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Metastatic Colorectal CancerPhase 1/2NCT01075048

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

A Phase 1/2 study testing Tivantinib, Cetuximab and Irinotecan in people with Metastatic Colorectal Cancer, run by Daiichi Sankyo at 40 sites in 5 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Tivantinib, Cetuximab and Irinotecan
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
131 participants
Where
40 sitesin 5 countries
Study dates
26 Jan 2010to 20 Feb 2015
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

40 sites in 5 countries.

40 sites in 5 countries

United States24 sites

  • Study site

    Baltimore, Maryland, 21237

  • Study site

    Beverly Hills, California, 90211-1850

  • Study site

    Boynton Beach, Florida, 33435

  • Study site

    Buffalo, New York, 14263

  • Study site

    Canton, Ohio, 44718

  • Study site

    Centralia, Illinois, 62801

  • Study site

    Charleston, South Carolina, 29403

  • Study site

    Cincinnati, Ohio, 45242

  • Study site

    Columbia, South Carolina, 29210

  • Study site

    Encinitas, California, 92024

  • Study site

    Fort Collins, Colorado, 80528

  • Study site

    Fort Myers, Florida, 33916

  • Study site

    Fountain Valley, California, 92708

  • Study site

    Hagerstown, Maryland, 21740

  • Study site

    Houston, Texas, 77030

  • Study site

    Lake Success, New York, 11042

  • Study site

    Metairie, Louisiana, 70006

  • Study site

    Nashville, Tennessee, 372203

  • Study site

    Norwich, Connecticut, 06360

  • Study site

    Oklahoma City, Oklahoma, 73104

  • Study site

    Omaha, Nebraska, 68114

  • Study site

    Orlando, Florida, 32836

  • Study site

    Riverside, California, 92501

  • Study site

    Seattle, Washington, 98104

Other trials in United States

Russia6 sites

  • Study site

    Chelyabinsk, 454087

  • Study site

    Kursk, 305035

  • Study site

    Moscow, 125367

  • Study site

    Pyatigorsk, 357502

  • Study site

    Saint Petersburg, 194044

  • Study site

    Samara, 443031

Other trials in Russia

Germany4 sites

  • Study site

    Halle

  • Study site

    Leer, 26789

  • Study site

    Mannheim, 68167

  • Study site

    München, 81675

Other trials in Germany

France3 sites

  • Study site

    Bayonne, 64100

  • Study site

    Lille, 59020

  • Study site

    Marseille, 13285

Other trials in France

Italy3 sites

  • Study site

    Milan, 20089

  • Study site

    Reggio Emilia, 42100

  • Study site

    Treviglio, 24047

Other trials in Italy

About this study

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

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.

Read the 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.
Being tested
Tivantinib, Placebo, Cetuximab, Irinotecan
Keywords
Colorectal cancer, wild-type KRAS, irinotecan, cetuximab, second-line therapy
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TivantinibDrug

    Also called ARQ 197

    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.

  • PlaceboDrug

    Placebo to match ARQ 197, administered twice daily. Administered until disease progression, unacceptable toxicity or other discontinuation criteria is met.

  • CetuximabDrug

    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.

  • IrinotecanDrug

    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.

Study groups in NCT01075048
Study groupRoleWhat they receive
Phase 2: Tivantinib, cetuximab, irinotecanExperimentalTivantinib in combination with irinotecan and cetuximab.
Receives: Drug: Tivantinib; Drug: Cetuximab; Drug: Irinotecan
Phase 2: Placebo, cetuximab, irinotecanPlacebo comparatorPlacebo in combination with irinotecan and cetuximab
Receives: Drug: Placebo; Drug: Cetuximab; Drug: Irinotecan
Phase 1: Tivantinib, cetuximab, irinotecanExperimentalTivantinib in combination with irinotecan and cetuximab.
Receives: Drug: Tivantinib; Drug: Cetuximab; Drug: Irinotecan

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    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).

    Measured: Baseline up to 80 weeks postdose

  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

    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).

    Measured: Baseline up to 80 weeks postdose

Secondary outcomes (5)

  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

    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.

    Measured: Baseline up to 2 years 10 months postdose

  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

    Overall survival is defined as the time from randomization date to the date of death.

    Measured: Baseline up to 5 years 1 month postdose

  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

    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.

    Measured: Baseline up to 80 weeks postdose

  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

    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.

    Measured: Baseline up to 30 days after last dose, up to 5 years 1 month

  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

    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.

    Measured: Baseline up to 30 days after last dose, up to 5 years 1 month

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Feb 2010 (estimated)
  2. Study start26 Jan 2010
  3. Primary completion12 Oct 2012
  4. Study completion20 Feb 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Phase 1 is single group open label with one arm. Phase 2 is parallel, double-blind design with two arms.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
131 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01075048
Sponsor's protocol ID
ARQ197-A-U252
Status last verified
Mar 2021
First submitted
17 Feb 2010
Last updated
8 Apr 2021
Data monitoring committee
Yes
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Tivantinib, Cetuximab and Irinotecan in people with Metastatic Colorectal Cancer, run by Daiichi Sankyo at 40 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 40 sites in United States, Russia, Germany, France, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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 (time frame: Baseline up to 80 weeks postdose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01075048.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2021.

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