Phase II trial in inoperable œsophageal cancer evaluating the feasibility of the combination of definitive chemoradiation with the immune checkpoint blockers Nivolumab +/- Ipilimumab (CRUCIAL)
- Conditions
- oesophageal squamous cell carcinoma and oeasophageal adenocarcinomaMedDRA version: 20.0Level: PTClassification code 10061534Term: Oesophageal squamous cell carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10030137Term: Oesophageal adenocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-000053-53-ES
- Lead Sponsor
- European Organisation for Research and Treatment of Cancer
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 130
•Histologically proven oesophageal squamous cell carcinoma or adenocarcinoma
•Both early stage and locally advanced tumor patients (according to TNM staging version 8):
•T1, N1-3, M0 after complete work-up
•T2, N0-3, M0 after complete work-up
•T3, N0-3, M0
•Patient eligible for definitive chemoradiation and not considered for primary surgery after multidisciplinary meeting decision or patient refuses to undergo surgery
•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 adequate birth control measures, as defined by the investigator, 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
-Sex
•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
•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
•History of hypersensitivity to study drugs or any excipient (refer to SmPCs for ipilimumab, nivolumab, 5-FU and oxaliplatin)
•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.
•Known severe systemic autoimmune disease affecting the lungs or the bowel
•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)
•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 foll
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: 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.;Secondary Objective: 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).;Primary end point(s): •Progression-free survival rate at 12 months (PFS-12) using RECIST 1.1<br>•Safety;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
- Secondary Outcome Measures
Name Time Method Secondary end point(s): •Best overall response according to RECIST 1.1 <br>•Progression-free survival using RECIST 1.1<br>•Pattern of first cause of progression (local relapse/progression, regional relapse/progression, distant metastasis)<br>•Percentage of patients receiving the planned chemoradiation <br>•Compliance to each protocol treatment (radiotherapy, FOLFOX, nivolumab +/- ipilimumab).<br>•Failure-free survival<br>•Overall survival<br>•Progression-free survival using iRECIST (exploratory endpoint);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