Double Blind Placebo Controlled Controlled Study of Adjuvant MEDI4736 In Completely Resected NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to find out whether it is better to receive a new drug, MEDI4736, or better to receive no further treatment after surgery (and possibly chemotherapy) for lung cancer.

Official Title
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A Phase III Prospective Double Blind Placebo Controlled Randomized Study of Adjuvant MEDI4736 In Completely Resected Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: MEDI4736
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of primary non-small cell carcinoma of the lung. according to WHO Classification of Tumours (WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. WHO/IARC Classification of Tumours, 4th Edition, Volume 7). Patients with large-cell neuroendocrine carcinomas are not eligible. Patients must be classified post-operatively as Stage IB (≥ 4cm in the longest diameter), II or IIIA on the basis of pathologic criteria. Note: Although T3N2M0 tumours have been reclassified to stage IIIB in the 8th edition of the IASLC staging system, these patients remain eligible (as stage IIIA under the 7th edition criteria). Complete surgical resection of the primary NSCLC is also mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. Resection may be accomplished by open or VATS techniques Note: Patients with synchronous primary tumours will not be eligible due to the potential uncertainty regarding their appropriate PD-L1 status. Prior Systemic Therapy: Pre-operative (neo-adjuvant) platinum based or other chemotherapy is not permissible. Patients may have received prior post-operative platinum based chemotherapy as per standard of care. No prior anticancer therapy for treatment of NSCLC other than standard post-operative adjuvant chemotherapy is permissible. Radiation: • Patients with N2 disease only who receive adjuvant post-operative radiation therapy are eligible provided they meet the protocol specified timing criteria for surgery, adjuvant chemotherapy and randomization. Pre-operative radiation therapy is not permissible. The patient must have an ECOG performance status of 0, 1. Hematology: . Absolute neutrophil count ≥ 1.5 x 109/L or ≥ 1,500/µl Platelets ≥ 100 x 109/L or ≥ 100,000/µl Biochemistry: Total bilirubin* ≤ institutional upper limit of normal Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal AST(SGOT) and ALT(SGPT) ≤ 2.5 x institutional upper limit of normal Creatinine Clearance ≥ 40 ml/min * excluding Gilbert's syndrome Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft Formula: Females: GFR = 1.04 x (140-age) x weight in kg serum creatinine in μmol/L Males: GFR = 1.23 x (140-age) x weight in kg serum creatinine in μmol/L Patient able and willing to complete the QoL, economics and other questionnaires. The baseline assessment must already have been completed within required timelines prior to randomization. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up Protocol treatment is to begin within 2 working days of patient randomization Exclusion Criteria: Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other malignancies curatively treated with no evidence of disease for ≥ 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy. A combination of small cell and non-small cell lung cancer, pulmonary carcinoid tumour or large-cell neuroendocrine carcinoma (LCNEC). History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: patients with Grave's disease and/or psoriasis not requiring systemic therapy within the last two years from randomization and patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement are not excluded. History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy. Live attenuated vaccination administered within 30 days prior to randomization. History of hypersensitivity to MEDI4736 or any excipient. Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, must have a LVEF > 50% within 12 weeks prior to randomization. Concurrent treatment with other investigational drugs or anti-cancer therapy. Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. This includes but is not limited to: known clinical diagnosis of tuberculosis; known active hepatitis B infection (positive HBV surface antigen (HBsAg)). Patients with a past or resolved hepatitis B infection (defined as presence of hepatitis B core antibody (anti-HBc) and absence of HBSAg) are eligible; known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA; known human immunodeficiency virus infection (positive HIV antibodies). known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function Pregnant or lactating women. Women of childbearing potential must have a urine pregnancy test proven negative within 14 days prior to randomization. Men and women of child-bearing potential must agree to use adequate contraception.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI4736<br>MEDI4736 by intravenous infusion. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier. | Drug: MEDI4736<br> <br> |
| Placebo Comparator: Placebo<br>PLACEBO by intravenous infusion. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Disease free survival (DFS) for patients with NSCLC that is PD-L1 expression TC ≥ 25% and patients without common activating EGFR mutations or ALK gene rearrangements |  | 6.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival in the remaining 5 patient sub-populations defined by PD-L1 expression levels and EGFR/ALK status | (PD-L1 TC ≥ 1% and patients without common activating EGFR mutations or ALK gene rearrangements; all patients without common activating EGFR mutations or ALK gene rearrangements; all PD-L1 TC ≥ 25%; all PD-L1 TC ≥ 1%; all randomized patients) | 8 years | 
| Compare overall survival (OS) for patients in the six patient sub-populations defined by PD-L1 expression levels and EGFR/ALK status |  | 8 years | 
| Compare Lung cancer specific survival for patients in the six patient sub-populations defined by PD-L1 expression levels and EGFR/ALK status |  | 8 years | 
| Evaluate the nature, severity and frequency of adverse effects and tolerability of MEDI4736 | All patients who receive at least one dose of MEDI4376/placebo will be included in the safety analysis. Descriptive summary tables will be presented on safety parameters by treatment arm. There will be safety monitoring by the CCTG Data Safety Monitoring Committee (DSMC) every 6 months | every 6 months | 
| Evaluate the Quality of life in the six patient sub-populations defined by PD-L1 expression levels and EGFR/ALK status | The quality of life (QoL) of patients will be assessed using EORTC QLQ-C30 and the lung cancer module (QLQ-LC13) incorporated. | 8 years | 
| Determine survival benefits participants judge necessary to make adjuvant immunotherapy worthwhile |  | 8 years | 
| Determine the incremental cost effectiveness and cost utility ratios for MEDI4736 |  | 8 years | 
| Evaluate the predictive/prognostic significance of PD-L1 expression |  | 8 years | 
| Evaluation of changes in plasma/serum cytokines and other blood and tissue based biomarkers after treatment with MEDI4736 and at disease event |  | 8 years | 
| Explore polymorphisms that may be associated with outcomes |  | Baseline only |