| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Localised unresectable adenocarcinoma or squamous cell carcinoma of the oesophagus without any prior chemotherapy, surgery, or radiotherapy |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| 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 |
| To assess the efficacy of durvalumab (MEDI4736), initially in combination with radiochemotherapy (FOLFOX and IMRT) and then as maintenance therapy for treating patients with localised unresectable oesophageal cancer, in terms of PFS (centrally reviewed; cPFS). |
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| E.2.2 | Secondary objectives of the trial |
To assess the efficacy in terms of local PFS.
To assess the efficacy in terms of overall survival.
To evaluate the safety and tolerance of the study treatments.
To evaluate the quality of life.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ancillary studies :
- Tissue: Biomarkers to predict response to treatment (central pathology review).
- Study of gut microbiota to determine if intestinal bacteria are predictive of tumour response.
- Blood samples: Proteomic analysis to identify biomarkers of response to radiochemotherapy +/- anti-PD-L1 (durvalumab). |
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| E.3 | Principal inclusion criteria |
1. Histologically proven squamous cell carcinoma or adenocarcinoma of the oesophagus,
2. Unresectable disease due to anatomical consideration or medical condition,
3. Presence of at least one measurable lesion >10 mm with spiral CT scan,
4. Age ≥18 years old,
5. WHO performance status <2 (i.e., 0 or 1),
6. Body weight >35 kg,
7. Life expectancy of at least 12 weeks ,
8. Adequate haematology laboratory data within the 7 days before randomization
a. Absolute neutrophils >1.5 x 109/L
b. Platelets >100 x 109/L
c. Haemoglobin ≥9 g/dL,
9. Adequate Biochemistry laboratory data within the 7 days before randomization
a. Total bilirubin ≤1.5 x upper limit of normal (ULN)
b. Transaminases ≤2.5 x ULN
c. Alkaline phosphatases ≤5 x ULN,
d. Measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL >40 mL/min by the Cockcroft-Gault formula,
e. Glycaemia ≤1.5 x ULN
f. Cholesterolaemia ≤7.30 mmol/L,
g. Albumin >28 g/L
10. Adequate haemostasis laboratory data within 7 days prior to randomization: prothrombin time (PT) within the normal range,
11. Women should be post-menopaused or willing to accept the use an effective contraceptive regimen during the treatment period and for at least 6 months after the end of the study. All non-menopausal women should have a negative pregnancy test within 72 h prior to randomization. Men should accept to use an effective contraception during treatment period and at least 3 months after the end of the study.
12. Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses,
13. Patient affiliated to a social security regimen. |
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| E.4 | Principal exclusion criteria |
1. Previous treatment with another PD-1, PD-L1 including durvalumab or CTLA-4 inhibitor
2. Metastatic disease,
3. No prior therapy for pathology investigated including chemotherapy or radiotherapy prior to the study, except anterior out of field radiotherapy, received for treatment of another primary tumor considered in remission,
4. Patients should not receive live vaccine 30 days prior to study drug
5. Female patients who are pregnant or breastfeeding
6. Uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, pulmonary failure, chronic renal or hepatic diseases, active peptic ulcer disease or gastritis, active bleeding, diatheses... (non-exhaustive list),
7. Clinically significant cardiac disease or impaired cardiac function, such as:
a. Congestive heart failure requiring treatment (New York Heart Association [NYHA] grade ≥2), left ventricular ejection fraction (LVEF) <50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO), or uncontrolled arterial hypertension defined by blood pressure >140/100 mmHg at rest (average of 3 consecutive readings),
b. History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high- grade/complete AV-blockage,
c. Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), <3 months prior to screening,
d. MeanQT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s Correction.
8. Current or prior use of immunosuppressive medication within 28 days before the first administration of durvalumab (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) - Topical, inhaled, nasal, and ophthalmic steroids are allowed,
9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
a. Patients with vitiligo or alopecia
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stabilised with hormone replacement therapy
c. Any chronic skin condition that does not require systemic therapy
d. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
e. Patients with coeliac disease controlled by diet alone
10. Known primary immunodeficiency or active HIV,
11. Patient with a dihydropyrimidine dehydrogenase (DPD) deficiency (the test should be done for all patients before 5-FU administration)* ,
12. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive HBS antibody test for hepatitis B or hepatitis C virus ribonucleic acid (HCV antibody),
13. History of organ transplantation requiring the use of immunosuppressive medication,
14. History of active tuberculosis or latent disease capable of reactivation,
15. Current pneumonitis or interstitial lung disease,
16. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only,
17. History of severe allergic reactions or hypersensitivity to any unknown allergens or any components of the study drug (refer to IB of durvalumab section 5.4.2.2).
18. Any prior corticosteroid-refractory immune-related adverse event (irAE),
19. Oeso-tracheal or oeso-bronchial fistulae,
20. Participation in another therapeutic trial within the 30 days prior to study inclusion,
21. Patients deprived of liberty or under guardianship,
22. Patients unable to adhere to the protocol for geographical, social, or psychological reasons.
* As per the ANSM’s recommendations the risk of not testing DPD in patient before being administered 5-FU (See Appendices 6 to 9) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is defined by a blinded independent centralized revue of progression free survival. cPFS is defined as the time from randomization until progression or death; patients alive and without documented progression at last follow-up news have PFS censored at this date or at initiation of new anticancer treatment (if applicable). Progression will be defined with central external reviewing of TDM per RECIST criteria 1.1, (see appendix 2). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
PFS is defined at the time from randomization until disease progression or death; patients alive without progression at last follow up will be censored at this date.
Overall survival (OS): OS is defined as the time between randomization and death due to any cause. Patients still alive at the time of analysis (including those lost to follow up) will be censored at the last date that they were known to be alive.
Safety will be evaluated using NCI CTCAE v5.0 (see Appendix 3).
Quality of life: EORTC QLQ C30 and Oes18.
Ancillary studies:
- To determine whether the expression level of cytoplasmic peri-tumoral and tumoral PD-L1, macrophages and TILs predicts response to treatment (central reviewing CHU Toulouse).
- Study of gut microbiota to determine if baseline intestinal bacteria correlates with tumor response
- Blood for proteomic analysis comparing long term responder after radiochemotherapy with anti-PD-L1 (durvalumab) to non-responder to identify biomarkers. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 12 |
| 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 | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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