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

• ClinicalTrials.gov Identifier: NCT01395758
• Recruitment Status: Completed
• First Posted: July 18, 2011
• Results First Posted: April 3, 2018
• Last Update Posted: April 3, 2018
• Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Tracking Information

• First Submitted Date: July 1, 2011
• First Posted Date: 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: July 2011
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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. ]

Current Secondary Outcome Measures (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 (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer
• Official Title: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Non-Small Cell Lung Cancer

Intervention

• 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

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 5, 2018): 96
• Original Estimated Enrollment (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

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 Lung Cancer Mutation Consortium [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 epidermal growth factor receptor (EGFR) inhibitors
2. Previous receipt of any c-MET inhibitor (a receptor tyrosine kinase) 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 prostate-specific antigen (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 central nervous system [CNS] metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications)
14. 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: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01395758
• Other Study ID Numbers: ARQ 197-218
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Study Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Verification Date: March 2018