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

Daiichi Sankyo

Status and phase: Terminated; Phase 3

Conditions: Non Squamous, Non-small-cell Lung Cancer

Treatments: Drug: Erlotinib; Drug: Placebo; Drug: Tivantinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01244191

ARQ197-A-U302

2010-022365-10 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 1,048 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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1,048 participants in 2 patient groups

Tivantinib and erlotinib

Experimental group

Description:

Tivantinib 720 mg daily (360 mg twice a day) in combination with 150 mg of erlotinib, given once a day

Treatment:

Drug: Tivantinib

Drug: Erlotinib

Placebo and erlotinib

Active Comparator group

Description:

Tivantinib placebo given twice a day in combination with 150 mg of erlotinib, given once a day

Treatment:

Drug: Placebo

Drug: Erlotinib