E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
oesophageal squamous cell carcinoma and oeasophageal adenocarcinoma |
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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] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061534 |
E.1.2 | Term | Oesophageal squamous cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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) |
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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 |
The primary objective of the trial is to assess the feasibility and the safety of the addition of immunotherapy with PD-1 antibody nivolumab +/- CTLA-4 antibody ipilimumab to concomitant chemoradiotherapy in inoperable patients with early or locally advanced oesophageal cancer and to select the more promising experimental arm among the two possible combinations in terms of activity (based on PFS at 12 months according to RECIST v1.1) for further evaluation in a phase III trial. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives will aim to evaluate progression-free survival, failure-free survival and overall survival and pattern first cause of progression (including incidence of distance metastasis). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Histologically proven oesophageal squamous cell carcinoma or adenocarcinoma
•Both early stage and locally advanced tumor patients (according to TNM staging version 8):
•Any stage III or any stage IVA
•Stage IIA and IIB, only if not operable after complete work up
•If squamous cell carcinoma, T1 N1 M0, only if not operable after complete work up
•Patient eligible for definitive chemoradiation and not considered for primary surgery after multidisciplinary meeting decision or patient refuses to undergo surgery
•Prior surgery, other than surgery for primary tumor, is allowed if completed at least 4 weeks before randomization
•Subject must be previously untreated with systemic treatment given as primary therapy for advanced or metastatic disease
•At least one measurable lesion by CT scan or MRI based on RECIST version 1.1 with radiographic tumor assessment performed within 28 days prior to randomization
•Availability of adequate tissue for immunohistochemical staining
•Age ≥ 18 years
•WHO performance status 0 or 1
•Adequate organ function within 14 days prior to randomization:
•White blood cell (WBC) count ≥ 2.0 x 109/L (≥ 2000 per mm3)
•Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm3)
•Platelet count ≥ 100 x 109/L (≥ 100,000 per mm3)
•Hemoglobin ≥ 9.0 g/dL (≥ 5.59 mmol/l)
•Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN
•AST (SGOT) and ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
•Lipase < 2.0 x the ULN and no radiologic or clinical evidence of pancreatitis
•Potassium within normal ranges as per local lab values
•Measured/calculated creatinine clearance ≥ 60 mL/min (according to Cockroft-Gault, appendix H);
•International Normalized Ratio (INR) and/or Prothrombin Time (PT) and additionally Partial Thromboplastin Time (PTT) must be within the normal ranges as per institution's standard.
Note: Patients receiving anticoagulant therapy (have to be shifted to Low molecular weight heparin (LMWH) before treatment start; as Warfarin and related 4-hydroxycoumarin-containing molecules are not permitted) are eligible if their PTT and PT or INR is within the recommended range for the desired level of anticoagulation.
•Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to randomization.
Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.
•Patients of childbearing / reproductive potential should use highly effective birth control measures, during the study treatment period and for at least 5 months for a woman and 7 months for a man after the last study treatment.
Note:
A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
-Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
-Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
-Intrauterine device (IUD)
-Intrauterine hormone-releasing system (IUS)
-Bilateral tubal occlusion
-Vasectomized partner
-Sexual abstinence (if accepted by national regulations)
Acceptable birth control methods that result in a failure rate of more than 1% per year include:
-Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
-Male or female condom with or without spermicide
-Cap, diaphragm or sponge with spermicide.
A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods.
For sites and countries where applicable (e.g. Germany, etc.), please refer to
Clinical Trial Facilitation Group (CTFG) guidelines for further recommendation.
•Female patients who are breast feeding should discontinue nursing prior to the first dose of study medication and must not be breast feeding during the trial treatment and for a period of at least 5 months following the last administration of trial drug(s).
•Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
•Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
•Cancer of cervical oesophagus (15 to 19 cm from dental ridge)
•Known Her2 positive adenocarcinoma
•Weight loss > 15 % over the last 3 months without improvement after nutritional support
•Patient with cardiac dysfunction e.g. symptomatic congestive heart failure, uncontrolled hypertension, myocardial infarction within 6 months prior to randomization, clinically significant active heart disease
• Mean resting corrected QT interval (QTc) >450 msec for men and >470 msec for women, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value
• Personal or family history of congenital long QT syndrome
•Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.
Note: Testing for HIV must be performed at sites where mandated locally.
•Any prior treatment for advanced disease including treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
•Live vaccines within 30 days prior to the first dose of study therapy. Examples of live vaccines include, but are not limited to the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine
•Known history of solid organ/tissue or allogeneic stem cell transplant
•History of hypersensitivity to study drugs or any excipient (refer to SmPCs for ipilimumab, nivolumab, 5-FU and oxaliplatin)
•Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required). In case of specific recommendations due to institutional and/or national guidelines please proceed accordingly
•Current participation or treatment with an investigational agent or use of an investigational agent within 4 weeks of the first dose of study treatment
•Serious comorbidity or life expectancy less than one year
•Contraindication to chemoradiation therapy
•Treatment history of radiotherapy
•Child-Pugh B/C and patients with history of acute or chronic pancreatitis
•Patient with Type I diabetes mellitus, or skin disorders (such as vitiligo, psoriasis, or alopecia) except if not requiring systemic treatment or with hyperthyroidism or hypothyroidism except if the patient is stable on hormone replacement.
Note: in cases of uncertainty, it is recommended that the EORTC medical monitor be consulted prior to signing informed consent.
• Active infection requiring therapy
•Known severe systemic autoimmune disease affecting the lungs or the bowel
• Known interstitial lung disease
•Known contraindication to CT scans with IV contrast
•Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to enrollment (corticosteroid use as premedication for IV contrast allergies/reactions is allowed; daily prednisone at doses up to 10 mg or equivalent doses of any other corticosteroid is allowed as an example of replacement therapy)
• Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs such as brivudine
•Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
•Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. A specific attention should be given in order to detect any minor myasthenia signs at enrollment; acetylcholine receptor antibodies will be systematically tested when symptoms are suggestive of a myasthenia;
•History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible;
•Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Progression-free survival rate at 12 months (PFS-12) using RECIST 1.1
•Safety
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final analysis of the primary endpoint will occur when all patients achieved at least 15 months follow-up |
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E.5.2 | Secondary end point(s) |
•Best overall response according to RECIST 1.1
•Progression-free survival using RECIST 1.1
•Pattern of first cause of progression (local relapse/progression, regional relapse/progression, distant metastasis)
•Percentage of patients receiving the planned chemoradiation
•Compliance to each protocol treatment (radiotherapy, FOLFOX, nivolumab +/- ipilimumab).
•Failure-free survival
•Overall survival
•Progression-free survival using iRECIST (exploratory endpoint) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis of the secondary endpoints will occur when all patients achieved at least 15 months follow-up |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Radiotherapy, Biobanking, |
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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 | No |
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 | Information not present in EudraCT |
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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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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End of study occurs when all of the following criteria have been satisfied:
1. At least 100 days after the end of the protocol treatment of the last patient
and
2. Provided all patients have finished protocol specific procedures, not being otherwise part of the standard clinical practice
and
3. Provided the trial is mature for the analysis of the primary endpoint as defined in the protocol
and
4. The database has been fully cleaned and frozen for this analysis. |
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |