A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer (NSCLC)
- 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
- 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
- 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
- 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
- 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)
- 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
- 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
- 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
- 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.