Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib for the Treatment of Non-squamous, Non-small-cell Lung Cancer

Study Overview
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Brief Summary
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This study is to determine if the combination regimen of tivantinib with erlotinib will improve overall survival relative to erlotinib alone in subjects with locally advanced or metastatic non-squamous, non-small cell lung cancer who have received 1 or 2 prior systemic anti-cancer therapies.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of ARQ197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer (NSCLC)

Conditions
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Non Squamous, Non-small-cell Lung Cancer

Intervention / Treatment
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* Drug: Tivantinib
* Drug: Placebo
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous non-small-cell lung cancer. Measurable disease and documented disease progression following last prior therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1. Have received one or two prior lines of systemic anti-cancer therapy therapy for advanced or metastatic disease, one of which must be a platinum-doublet therapy. Patients who received only adjuvant treatment will be eligible only if disease progression occurred <6 months after completion of adjuvant therapy. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Resolution of any toxic effects of prior therapy (including radiotherapy) according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Grade ≤1 (with the exception of alopecia and ≤grade 2 neuropathy). Subject must have recovered from significant surgery-related complications. Demonstrate adequate bone marrow, liver, and renal functions, defined as: ALT, AST, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) in subjects with no liver metastasis and ≤5.0 x ULN in subjects with liver metastasis. Total bilirubin ≤ 1.5 × ULN (≤ 4 × ULN total and ≤1.5 × ULN direct bilirubin is acceptable for subjects with Gilbert's syndrome). ANC ≥1.5 × 10^9/L. Platelet count ≥100 × 10^9/L. Hemoglobin ≥9.0 g/dL (transfusion and/or growth factor support allowed). Serum creatinine ≤1.5 × ULN or creatinine clearance ≥ 60 mL/min. Archival and/or fresh biopsy tissue sample must be available for biomarker determination. The status of the following biomarkers will be collected in this study: EGFR and KRAS mutation status prior to randomization, and MET status post randomization If of child-bearing/reproductive potential (female or male), must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received If female and of childbearing potential, must have a negative result of a pregnancy test (serum or urine) within 72 hours prior to initiating study treatment. Must have signed and dated an approved Informed Consent Form (Including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including forseeable risks and possible side effects) Exclusion Criteria: Prior therapy with an EGFR inhibitor and/or ARQ 197 (or other known c-MET inhibitor). Receipt of any systemic anti-tumor treatment for NSCLC within 3 weeks prior to randomization. Receipt of palliative radiotherapy within 2 weeks or radiotherapy for curative intent of target lesions within 3 weeks prior to randomization. Lesions subjected to radiotherapy within 3 weeks prior to randomization may not be used as target lesions. Major surgical procedure within 3 weeks prior to randomization. History of cardiac disease: Congestive heart failure defined as Class II to IV per New York Heart Association classification; active coronary artery disease; previously diagnosed symptomatic bradycardia (subjects with asymptomatic bradycardia and heart rate above 50 bpm are allowed) or other cardiac arrhythmia defined as ≥Grade 2 according to NCI CTCAE, version 4.0, or uncontrolled hypertension; myocardial infarction that occurred within 6 months prior to study entry (myocardial infarction that occurred > 6 months prior to study entry is permitted). Clinically unstable central nervous system (CNS) metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or computed tomography (CT) scan within 4 weeks of randomization and have CNS metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications). Need to breastfeed a child during or within 12 weeks of completing the study. Significant gastrointestinal disorder that, in the opinion of the investigator, could interfere with absorption of ARQ 197 and/or erlotinib (eg, Crohn's disease, small or large bowel resection, malabsorption syndrome). Inability or unwillingness to swallow the complete doses of ARQ 197 or erlotinib. Any known contraindication to treatment with, including hypersensitivity to, ARQ 197 or erlotinib. History of malignancy other than NSCLC within the 5 years prior to randomization, with the exceptions of adequately treated intraepithelial carcinoma of the cervix uteri; prostate carcinoma with a prostate-specific antigen value <0.2 ng/mL; or basal or squamous-cell carcinoma of the skin. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Any other significant co-morbid condition that, in opinion of the investigator, would impair study participation or cooperation.

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: Tivantinib and erlotinib<br>Tivantinib 720 mg daily (360 mg twice a day) in combination with 150 mg of erlotinib, given once a day | Drug: Tivantinib<br>* Tivantinib 720 mg daily as 3 x 120 mg oral tablets given twice a day<br>* Other names: ARQ197;Drug: Erlotinib<br>* Erlotinib 150 mg oral tablets, given once a day<br>|
| Active Comparator: Placebo and erlotinib<br>Tivantinib placebo given twice a day in combination with 150 mg of erlotinib, given once a day | Drug: Placebo<br>* Tivantinib Placebo tablets given twice a day<br>* Other names: No drug;Drug: Erlotinib<br>* Erlotinib 150 mg oral tablets, given once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer | The overall survival (OS) was defined as the time from the date of randomization to the date of death from any cause. | Date of randomization up to date of death, up to approximately 1 year 11 months postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer | Progression-free Survival (PFS) was defined as the time from the date of randomization to the date of the first objective documentation of disease progression or date of death from any cause (whichever comes first). As per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria, progression was defined as at least a 20% increase in the sum of diameters of target lesions. | Date of randomization to disease progression or death (whichever comes first), up to 1 year 11 months postdose | 
| Overall Survival in the Epidermal Growth Factor Receptor Gene Wild-Type Subpopulation Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous NSCLC | The overall survival (OS) was defined as the time from the date of randomization to the date of death from any cause. | Date of randomization up to date of death, up to approximately 1 year 11 months postdose | 
| Progression-free Survival in the Epidermal Growth Factor Receptor (EGFR) Gene Wild-Type Subpopulation Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants Non-Squamous NSCLC | Progression-free Survival (PFS) was defined as the time from the date of randomization to the date of the first objective documentation of disease progression or date of death from any cause (whichever comes first). As per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria, progression was defined as at least a 20% increase in the sum of diameters of target lesions. | Date of randomization to disease progression or death (whichever comes first), up to 1 year 11 months postdose | 
| Best Overall Tumor Response Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer | The best overall response was defined as the best response (in the order of confirmed complete response [CR], confirmed partial response [PR], stable disease [SD], and progressive disease [PD]) among all overall responses recorded from the start of treatment until the participant withdrew from the study. If there was no tumor assessment after the first dose of study drug, the best overall response was classified as Inevaluable. Based on RECIST v1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. | From baseline up to disease progression or the development of unacceptable toxicity (whichever occurs first), up to 1 year 11 months postdose | 
| Duration of Response Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer | Duration of response was defined for participants with confirmed CR or PR as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of progressive disease. Duration of SD was defined for participants whose best response was SD as the time from the randomization date to the date of the first documentation of progressive disease. | From the date of first objective response (CR or PR) or SD to date of progressive disease, up to 1 year 11 months postdose | 
| Treatment-Emergent Adverse Events Reported in ≥5% of Participants Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous, Non-Small-Cell Lung Cancer | Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsened in severity after the initiation of study treatment administration. | Baseline up to 30 days after last dose, up to 1 year 11 months postdose | 
| Treatment-Emergent Adverse Events Related to Tivantinib/Placebo Experienced by ≥5% of Participants Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous NSCLC | Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsened in severity after the initiation of study treatment administration. | Baseline up to 30 days after last dose, up to 1 year 11 months postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non squamous, non-small-cell lung cancer, Epidermal growth factor receptor, c-Met inhibitor