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-DE
- 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):
•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
•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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method