| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer (NSCLC) of clinical stages IB, II and selected stage III A |
|
| E.1.1.1 | Medical condition in easily understood language |
| early stage non-small lung cancer |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 |
| The primary objective of this study is to determine the feasibility of four weeks of preoperative immunotherapy with nivolumab (240 mg q2w), nivolumab (240 mg q2w) plus relatlimab (80 mg q2w), and nivolumab (240 mg q2w) plus relatimab (240 mg q2w) in patients with early stage or locally advanced non-small cell lung cancer eligible for curative resection. |
|
| E.2.2 | Secondary objectives of the trial |
• Estimation of pathological tumor response rate (rate of complete pathological responses defined as absence of viable tumor cells on routine hematoxylin and eosin staining of resected tumors and lymph nodes; rate of major pathological responses defined as 10% or less viable tumor cells on routine hematoxylin and eosin staining of resected tumors)
• Estimation of complete (R0) resection rate
• Assessment of radiologic response on computed tomography per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Assessment of disease-free survival rate at 12 months per RECIST version 1.1
• Assessment of overall survival rate at 12 months
• Assessment of safety and tolerability of preoperative immunotherapy
• Estimation of morbidity and mortality within 90 days of surgery
• Exploratory translational analyses for investigation of immunomodulatory and anticancer activity of preoperative treatment with nivolumab and nivolumab/relatlimab combination therapy |
|
| 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 |
| Translational Research Project |
|
| E.3 | Principal inclusion criteria |
• Patients with histologically (core biopsy) or cytologically (e.g. bronchoscopy-guided biopsy) confirmed non-small cell lung cancer (NSCLC) eligible for anatomic resection, with the following specifications:
o Clinical stages I B, II and selected stage III A (T3 N1, T4 with satellite nodule in the same lung N0/N1, selected T1a-T2b N2 cases considered suitable for primary surgical approach by the multidisciplinary tumor board) according to UICC 8th edition
• Males and females, ages >= 18 years, inclusive
o Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment.
o Women of childbearing potential (WOCBP) must agree to follow instructions for highly effective method(s) of contraception for the duration of treatment with study medication plus 5 months after the last dose of the study drug.
• ECOG ≤ 1
• Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3) by PET/CT and/or invasive mediastinal lymph node staging by EBUS-TBNA and/or staging mediastinoscopy as indicated by current guidelines.
• Exclusion of distant metastases by standard of care imaging studies, which include but are not limited to PET/CT or PET/MRI, or CT or MRI of thorax, abdomen, pelvis, and bone scan. Asymptomatic brain metastases will be excluded by MRI or contrast-enhanced CT as indicated by current guidelines.
• Measurable target tumor prior to immunotherapy using standard imaging techniques.
• Sufficient pulmonary function to undergo curative lung cancer surgery, ppFEV1>30%, ppDLCO>30%, ppVO2max>=10 ml/min/kg (if CPET was mandated per local guidelines)
• Adequate hematological, hepatic and renal function parameters:
o Leukocytes ≥ 2,000/mm³, platelets ≥ 100,000/mm³, absolute neutrophil count (ANC) ≥ 1,500/µL, hemoglobin ≥ 9 g/dL (5.58 mmol/L),
o Anti-platelet therapy (such as but not limited to clopidogrel) should be discontinued pre-operatively according to local standards. If this therapy cannot be interrupted due to severe cardiovascular comorbidity, patient is ineligible for the trial
o Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the upper limit of normal (ULN) (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon or direct oral anticoagulants are to be bridged according to local standards and have achieved stable coagulation profile prior to surgery.
o Serum creatinine ≤ 1.5 x upper limit of normal
o Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
• Sufficient cardiac left ventricular defined as LVEF ≥ 50% documented either by echocardiography or MUGA (echocardiography preferred test, MUGA not used in German site) within 6 months before first administration of study drug
• Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
|
|
| E.4 | Principal exclusion criteria |
•Active or history of autoimmune disease or immune deficiency, including, but not limited to [...]. Patients with the following conditions are not excluded from participation: *Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen * Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment, in particular corticosteroids
•Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. [...]
•Subjects who have undergone organ transplant or allogeneic stem cell transplantation.
•ppFEV1<30%, ppDLCO<30%, ppVO2max <10 ml/min/kg (if CPET was mandated per local guidelines)
•Uncontrolled or significant cardiovascular disease including, but not limited to [...]
•History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc. )
•Cardiovascular disease-related requirement for daily supplemental oxygen
•History of two or more myocardial infarctions or two or more coronary revascularization procedures
•Subjects with history of myocarditis, regardless of etiology
•Troponin T (TnT) or I (TnI) >2× institutional ULN. [...]
•Patients with active neurological disease should be excluded.
•Active malignancy or a prior malignancy within the past 3 years. Patients with the following conditions are not excluded from participation: o Patients with completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma insitu, breast carcinoma in-situ, non-invasive intestinal polyps, and patients with isolated elevation in prostate-specific antigen or low risk prostate cancer managed with active surveillance or
watchful waiting in the absence of radiographic evidence of metastatic prostate cancer.
•Known history of positive test for HIV-1 and HIV-2 or known AIDS. [...]
•Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative).
•Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
•Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication
•Peripheral polyneuropathy NCI CTCAE Grade ≥2
•History of gastric perforation or fistulae in past 6 months
•Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.
•The patient has undergone major surgery within 28 days prior to enrollment except staging mediastinoscopy, diagnostic VATS or implantation of a venous port-system.
•Any other concurrent preoperative antineoplastic treatment including irradiation
•Pregnant women
•Breastfeeding women
•Insufficient cardiac left ventricular function defined as LVEF<50% by echocardiography (outside Germany: or MUGA scan) within 6 months before first administration of study drug
•A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
•Subjects with history of severe toxicity or life-threatening toxicity (grade 3 or 4) related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy.
•Subjects with history of severe or life-threatining (grade 3 or 4) infusion-related reactions to prior immune therapy
•Prior treatment with LAG-3 targeting agent
•Participation in another interventional clinical study within the last 3 months [...]
•Previous treatment with nivolumab or relatlimab
•Previous immunotherapy for lung cancer
•Criteria which in the opinion of the investigator preclude participation
•Any contraindications against nivolumab or relatlimab
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary variable is the number of patients undergoing curatively intended surgery of non-small cell lung cancer within 43 days of initiation of study therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome is continuously assessed for each study arm |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate (RECIST 1.1)
• Pathological response rate (complete pathological responses defined as absence of viable tumor cells on routine hematoxylin and eosin staining of resected tumors and lymph nodes; rate of major pathological responses defined as 10% or less viable tumor cells on routine hematoxylin and eosin staining of resected tumors)
• R0 resection rate
• Disease-free survival rate at 12 months per RECIST version 1.1
• Overall survival rate at 12 months
• Safety and tolerability of preoperative immunotherapy
• Morbidity and mortality within 90 days of curative surgery |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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