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

Tracking Information
First Submitted Date ICMJE	July 1, 2011
First Posted Date ICMJE	July 18, 2011
Results First Submitted Date	January 31, 2018
Results First Posted Date	April 3, 2018
Last Update Posted Date	April 3, 2018
Study Start Date ICMJE	July 2011
Actual Primary Completion Date	August 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 5, 2018)	Progression-free Survival (PFS) Among Subjects With KRAS Mutation Positive NSCLC (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Single Agent Chemotherapy. [ Time Frame: Date of randomization until disease progression per RECIST (v 1.1) or death from any cause, whichever came first, assessed up to 24 months. ]; Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or progression of existing non-target lesions are also considered progression.
Original Primary Outcome Measures ICMJE; (submitted: July 14, 2011)	The primary objective of this study is to evaluate median progression-free survival (PFS) among subjects with KRAS mutation positive NSCLC (ITT population) treated with erlotinib plus ARQ 197 compared to single agent chemotherapy. [ Time Frame: Date of randomization until disease progression per RECIST (Version 1.1) or death from any cause, whichever came first, assessed up to 24 months. ]
Change History	Complete list of historical versions of study NCT01395758 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 5, 2018)	Overall Survival (OS) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib Compared to Chemotherapy. [ Time Frame: Date of randomization to the date of death from any cause, assessed up to 24 months ]OS is calculated from the date of randomization until death from any cause.; Objective Response Rate (ORR) Among All Eligible Subjects (ITT Population) Treated With Erlotinib Plus Tivantinib 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 ]Per RECIST v1.1, Complete Response (CR) = disappearance of all lesions and Partial Response (PR) = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.; ORR Among Subjects in the Crossover Period Treated With Erlotinib Plus Tivantinib [ 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. ]Per RECIST v1.1, CR = disappearance of all lesions and PR = at least 30% decrease in the sum of diameters of target lesions. ORR = (CR+PR)/# subjects.
Original Secondary Outcome Measures ICMJE; (submitted: July 14, 2011)	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 ]; 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 ]; 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. ]; 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. ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Official Title ICMJE	A Phase 2 Randomized Open-label Study of Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Previously Treated KRAS Mutation Positive Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Brief Summary	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.
Detailed Description	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 choice) single-agent chemotherapy agents including pemetrexed, docetaxel, or gemcitabine.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Metastatic Non-Small Cell Lung Cancer
Intervention ICMJE	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 Investigator's choice of a single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered according to the approved label.
Study Arms	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 Investigator's choice of single agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) administered in 3-week cycles according to the approved label until disease progression or unacceptable toxicity. Subjects who discontinued chemotherapy can be switched to the crossover arm (tivantinib plus erlotinib) and continue treatment until disease progression or unacceptable toxicity. Intervention: Drug: Pemetrexed, docetaxel or gemcitabine
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: March 5, 2018)	96
Original Estimated Enrollment ICMJE; (submitted: July 14, 2011)	98
Actual Study Completion Date	August 2016
Actual Primary Completion Date	August 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Provide signed and dated informed consent prior to study-specific screening procedures; Male or female at least 18 years of age; Histologically or cytologically confirmed inoperable locally advanced or metastatic (stage IVA/IVB) NSCLC; Documented KRAS mutation positive status (per Lung Cancer Mutation Consortium [LCMC] guidelines; see www.golcmc.com); At least one prior chemotherapy regimen for advanced NSCLC; Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; 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; Females of childbearing potential must have a negative serum pregnancy test; Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease; Total bilirubin ≤ 1.5 × ULN; Serum creatinine ≤ 1.5 × ULN; Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; Platelets ≥ 100 x 10^9/L; Hemoglobin ≥ 10 g/dL (transfusion is allowed at least 7 days prior to randomization); Subjects must agree to allow testing for c-Met status if archival and/or fresh tissue biopsy samples are available. Exclusion Criteria: Previous receipt of erlotinib or other epidermal growth factor receptor (EGFR) inhibitors; Previous receipt of any c-MET inhibitor (a receptor tyrosine kinase) or other c-MET-targeted therapy, including ARQ 197, MetMab, crizotinib; 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).; Inability or unwillingness to receive ARQ 197, erlotinib, docetaxel, gemcitabine, and/or pemetrexed including contraindications, hypersensitivity, or prior administration; Receipt of any anti-tumor treatment for NSCLC within 3 weeks (2 weeks for radiotherapy) prior to randomization; Pregnant or breastfeeding; Significant gastrointestinal disorder that could, in the opinion of the Investigator, interfere with the absorption of ARQ 197 and/or erlotinib; Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation; Other malignancies within the last three years, with the exception of adequately treated intraepithelial carcinoma of the cervix uteri, prostate carcinoma with a prostate-specific antigen (PSA) value < 0.2 ng/mL or basal or squamous cell carcinoma of the skin; Known human immunodeficiency virus (HIV), or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; Major surgical procedure within 4 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 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); 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 central nervous system [CNS] metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications); Known EGFR-mutation positive status
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01395758
Other Study ID Numbers ICMJE	ARQ 197-218
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	ArQule
Study Sponsor ICMJE	ArQule
Collaborators ICMJE	Not Provided
Investigators ICMJE	Not Provided
PRS Account	ArQule
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP