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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01075048
Recruitment Status : Completed
First Posted : February 24, 2010
Results First Posted : August 14, 2020
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Tivantinib Drug: Placebo Drug: Cetuximab Drug: Irinotecan Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 131 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase 1 is single group open label with one arm. Phase 2 is parallel, double-blind design with two arms.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : January 26, 2010
Actual Primary Completion Date : October 12, 2012
Actual Study Completion Date : February 20, 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 2: Tivantinib, cetuximab, irinotecan
Tivantinib in combination with irinotecan and cetuximab.
Drug: Tivantinib
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.
Other Name: ARQ 197

Drug: Cetuximab
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.

Drug: Irinotecan
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.

Placebo Comparator: Phase 2: Placebo, cetuximab, irinotecan
Placebo in combination with irinotecan and cetuximab
Drug: Placebo
Placebo to match ARQ 197, administered twice daily. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.

Drug: Cetuximab
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.

Drug: Irinotecan
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.

Experimental: Phase 1: Tivantinib, cetuximab, irinotecan
Tivantinib in combination with irinotecan and cetuximab.
Drug: Tivantinib
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.
Other Name: ARQ 197

Drug: Cetuximab
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.

Drug: Irinotecan
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.




Primary Outcome Measures :
  1. 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 [ Time Frame: Baseline up to 80 weeks postdose ]
    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).

  2. 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 [ Time Frame: Baseline up to 80 weeks postdose ]
    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).


Secondary Outcome Measures :
  1. 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 [ Time Frame: Baseline up to 2 years 10 months postdose ]
    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.

  2. 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 [ Time Frame: Baseline up to 5 years 1 month postdose ]
    Overall survival is defined as the time from randomization date to the date of death.

  3. 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 [ Time Frame: Baseline up to 80 weeks postdose ]
    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.

  4. 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 [ Time Frame: Baseline up to 30 days after last dose, up to 5 years 1 month ]
    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.

  5. 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 [ Time Frame: Baseline up to 30 days after last dose, up to 5 years 1 month ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01075048


Locations
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United States, California
Beverly Hills, California, United States, 90211-1850
Encinitas, California, United States, 92024
Fountain Valley, California, United States, 92708
Riverside, California, United States, 92501
United States, Colorado
Fort Collins, Colorado, United States, 80528
United States, Connecticut
Norwich, Connecticut, United States, 06360
United States, Florida
Boynton Beach, Florida, United States, 33435
Fort Myers, Florida, United States, 33916
Orlando, Florida, United States, 32836
United States, Illinois
Centralia, Illinois, United States, 62801
United States, Louisiana
Metairie, Louisiana, United States, 70006
United States, Maryland
Baltimore, Maryland, United States, 21237
Hagerstown, Maryland, United States, 21740
United States, Nebraska
Omaha, Nebraska, United States, 68114
United States, New York
Buffalo, New York, United States, 14263
Lake Success, New York, United States, 11042
United States, Ohio
Canton, Ohio, United States, 44718
Cincinnati, Ohio, United States, 45242
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
United States, South Carolina
Charleston, South Carolina, United States, 29403
Columbia, South Carolina, United States, 29210
United States, Tennessee
Nashville, Tennessee, United States, 372203
United States, Texas
Houston, Texas, United States, 77030
United States, Washington
Seattle, Washington, United States, 98104
France
Bayonne, France, 64100
Lille cedex, France, 59020
Marseille cedex, France, 13285
Germany
Halle, Germany
Leer, Germany, 26789
Mannheim, Germany, 68167
Munchen, Germany, 81675
Italy
Milano, Italy, 20089
Reggio-Emilia, Italy, 42100
Treviglio, Italy, 24047
Russian Federation
Chelyabinsk, Russian Federation, 454087
Kursk, Russian Federation, 305035
Moscow, Russian Federation, 125367
Pyatigorsk, Russian Federation, 357502
Saint-Petersburg, Russian Federation, 194044
Samara, Russian Federation, 443031
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
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Study Director: Clinical Study Leader Daiichi Sankyo, Inc.
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT01075048    
Other Study ID Numbers: ARQ197-A-U252
First Posted: February 24, 2010    Key Record Dates
Results First Posted: August 14, 2020
Last Update Posted: August 14, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
Keywords provided by Daiichi Sankyo, Inc.:
Colorectal cancer
wild-type KRAS
irinotecan
cetuximab
second-line therapy
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Cetuximab
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological