Clinical trial NCT01075048: ARQ 197 in Combination With Chemotherapy in Patients With Metastatic Colorectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Colorectal cancer
wild-type KRAS
irinotecan
cetuximab
second-line therapy
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2010-02-24
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1 is single group open label with one arm. Phase 2 is parallel, double-blind design with two arms.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. All participants must express the wild-type form of the gene KRAS.
3. Measurable disease according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria, Version 1.1.
4. Male or female \>= to 18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade \<= to 1.
7. 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).
8. 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.
9. All female participants of childbearing potential must each have a negative pregnancy test (serum or urine) result before initiating study treatment.
10. 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:

1. Prior therapy with an Epidermal Growth Factor Receptor (EGFR) inhibitor.
2. 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).
3. Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study.
4. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy, or any other investigational anticancer agent within 4 weeks prior to start of study treatment.
5. 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).
6. Malabsorption syndrome, chronic diarrhea (lasting greater than 4 weeks), inflammatory bowel disease, or partial bowel obstruction.
7. 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.
8. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.
9. 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.
10. Clinically significant active infection that requires antibiotic therapy.
11. Previous administration of ARQ 197.
12. 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.
13. 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.
14. Inability to swallow oral medications.
15. Pregnant or nursing females.

Primary outcomes:
measure: 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
timeFrame: Baseline up to 80 weeks postdose
measure: 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
timeFrame: Baseline up to 80 weeks postdose
Secondary outcomes:
measure: 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
timeFrame: Baseline up to 2 years 10 months postdose
measure: 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
timeFrame: Baseline up to 5 years 1 month postdose
measure: 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
timeFrame: Baseline up to 80 weeks postdose
measure: 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
timeFrame: Baseline up to 30 days after last dose, up to 5 years 1 month
measure: 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
timeFrame: Baseline up to 30 days after last dose, up to 5 years 1 month
Other outcomes:
Locations:
city: Beverly Hills
country: United States
state: California
city: Encinitas
country: United States
state: California
city: Fountain Valley
country: United States
state: California
city: Riverside
country: United States
state: California
city: Fort Collins
country: United States
state: Colorado
city: Norwich
country: United States
state: Connecticut
city: Boynton Beach
country: United States
state: Florida
city: Fort Myers
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Centralia
country: United States
state: Illinois
city: Metairie
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Hagerstown
country: United States
state: Maryland
city: Omaha
country: United States
state: Nebraska
city: Buffalo
country: United States
state: New York
city: Lake Success
country: United States
state: New York
city: Canton
country: United States
state: Ohio
city: Cincinnati
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Charleston
country: United States
state: South Carolina
city: Columbia
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Bayonne
country: France
city: Lille cedex
country: France
city: Marseille cedex
country: France
city: Halle
country: Germany
city: Leer
country: Germany
city: Mannheim
country: Germany
city: Munchen
country: Germany
city: Milano
country: Italy
city: Reggio-Emilia
country: Italy
city: Treviglio
country: Italy
city: Chelyabinsk
country: Russian Federation
city: Kursk
country: Russian Federation
city: Moscow
country: Russian Federation
city: Pyatigorsk
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Samara
country: Russian Federation
Study officials:
affiliation: Daiichi Sankyo
name: Clinical Study Leader
role: STUDY_DIRECTOR
References: