| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Oesophago-gastric adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the oesophagus or stomach |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Primary endpoint: Progression-free survival (PFS)
In the HER-2 negative patients the PFS will be compared between the standard arm (A1) and capecitabine maintenance (A2) and then separately between standard arm (A1) and MEDI4736 maintenance (A3). Arms A2 and A3 will not be compared to each other.
In the HER-2 positive patients PFS will be compared between the two arms (B1 and B2). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary endpoints:
All secondary endpoints will be compared between groups as described above for the primary endpoint.
• Progression-free rate (PFR: SD or better) at 12 weeks, 6 months and 1 year
• Overall survival (OS)
• Objective response rate (ORR) by RECIST 1.1
• Analysis of efficacy endpoints (PFS, PFR, OS and ORR) will also be conducted according to biomarker status in relevant trial arms. In HER-2 negative patients outcomes in Arm A1 and Arm A3 will be compared according to PD-L1 expression status assessed by IHC (positive vs negative). In HER-2 positive patients Arms B1 and B2 will be compared according to Heregulin status on RT-PCR testing of tumour tissue (high vs low).
• Toxicity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction, or stomach.
• Completion of at least 6 cycles of first-line chemotherapy for locally advanced / metastatic disease (this must have included a platinum and fluoropyrimidine in all cases; HER-2 positive patients must have received trastuzumab alongside chemotherapy) with > stable disease on the end of treatment CT scan.
• Disease which, following first-line chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy.
• Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy.
• Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis.
• Uni-dimensionally measurable disease (CT or MRI as per RECIST).
• Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease.
• No prior radiotherapy in the advanced disease setting. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator.
• Male/female patients aged ≥18 years.
• WHO Performance status 0, 1 or 2.
• Patients should have a projected life expectancy of at least 3 months.
• Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be post-transfusion).
• Adequate renal function: calculated creatinine clearance ≥50ml/minute.
• Adequate liver function: serum bilirubin ≤1.5x ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present).
• Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 60 days following the last dose of assigned study drug(s).
• Written informed consent must be obtained from the patient before any study-specific procedures are performed.
|
|
| E.4 | Principal exclusion criteria |
• Concurrent enrolment in another clinical trial unless it is an observational (non-interventional) clinical study.
• Tumours of squamous histology.
• Documented brain metastases, central nervous system metastases or leptomeningeal disease.
• Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other anti-neoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be < grade 2 according to NCI CTCAE version 4.0.
• Any major surgery within 4 weeks prior to the start of study treatment.
• Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg).
• Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior history of clinically significant cardiac failure are excluded from study entry.
• History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
• Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
• Patients who are pregnant or lactating.
• Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection.
• Other clinically significant disease or co-morbidity which may adversely affect the safe delivery of treatment within this trial.
• Any other malignancies within the last 3 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
• Treatment with another investigational agent within 30 days of commencing study treatment.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival (PFS). The PFS will be calculated from the date of randomisation to the date of disease progression according to RECIST 1.1 criteria or death from any cause, whichever occurs first. Progression events will be determined by local investigator assessment. Patients lost to follow up or who remain alive without disease progression at the time of analysis will be censored at the date of last follow up.
In the HER-2 negative patients the PFS will be compared between the standard arm (A1) and capecitabine maintenance (A2) and then separately between standard arm (A1) and MEDI4736 maintenance (A3). Arms A2 and A3 will not be compared to each other.
In the HER-2 positive patients PFS will be compared between the two arms (B1 and B2). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint is progression-free survival (PFS). The PFS will be calculated from the date of randomisation to the date of disease progression according to RECIST 1.1 criteria or death from any cause, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
To evaluate the effects of maintenance therapies on the following:
• Progression-free rate (SD or better) at 12 weeks, 6 months and 1 year
• Overall survival (OS)
• Objective response rate (ORR) by RECIST 1.1
• Analysis of efficacy endpoints (PFS, PFR, OS and ORR) will also be conducted according to biomarker status in relevant trial arms. In HER-2 negative patients outcomes in Arm A1 and Arm A3 will be compared according to PD-L1 expression status assessed by IHC (positive vs negative). In HER-2 positive patients Arms B1 and B2 will be compared according to Heregulin status on RT-PCR testing of tumour tissue (high vs low).
• Toxicity
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Progression-free rate (defined as SD, PR or CR) at 12 weeks, 6 months and 1 year
• Overall survival-date of randomisation until the date of death. Patients who remain alive at the time of the analysis will be censored at the date of last follow up.
•Analysis of efficacy endpoints and toxicity will be ongoing.
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Surveillance only in the HER-2 negative pts. Single agent trastuzumab in the HER-2 positive pts. |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 90 |
| 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
|
| In order to allow significant events to occur for evaluation of secondary endpoints such as OS, the ‘end of study’ for the purposes of the European Clinical Trials Directive will be defined as one year after the last patient has had their last active study treatment. The sponsor will inform the MHRA and REC within 90 days of the ‘end of trial’ that the trial has closed, and will ensure that the final trial report is submitted within 12 months of this notification. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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