Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib for the Treatment of Non-squamous, Non-small-cell Lung Cancer
Condition: Non Squamous, Non-small-cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Tivantinib; Placebo; Erlotinib
Intervention description: Tivantinib 720 mg daily as 3 x 120 mg oral tablets given twice a day; Tivantinib Placebo tablets given twice a day; Erlotinib 150 mg oral tablets, given once a day
Intervention MeSH terms: Erlotinib Hydrochloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 1048.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non squamous, non-small-cell lung cancer; Epidermal growth factor receptor; c-Met inhibitor

Summary:

      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.
    

Eligibility criteria:

        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.