| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| T1-T2N0 esophageal adenocarcinoma including gastroesophageal junction (GEJ) with indication for radical surgery |
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| E.1.1.1 | Medical condition in easily understood language |
| Early stage esophageal cancer |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030137 |
| E.1.2 | Term | Oesophageal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| 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) |
|
| 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 |
| Assessment of the treatment efficacy of the combination of durvalumab and chemoradiation as organ preservative treatment option avoiding mortality and surgical complications with rate of clinical and pathological complete response (cCR/pCR) at time of endoscopic re-evaluation |
|
| E.2.2 | Secondary objectives of the trial |
Assessment of the 1-/2- and 3-year cCR/pCR rate
Assesment of the rate of salvage surgery
Assessment of the 90-day and 1-year mortality
Assessment ofs the quality of life (QoL)
Assessment of the safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient* has given written informed consent.
2. Patient is, in the investigator’s judgement, willing and able to comply with the study protocol including the planned surgical treatment.
3. Patient is ≥ 18 years of age at time of signing the written informed consent.
4. Patient has been diagnosed with histologically confirmed esophageal adenocarcinoma (including gastroesophageal junction (GEJ) (Siewert I-III)) with:
a. cT2 N0 M0 stage or T1 N0 M0 stage and a given indication for radical surgical resection to current S3-guidelines (this includes patients with a given indication for radical surgery after endoscopic-resection of a cT1-2 N0 M0 tumor [poor grading or L1/V1 invasion or basal R1 resection or deep submucosal infiltration]).
b. tumor is considered medically and technically resectable.
5. Tumor is tested centrally (with validated assays, e.g., Dako PD-L1 IHC 22C3 or 28-8) for PD-L1 according to combined positive score (CPS) and results must be available prior study enrollment. In addition, a representative tumor specimen that is suitable for central determination of PD-L1 TPS and MSI status is available. The analysis requires paraffin embedded biopsy samples of the tumor to be provided to the Sponsor.
6. The indication for preoperative radiochemotherapy is given.
7. Patient has not received prior cytotoxic or targeted therapy.
8. Patient has not had a prior complete esophagogastric tumor resection.
9. Patient has a ECOG ≤ 1.
10. Patient must have life expectancy of at least 12 weeks
11. Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last study treatment if it is in the core treatment phase or for at least 3 months after last study treatment occurred in the maintenance phase. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
12. Patient has a body weight > 30 kg
13. Patient has adequate hematological, hepatic and renal function as indicated by the following parameters:
a. Leukocytes ≥ 3,000/µL, platelets ≥ 100,000/µL without transfusion, absolute neutrophil count (ANC) ≥ 1,500/µL without granulocyte colony-stimulating factor support, hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this criterion.
b. Bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate transaminase and alanine transaminase ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN
c. Serum creatinine ≤ 1.5 x ULN, or glomerular filtration rate > 45 mL/min (calculated using the Cockcroft-Gault formula)
d. Serum albumin ≥ 25 g/L (2.5 g/dL)
e. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen
14. Patient has no human immunodeficiency virus (HIV) infection. NOTE: Patient with infection is eligible if he/she meets all the following criteria:
a. CD4 count is ≥350 cells/µL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications
b. Probable long-term survival with HIV if cancer were not present
c. Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study
d. HIV is not multi-drug resistant
e. Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication |
|
| E.4 | Principal exclusion criteria |
1.Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein
2.Patient has any known contraindication (including hypersensitivity) to docetaxel, 5-FU, leucovorin (calcium folinate), or oxaliplatin. In cases of pernicious anemia or other anemias due to vitamin B 12 deficiency, folinic acid (Leucovorin) is contraindicated and trial inclusion is not possible or only possible after compensation the anaemic status.
3.Patient has a known dihydropyrimidine dehydrogenase (DPD) deficiency
4.Patient has active or history of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
5.Patient had a prior allogeneic bone marrow transplantation or prior solid organ transplantation
6.Patient has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
7.Patient has active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to enrollment) or hepatitis C infection
8.Patient has active tuberculosis.
9.Patient has uncontrolled tumor-related pain (Patients requiring pain medication must be on a stable regimen at study entry.)
10.Patient received an administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 30 days after the last dose of durvalumab.
11.Patient had a prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibodies.
12.Patient had a treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment.
13.Patient had a treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed
a.Intranasal, inhaled, topical steroids or local steroid injections
b.Systemic corticosteroids at physiologic dose not to exceed 10mg/day of prednisone or its equivalent
c.Steroids as premedication for hypersensitivity reactions
14.Patient has a significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina.
15.Patient has a clinically significant valvular defect.
16.Patient has a history of malignancy other than EGA within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
17.Patient has peripheral polyneuropathy ≥ NCI CTCAE grade 2.
18.Patient has uncontrolled or symptomatic hypercalcemia.
19.Patient has a serious infection requiring oral or IV antibiotics within 14 days prior to study enrollment.
20.Patient has chronic inflammatory bowel disease.
21.Patient has clinically significant active gastrointestinal bleeding.
22.Patient underwent major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment.
23.Patient has evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results.
24.Patient participated in another interventional clinical study ≤ 30 days prior to study enrollment or participation in such a study at the same time as this study.
25.Patient has taken an investigational drug within 28 days prior to initiation of study drug.
26.Female patients, who are pregnant or breast feeding or planning to become pregnant within and 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of clinical and pathological complete response rate at time of endoscopic re-evaluation (at the end of the core study treatment) according to Becker criteria and investigator-based RECIST v1.1 assessment as well as endoscopic response criteria similar to the Japanese Gastric Cancer Association Guideline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At time of endoscopic re-evaluation (at the end of the core study treatment) |
|
| E.5.2 | Secondary end point(s) |
Rate of cCR/pCR at 1, 2 and 3 years after start of treatment (long term follow up)
Subgroup analysis of cCR/pCR rate at time of endoscopic re-evaluation and after 1 year according to following characteristics: MSI high, PD-L1 CPS>1 and PD-L1 CPS>5 and especially acc. to CPS ≥10 or <10
Rate of salvage surgery
90-day as well as 1-year mortality after start of treatment in non-surgery population and population with salvage surgery
Determination of the sites of tumor relapse
Incidence of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs)
Severity of adverse events by CTCAE v5.0 grade
Relationship of adverse events to the durvalumab, chemotherapy and/or radiation
Frequency of clinically significant abnormal laboratory parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Rate of cCR/pCR: 1, 2 and 3 years after start of treatment
Subgroup analysis of cCR/pCR rate: time of endoscopic re-evaluation and after 1 year
Mortality: 90 days and 1 year after start of treatment
Rate of salvage surgery, Sites of tumor relapse, Toxicity: continuously |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 25 |
| 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
|
| The global end of this trial is defined as the date of database closure to ensure the collection of survival data of patients and the active involvement of sites in the data cleaning process (e.g., addition source data may be requested or an additional monitoring visit may be necessary). |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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