Study of Molecular Response Adaptive Immuno-Chemotherapy in Patients With NSCLC

Study Overview
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Brief Summary
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The purpose of stage 1 of the study is to find out if blood tests can be used to see how the cancer is responding to treatment with pembrolizumab.

Detailed Description
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The standard or usual treatment for this disease is pembrolizumab given by needle every three weeks. This study will be done in two stages. The purpose of stage 1 of the study is to find out if we can use blood tests to see how the cancer is responding to treatment with pembrolizumab. A second stage of the study will take place once stage 1 is completed. In stage 2 blood tests will be used to help determine if patients whose cancer does not seem to be getting better on treatment with pembrolizumab, would do better on a different treatment.

Official Title
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A Biomarker-Directed, Open Label, Multi-Centre Phase II Study of Molecular Response Adaptive Immuno-Chemotherapy in Patients With Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic NSCLC. Patients with stage III disease are eligible if they are not candidates for surgical resection or definitive chemoradiation. Patients with Large Cell Neuroendocrine Carcinoma (LCNEC) are not eligible. Confirmed EGFR and ALK mutation-negative disease. Testing for EGFR and ALK is not required for patients with squamous histology. Patients must have a PD-L1 test result from a certified laboratory indicating PD-L1 expression Tumour Proportion Score (TPS) ≥ 1%. No prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced Stage III disease is allowed if at least 6 months have elapsed since the prior therapy and enrollment. Local therapy, e.g. palliative extra-cranial radiation, is allowed as long as a period of 2 weeks has passed since completion as ctDNA levels may be altered by radiotherapy. There is no requirement for delay for patients who have received brain radiation. Patients must have recovered to ≤ grade 1 from all reversible toxicity related to prior systemic or radiation therapy. Previous major surgery is permitted provided that surgery occurred at least 28 days prior to patient enrollment and that wound healing has occurred. Eligible to receive treatment with pembrolizumab. Reimbursement of pembrolizumab may not be uniform across all sites. In the event that the site/investigator is unable to provide access to the drug, the patient will not be eligible for this trial. Must be ≥ 18 years of age. ECOG performance status 0 or 1. Clinically and/or radiologically documented disease with at least one lesion measurable as defined by RECIST 1.1. Imaging investigations including CT of the chest, abdomen and pelvis and MRI of the brain (if known brain metastases) or other scans as necessary to document all sites of disease must be done within 28 days prior to enrollment. Adequate hematology and organ function as defined below (must be done within 14 days prior to enrollment). White Blood Cells ≥ 2.0 x 10^9/L (2000/μL) Absolute neutrophils ≥ 1.5 x 10^9/L (1500/μL) Platelets ≥ 100 x 10^9/L (100 x 10^3/μL) Bilirubin ≤ 1.5 x ULN (upper limit of normal)* AST and/or ALT ≤ 3 x ULN, < 5 x ULN for patients with liver metastases Serum creatinine or Creatinine clearance ≤ 1.5 x ULN OR ≥ 40 mL/min Patients must consent to provision of, and investigator must agree to submit, a representative archival formalin-fixed paraffin block of tumour tissue for correlative analyses when tumour tissue is available. Patients must consent to collection of liquid biopsy (blood) samples for ctDNA analysis by CLIA central laboratory and for correlative analysis by a research central laboratory. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment to the trial to document their willingness to participate. Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, collection of blood samples, response assessments and follow-up. Patients must agree to return to their primary care facility for response assessments as well as any adverse events which may occur through the course of the trial. In accordance with CCTG policy, protocol treatment with pembrolizumab is to begin within 2 working days of patient enrollment. Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation. Exclusion Criteria: Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with symptomatic central nervous system (CNS) metastases and/or CNS metastases requiring immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalents). Patients with known central nervous system metastases who are asymptomatic and on a stable dose of corticosteroids ≤ 10 mg/day prednisone equivalents prior to enrollment are eligible. Patients who are not suitable candidates for treatment with pembrolizumab according to the current guidance/indications described in the Product Monograph (Canada) or Drug Label (U.S.) including but not limited to patients with active infection, autoimmune disease, conditions that require systemic immunosuppressive therapy (such as transplant patients) and patients with a history of severe immune-mediated adverse reactions, or known hypersensitivity to pembrolizumab or its components. Patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders (such as hypo or hyperthyroidism or diabetes mellitus), can be considered for enrollment to this study provided pembrolizumab is administered with caution and patients are closely monitored History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements. Concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents Pregnant or lactating women. Men who are sexually active with women of childbearing potential and women of childbearing 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>200mg (or 2mg/kg) IV every 3 weeks for cycles 1-3 then as per standard of care for patients with PD-L1+ EGFR/ALK-NSCLC | Drug: Pembrolizumab<br>* 200mg IV 2 mg/kg IV 400 mg IV 4 mg/kg IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance rate between molecular response and radiologic response | Molecular response will be assessed by measuring changes in ctDNA levels in plasma | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to molecular response |  | 18 months | 
| Correlate molecular response to RECIST response based on changes in ctDNA levels |  | 18 months | 
| Correlate molecular response to progression-free survival based on changes in ctDNA levels |  | 18 months | 
| Correlate molecular response to overall survival based on changes in ctDNA levels |  | 18 months | 
| Explore the degree of ctDNA reduction with clinical outcomes assessed by measuring changes in ctDNA levels in plasma |  | 18 months |