ARQ 197 in Combination With Chemotherapy in Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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ARQ 197 or placebo in combination with irinotecan and cetuximab in participants with metastatic colorectal cancer (CRC), in participants with wild-type KRAS alleles who have failed front-line systemic therapy, to evaluate the safety, tolerability, and efficacy of ARQ 197, define the recommended dose for Phase 2. After the recommended dose is determined for Phase 2, participants receive study drug or placebo with irinotecan and cetuximab.

Detailed Description
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Phase 1/2 Multicenter study: Phase 1 portion is open-label to evaluate the safety of ARQ 197 administered in combination with irinotecan and cetuximab. Phase 2 portion is designed as a randomized, double-blind placebo-controlled study to assess the efficacy and safety of ARQ 197 or matching placebo administered in combination with irinotecan and cetuximab.

Official Title
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A Randomized, Placebo-Controlled, Phase 1/2 Study Of ARQ 197 in Combination With Irinotecan and Cetuximab in Subjects With Metastatic Colorectal Cancer With Wild-type KRAS Who Have Received Front-Line Systemic Therapy

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Tivantinib
* Drug: Placebo
* Drug: Cetuximab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with surgically unresectable locally advanced or metastatic disease who have received one prior line of chemotherapy. (The Phase 1 portion of the study will be open for enrollment for subjects who received 1 or more prior therapies). Both relapsed and refractory CRC are allowed. All participants must express the wild-type form of the gene KRAS. Measurable disease according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria, Version 1.1. Male or female >= to 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade <= to 1. Adequate bone marrow, liver, and renal functions, defined as: Hemoglobin >= to 9.0 g/dL (transfusion and/or growth factor support allowed). Absolute neutrophil count (ANC) >= to 1.5 x 10^9/L. Platelet count >= to 75 x 10^9/L. Serum creatinine <= to 1.5 x upper limit of normal (ULN) or creatinine clearance >= to 60 mL/min. Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase <= to 2.5 x ULN in subjects with no liver metastasis and <= to 5.0 x ULN in participants with liver metastasis. Total bilirubin <= to 1.5 x ULN (<= to 4 x ULN and direct bilirubin <= to 1.5 x ULN is acceptable for subjects with Gilbert's syndrome). Male and female participants of child-bearing potential 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. All female participants of childbearing potential must each have a negative pregnancy test (serum or urine) result before initiating study treatment. Participants must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Independent Ethics Committee (IEC) or Institutional Review Board (IRB)-approved informed consent form (ICF) (including HIPAA authorization, if applicable) before performance of any study specific procedures or tests. Exclusion Criteria: Prior therapy with an Epidermal Growth Factor Receptor (EGFR) inhibitor. History of malignancy other than CRC, unless there is an exception that the malignancy has been cured and no tumor-specific treatment for the malignancy has been administered within the 5 years prior to initiation of study treatment (participants with a history of basal cell carcinoma or benign tumor of cervix can be enrolled if diagnosis and treatment occurred less than 3 years prior to randomization). Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 4 weeks prior to start of study treatment. History of cardiac disease: Congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification. Active coronary artery disease (CAD). Previously diagnosed bradycardia or other cardiac arrhythmia defined as Grade 2 or higher according to NCI CTCAE, version 4.0, or uncontrolled hypertension. Myocardial infarction that occurred within 6 months prior to start of study treatment (myocardial infarction that occurred greater than 6 months before the start of study treatment is permitted). Malabsorption syndrome, chronic diarrhea (lasting greater than 4 weeks), inflammatory bowel disease, or partial bowel obstruction. Known metastatic brain or meningeal tumors, unless the participant is greater than 6 months from definitive therapy, has a negative imaging study within 4 weeks of first dose of study treatment, and is clinically stable (no concomitant therapy, including supportive therapy with steroids or anticonvulsant medications) with respect to the tumor at the time of first dose of study treatment. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis. Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement with the tumor. Participants with minimal pleural effusion may be eligible upon request by Investigator and approval by Sponsor. Clinically significant active infection that requires antibiotic therapy. Previous administration of ARQ 197. Substance abuse or medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the participant's participation in the clinical trial or evaluation of the clinical trial results. Any condition that is unstable or that could jeopardize the safety of the subject and the participant's protocol compliance including known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inability to swallow oral medications. Pregnant or nursing females.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1 is single group open label with one arm. Phase 2 is parallel, double-blind design with two arms.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2: Tivantinib, cetuximab, irinotecan<br>Tivantinib in combination with irinotecan and cetuximab. | Drug: Tivantinib<br>* ARQ 197 is supplied as a 120-mg capsule, administered twice daily at the dose determined in the Phase 1 portion of the study. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>* Other names: ARQ 197;Drug: Cetuximab<br>* Cetuximab 500 mg/ m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>Drug: Irinotecan<br>* 60 minutes after cetuximab, Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>|
| Placebo Comparator: Phase 2: Placebo, cetuximab, irinotecan<br>Placebo in combination with irinotecan and cetuximab | Drug: Placebo<br>* Placebo to match ARQ 197, administered twice daily. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>Drug: Cetuximab<br>* Cetuximab 500 mg/ m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>Drug: Irinotecan<br>* 60 minutes after cetuximab, Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>|
| Experimental: Phase 1: Tivantinib, cetuximab, irinotecan<br>Tivantinib in combination with irinotecan and cetuximab. | Drug: Tivantinib<br>* ARQ 197 is supplied as a 120-mg capsule, administered twice daily at the dose determined in the Phase 1 portion of the study. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>* Other names: ARQ 197;Drug: Cetuximab<br>* Cetuximab 500 mg/ m^2 intravenous infusion over 120 minutes at the first cycle, then over 60-minutes at subsequent cycles. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>Drug: Irinotecan<br>* 60 minutes after cetuximab, Irinotecan 180 mg/m^2 intravenous infusion over 30 - 90 minutes. Administered on Day 1 and Day 15 of each 28 day cycle. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Participants With Metastatic Colorectal Cancer With Wild-Type K-ras Oncogene (KRAS) Who Have Received Front-Line Systemic Therapy | Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause (as of data cutoff 12 Oct 2012). | Baseline up to 80 weeks postdose | 
| Progression-Free Survival (PFS) Using Computed Best Response Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Received Front-Line Systemic Therapy | Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause (as of data cutoff 12 Oct 2012). | Baseline up to 80 weeks postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Tumor Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Subjects With Metastatic Colorectal Cancer Who Have Received Front-Line Systemic Therapy | Best overall tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria included complete response (CR) defined as the disappearance of all target lesions; partial response (PR) defined as a ≥30% decrease in the longest diameter of target lesions; stable disease (SD) defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response was defined as CR+PR. | Baseline up to 2 years 10 months postdose | 
| Overall Survival (OS) Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Participants With Metastatic Colorectal Cancer With Wild-Type K-ras Oncogene (KRAS) Who Have Received Front-Line Systemic Therapy | Overall survival is defined as the time from randomization date to the date of death. | Baseline up to 5 years 1 month postdose | 
| Duration of Response and Stable Disease Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Participants With Metastatic Colorectal Cancer With Wild-Type KRAS Who Have Received Front-Line Systemic Therapy | Duration of response was defined for participants with complete response (CR)/partial response (PR) as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of progressive disease. Duration of stable disease (SD) was defined for participants whose best response was SD at the time from the randomization date to the date of the first documentation of progressive disease. Based on Response Evaluation Criteria in Solid Tumors version 1.1, CR is defined as a disappearance of all target lesions, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. | Baseline up to 80 weeks postdose | 
| Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Subjects With Metastatic Colorectal Cancer Who Have Received Front-Line Systemic Therapy | A treatment-emergent adverse event (TEAE) was defined as an AE that had an onset date on or after the first dose of study drug, cetuximab, or irinotecan up to and including 30 days after the last dose of any study drug and worsened in severity after the first dose of study drug relative to the pre-treatment state. | Baseline up to 30 days after last dose, up to 5 years 1 month | 
| Treatment-Emergent Infection and Infestation Adverse Events Following Treatment With Tivantinib (ARQ 197) in Combination With Irinotecan and Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Received Front-Line Systemic Therapy | A treatment-emergent adverse event (TEAE) was defined as an AE that had an onset date on or after the first dose of study drug, cetuximab, or irinotecan up to and including 30 days after the last dose of any study drug and worsened in severity after the first dose of study drug relative to the pre-treatment state. | Baseline up to 30 days after last dose, up to 5 years 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, wild-type KRAS, irinotecan, cetuximab, second-line therapy