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 |
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E.1.1.1 | Medical condition in easily understood language |
early stage non-small lung 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 | 21.1 |
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) |
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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 this study is to determine the feasibility of four weeks of preoperative immunotherapy with nivolumab, and nivolumab plus relatlimab in patients with early stage or locally advanced non-small cell lung cancer eligible for curative resection. |
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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
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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 |
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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 half-lives of study treatment plus 30 days (duration of ovulatory cycle) post treatment completion for a total of 165 days (approximately 24 weeks) (Appendix IV). This applies to both treatment arms, nivolumab monotherapy and nivolumab/relatlimab combination therapy.
o Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception and fetal protection (Appendix IV) for the duration of treatment with study medication plus 5 half-lives of the study treatment plus 90 days (duration of sperm turnover) for a total of 225 days (approximately 33 weeks) post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time. This applies to both treatment arms, nivolumab monotherapy and nivolumab/relatlimab combination therapy.
• 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:
• 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
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E.4 | Principal exclusion criteria |
• Active or history of autoimmune disease or immune deficiency
• 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, any of the following:
o Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
o Uncontrolled angina within the 3 months prior to consent
o Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
o QTc prolongation > 480 msec
o Pulmonary hypertension (sPAP >35 mmHg)
• History of other clinically significant cardiovascular disease
• 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 upper limit of normal (ULN). Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are within ULN. If TnT or TnI levels are >1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee.
• Patients with active neurological disease should be excluded.
• Active malignancy or a prior malignancy within the past 3 years.
• Known history of positive test for human immunodeficiency virus (HIV-1 and HIV-2) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV-1 and HIV-2 must be performed at screening.
• 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)
• 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
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome is continuously assessed for each study arm |
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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
• Radiomorphologic response per RECIST 1.1
• 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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
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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 | 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 |