior to study entry
iv. No prior therapy for GOA
v. Adequate cardio-pulmonary reserve as assessed by: Supervised Incremental Shuttle Walk threshold > 350 metres, or formal CPET testing with an anaerobic threshold ≥9 mls/min/kg.
vi. 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)
viii. Adequate renal function: glomerular filtration rate (GFR) ≥30ml/min calculated (as per local practice) or measured. If the calculated GFR is <60ml/min then a measured GFR is required. The measured GFR should always take precedence over the calculated GFR
ix. Adequate liver function
• Serum bilirubin ≤1.5x ULN
• ALT/AST ≤2.5x ULN
x. Adequate coagulation profile
• International Normalised Ratio (INR) < 1.5
• Activated Prothrombin Time (APTT) < 1.5xULN
xi. Patients on oral anticoagulation are advised to change to low molecular weight heparin prior to study entry, to be eligible
xii. ECOG performance status 0 or 1
xiii. BMI ≤35
xiv. Patient is fit to undergo all protocol investigations and receive all protocol treatment based on the assessment in the surgical and oncology clinics
xv. Male/female patients aged ≥18 years
xvi. 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.
xvii. Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans |
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| E.4 | Principal exclusion criteria |
Patients are not eligible for the trial if any of the exclusion criteria below are met:
i. Any contraindication or known hypersensitivity reaction to any of the study drugs, or components of Folinic acid, Oxaliplatin, or 5FU
ii. 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)
iii. Known dihydropyrimidine dehydrogenase (DPD) deficiency
iv. Patients who have received chemotherapy, radiotherapy or immunotherapy for a previous malignancy
v. Any previous malignancy, with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
vi. Patients recommended to have radiotherapy as part of routine management for their GOA are ineligible
vii. Any immunodeficiency disorder
viii. 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
ix. Prior organ transplantation, including allogeneic stem-cell transplantation
x. History of inflammatory bowel disease
xi. Patients with a history of interstitial lung disease or radiological evidence of pulmonary fibrosis
xii. Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within the previous year
xiii. 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)
xiv. 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.
xv. Major surgery, major trauma or open biopsy within 28 days prior to registration (not including staging laparoscopy)
xvi. Evidence of bleeding diathesis or coagulopathy
xvii. Active non-healing wound, ulcer or bone fracture requiring therapy
xviii. Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection
xix. Known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)
xx. 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
xxi. Pregnancy must be excluded with a negative serum pregnancy test, within 7 days before initiation of therapy. Female patients must be surgically sterile or be postmenopausal or must agree to use highly effective contraception. Male patients must be surgically sterile or must agree to use highly effective contraception, defined as methods with a failure rate of <1% per year
xxii. Any patient specific factors which are likely to interfere with compliance of trial specific procedures or treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety run-in phase: The primary endpoint for the safety run-in phase will be to establish the maximum administered dose (MAD) of Avelumab in combination with FOLFOX that will be recommended for use in the main phase of the trial.
Main (efficacy) phase: The primary endpoint is the pathologic complete response rate (pCR rate).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety run in:
Once 6-12 patients have been treated, each for at least 28 days. We anticipate this part to complete within 6 months.
Main efficacy phase:
Once 38 patients have been treated at the dose level recommended in the safety run in phase and have undergone surgery. This phase is expected to complete within 2 years |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
1) Safety of peri-operative FOLFOX-A in patients with operable gastro-oesophageal adenocarcinoma
2) To assess further efficacy measures including:
- Mandard pathological regression grading assessed in the resection specimen
- Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria, additional radiological response criteria may also be applied
- R0 resection rate
- PFS
- OS
- Heterogeneity of regression grading of the primary cancer in comparison to lymph node metastatic cancer
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The following endpoints will be reported after ~2 y, when 38 patients have undergone surgery:
-Safety of peri-operative FOLFOX-A in patients with operable gastro-oesophageal adenocarcinoma
-Mandard pathological regression grading assessed in the resection specimen
-Radiological response rate assessed at the pre-operative scan using RECIST 1.1 criteria, additional radiological response criteria may also be applied
-R0 resection rate
-Heterogeneity of regression grading of the primary cancer in comparison to lymph node metastatic cancer
Survival endpoints will be reported as 1 year and 2 year PFS/OS, approximately 3 and 4 y after study start. Kaplan Meier analysed will be performed once sufficient events have occurred and when the last patient had the last follow visit (~y 7).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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