CABozantinib in Non-Small Cell Lung Cancer (NSCLC) Patients With MET Deregulation

Study Overview
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Brief Summary
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This is a multicenter, single arm, phase II study evaluating efficacy in terms of RR in a cohort of NSCLC with MET amplification or MET exon 14 skipping mutation pre-treated or not with MET inhibitors.

Detailed Description
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The study population will include NSCLC patients with MET amplification or MET exon 14 skipping mutation pre-treated or not with MET inhibitors. Elegible NSCLC patients with MET exon 14 skipping mutations or MET amplification will be treated with open label orally cabozantinib 60 mg/daily, cycles each 28 days. Disease evaluation will be performed every two months (8 weeks). Patients will be treated with cabozantinib until disease progression, unacceptable toxicity or patient refusal.Treatment will be continued until disease progression, unacceptable toxicity or patient refusal. Treatment beyond disease progression is allowed if considered appropriate by the investigator.

Official Title
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Phase II Single Arm Study With CABozantinib in Non-Small Cell Lung Cancer Patients With MET Deregulation

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Citological or histological diagnosis of non-small-cell-lung cancer (NSCLC) stage III B (not suitable for local treatments with curative intent) or stage IV. Tissue samples available for MET analysis (archivial tissue or tissue collected at study entry); patients without archival tumor tissue or refusing new biopsy at study entry, are eligible if MET mutation is detected in cf-DNA Presence of MET mutations (exon 14 skipping mutation ONLY) detected in tissue or cf-DNA at the local lab or in the central lab or MET amplification (MET/CEP7 ratio > 2.2) detected in the central lab ONLY. Measurable disease according to RECIST criteria version 1.1 At least 1 prior line of standard therapy (chemotherapy and/ or immunotherapy) Performance status 0-1 (ECOG) Age ≥18 years Patients potentially fertile using adequate methods of contraception in order to avoid childbearing. Contraceptive methods must be respected by male and female patients and their partners during study treatment period and at least 4 months after completing therapy Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to enrollment: ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support Platelet count ≥ 100,000/μL without transfusion Hemoglobin ≥ 9.0 g/dL Patients may be transfused to meet this criterion AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions: Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN. Serum bilirubin ≤ 1.25 × ULN Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled Calculated creatinine clearance (CRCL) ≥ 45 mL/min or calculated CRCL must be ≥ 60 mL/min Patient compliance to the study procedure Written informed consent Exclusion Criteria: Tissue sample not available in patients without MET exon 14 skipping mutation detected in cf-DNA No possibility to assess MET status Absence of any measurable disease according to RECIST criteria Co-existence of driver events, including EGFR mutations, KRAS mutations, ALK rearrangements or ROS-1 rearrangements No prior therapy Concomitant chemotherapy or immunotherapy or radiotherapy Symptomatic brain metastasis Uncontrolled significant inter-current or recent illness, including cardio-vascular disorders and gastro-intestinal disorders Major surgery within 2 months before first dose of study treatment Concomitant anti-coagulation with oral anti-coagulants or plated inhibitors History of significant bleeding, trachea-bronchial tree/major blood vessels invading tumors, cavity pulmonary lesions and GI disorders associated with a risk of perforation or fistula formation Diagnosis of another cancer in the last 3 years, except for in situ carcinoma of cervix, breast and bladder or skin carcinoma (squamous or basalioid) Pregnancy or breastfeeding

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: Cabozantinib<br>Elegible NSCLC patients with MET exon 14 skipping mutations or MET amplification will be treated with open label orally cabozantinib 60 mg/daily, cycles each 28 days. | Drug: Cabozantinib<br>* Patients will be treated with cabozantinib 60 mg/daily (cycles each 28 days) until progression, toxicity or patient refusal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) (complete + partial responses) | RR will be evaluated by investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Partial and complete responses will be confirmed following RECIST criteria 1.1. Disease evaluation will be performed every two months (8 weeks). | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Disease evaluation will be performed every 8 weeks | Up to 36 months | 
| Overall survival (OS) | Disease evaluation will be performed every 8 weeks | Up to 36 months | 
| Disease Control Rate (DCR: stable disease + partial response + complete response) | Disease evaluation will be performed every 8 weeks | Up to 36 months | 
| Exploratory biomarkers | At baseline, at the first disease evaluation and at progression of disease a blood sample will be collected for biomarkers analyses | Up to 36 months |