Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer

• To evaluate median overall survival (OS) among all eligible subjects (ITT population) treated with erlotinib plus ARQ 197 compared to chemotherapy. [ Time Frame: Date of randomization to the date of death from any cause, assessed up to 24 months ] [ Designated as safety issue: No ]
• To determine the objective response rate (ORR) among all eligible subjects (ITT population) treated with erlotinib plus ARQ 197 compared to chemotherapy. [ Time Frame: Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months ] [ Designated as safety issue: No ]
• To determine the objective response rate (ORR) among subjects randomly assigned to chemotherapy who cross over following disease progression to receive erlotinib plus ARQ 197 and who are evaluable for a post-progression scan on crossover therapy. [ Time Frame: Date of randomization to the date of death from any cause or to the date that the subject discontinues from the study, assessed up to 24 months. ] [ Designated as safety issue: No ]
• To further characterize the safety (adverse events) of ARQ 197 in combination with erlotinib in subjects with KRAS mutation positive NSCLC. [ Time Frame: Every three weeks throughout the study period and up to 30 days after the last dose of study medication, assessed up to 24 months. ] [ Designated as safety issue: Yes ]

The purpose of this study is to evaluate progression-free survival among subjects with KRAS mutation positive Non-Small Cell Lung Cancer (NSCLC) treated with erlotinib plus tivantinib (ARQ 197) compared to single agent chemotherapy.

This is a randomized, open-label Phase 2 study designed to compare treatment with erlotinib plus tivantinib (ARQ 197) versus single agent chemotherapy in subjects with previously treated KRAS mutation positive NSCLC. Eligible subjects are randomly assigned to receive erlotinib plus tivantinib or one of three (based on Investigator's decision) single-agent chemotherapy agents including pemetrexed, docetaxel, or gemcitabine.

• Drug: ARQ 197 plus erlotinib
  Eligible subjects will be randomly assigned to receive erlotinib plus ARQ 197.
  Other Name: Tivantinib
• Drug: Pemetrexed, docetaxel or gemcitabine
  A single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered according to approved labeling.

• Experimental: tivantinib (ARQ 197) plus erlotinib arm

  Eligible subjects will be randomly assigned to receive erlotinib plus tivantinib (ARQ 197).

  Treatment will be open-label and continue until progression of disease, unacceptable toxicity, or another discontinuation criterion is met.

  Intervention: Drug: ARQ 197 plus erlotinib
• Active Comparator: Chemotherapy arm
  A single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered according to approved labeling
  Intervention: Drug: Pemetrexed, docetaxel or gemcitabine

Inclusion Criteria:

1. Provide signed and dated informed consent prior to study-specific screening procedures
2. Male or female at least 18 years of age
3. Histologically or cytologically confirmed inoperable locally advanced or metastatic (stage IVA/IVB) NSCLC
4. Documented KRAS mutation positive status (per LCMC guidelines; see www.golcmc.com)
5. At least one prior chemotherapy regimen for advanced NSCLC
6. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
8. Male or female subjects of child-producing potential must agree to use double barrier contraception, oral contraceptives or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment
9. Females of childbearing potential must have a negative serum pregnancy test
10. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease
11. Total bilirubin ≤ 1.5 × ULN
12. Serum creatinine ≤ 1.5 × ULN
13. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
14. Platelets ≥ 100 x 10^9/L
15. Hemoglobin ≥ 10 g/dL (transfusion is allowed at least 7 days prior to randomization)
16. Subjects must agree to allow testing for c-Met status if archival and/or fresh tissue biopsy samples are available.

Exclusion Criteria:

1. Previous receipt of erlotinib or other EGFR
2. Previous receipt of any c-MET inhibitor or other c-MET-targeted therapy, including ARQ 197, MetMab, crizotinib
3. Prior receipt of chemotherapy agent selected for administration in this study (e.g., if subject was treated with gemcitabine, he is not eligible to receive gemcitabine in this study but eligible to receive pemetrexed or docetaxel).
4. Inability or unwillingness to receive ARQ 197, erlotinib, docetaxel, gemcitabine, and/or pemetrexed including contraindications, hypersensitivity, or prior administration
5. Receipt of any anti-tumor treatment for NSCLC within 3 weeks (2 weeks for radiotherapy) prior to randomization
6. Pregnant or breastfeeding
7. Significant gastrointestinal disorder that could, in the opinion of the Investigator, interfere with the absorption of ARQ 197 and/or erlotinib
8. Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation
9. Other malignancies within the last three years, with the exception of adequately treated intraepithelial carcinoma of the cervix uteri, prostate carcinoma with a PSA value < 0.2 ng/mL or basal or squamous cell carcinoma of the skin
10. Known human immunodeficiency virus (HIV), or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
11. Major surgical procedure within 4 weeks prior to randomization
12. 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 bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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)
13. Clinically unstable central nervous system metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or CT scan within 4 weeks of randomization and have CNS metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications)
14. Known EGFR-mutation positive status