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Study of Dalotuzumab (MK-0646) in Combination With Cetuximab and Irinotecan in Metastatic Colorectal Cancer (MK-0646-004)

Primary Purpose

Metastatic Colorectal Cancer

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

dalotuzumab

irinotecan hydrochloride

cetuximab

placebo

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participant must have confirmed wtKRAS CRC.
Participant must have previously failed both irinotecan and oxaliplatin containing regimens, and should have progressed on or within 3 months of completing their last line of therapy with objective evidence of progression as verified by previous radiologic scans.

Exclusion Criteria:

Participant has had cancer treatment within 2 weeks before the first dose of study drug(s) or if the side effects from the drugs have not gone down to a certain level 2 weeks before the first dose of study drugs.
Participant has had a bad side effect to irinotecan therapy.
Participant has human immunodeficiency virus (HIV).
Participant has Hepatitis B or C.
Participant is pregnant or breast feeding or planning to have a child while on this study.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Arm Label

Dalotuzumab 10 mg/kg Q1W (DB)

Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL)

Dalotuzumab 10 mg/kg Q1W (OL)

Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB)

Placebo + Cetuximab + Irinotecan (DB)

Arm Description

In double-blind (DB) Week 1, participants receive cetuximab 400 mg/m^2 intravenously (IV) loading dose and irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m^2 IV one time each week (Q1W) maintenance dose, irinotecan IV Q1W and DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment.

In the open-label (OL) portion of the study, ≥6 participants receive cetuximab 400 mg/m^2 Q1W + irinotecan Q1W at their pre-study dosage + OL dalotuzumab (loading dose of 15 mg/kg IV followed by a maintenance dose of 7.5 mg/kg 2 weeks later) to verify the safety of the regimen. In DB Week 1, participants receive cetuximab 400 mg/m^2 IV + irinotecan IV. In DB Week 2, participants receive cetuximab 250 mg/m^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants receive cetuximab 250 mg/m^2 IV + irinotecan IV. Starting with DB Week 4, participants receive cetuximab 250 mg/m^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 7.5 mg/kg IV Q2W for up to 32 months of treatment.

In the OL portion of the study, ≥6 participants receive cetuximab 400 mg/m^2 Q1W+ irinotecan Q1W at their pre-study dosage + OL dalotuzumab 10 mg/kg IV Q1W to verify the safety of the regimen. In DB Week 1, participants receive cetuximab 400 mg/m^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment.

In DB Week 1, participants receive cetuximab 400 mg/m^2 IV + irinotecan IV at their pre-study dosage. In DB Week 2, participants receive cetuximab 250 mg/m^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants receive cetuximab 250 mg/m^2 IV + irinotecan IV. Starting with DB Week 4, participants receive cetuximab 250 mg/m^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 7.5 mg/kg IV Q2W for up to 32 months of treatment.

In DB Week 1, participants receive cetuximab 400 mg/m^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants receive cetuximab 250 mg/m^2 IV Q1W + irinotecan IV Q1W + DB normal saline (placebo) IV Q1W for up to 32 months of treatment.

Outcomes

Primary Outcome Measures

Overall Survival (OS)

The OS of participants with metastatic colorectal cancer (CRC) expressing the KRAS wild-type (wtKRAS) tumor genotype (indicating no detection of KRAS mutation) was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS was analyzed using the Kaplan-Meier method and is reported in months.

Progression-free Survival (PFS)

The PFS of participants with metastatic CRC expressing the wtKRAS genotype was defined as the time from the first day of study treatment to the first documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST 1.0) as documented by an independent core laboratory, or death due to any cause, whichever occurred first. Disease progression was defined as either a 20% or greater relative increase in the sum of diameters of target lesions OR an absolute increase of at least 5mm in the sum of lesions or the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and is reported in months.

Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity

An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. (Grade 3=Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4=Life-threatening consequences; urgent intervention indicated. Grade 5=Death related to AE.) Participants were monitored for AEs until the earlier of study discontinuation or 30 days after dalotuzumab/placebo discontinuation. AE grades were assessed using the National Cancer Institute (NCI) CTCAE, version 3.0.

Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity

An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. (Grade 3=Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4=Life-threatening consequences; urgent intervention indicated. Grade 5=Death related to AE.) Drug-related AEs were those AEs that were possibly, probably, or definitely related to study drug or protocol-specified procedures. Participants were monitored for AEs related to dalotuzumab or placebo until the earlier of study discontinuation or 30 days after dalotuzumab/placebo discontinuation. AE grades were assessed using the NCI CTCAE, version 3.0.

Percentage of Participants Who Discontinue Study Drug Due to an AE

Percentage of Participants Who Experience an AE of Infusion Site Reaction

The percentage of participants who experienced an AE of infusion site reaction is presented.

Secondary Outcome Measures

Overall Response Rate (ORR) of Dalotuzumab in Combination With Cetuximab + Irinotecan Versus ORR of Cetuximab + Irinotecan Alone in Participants With Wild Type of Colorectal Cancer

ORR, using RECIST 1.0, was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR; disappearance of all target lesions) or Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) at any time during the study, based on central radiology review.

Full Information

NCT ID

NCT00614393

First Posted

January 17, 2008

Last Updated

July 12, 2018

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT00614393

Brief Title

Study of Dalotuzumab (MK-0646) in Combination With Cetuximab and Irinotecan in Metastatic Colorectal Cancer (MK-0646-004)

Official Title

A Phase II/III Study of Dalotuzumab (MK-0646) Treatment in Combination With Cetuximab and Irinotecan for Patients With Metastatic Colorectal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

July 2018

Overall Recruitment Status

Completed

Study Start Date

December 24, 2007 (Actual)

Primary Completion Date

June 1, 2010 (Actual)

Study Completion Date

March 7, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study will compare the safety and efficacy of dalotuzumab (MK-0646) in combination with cetuximab and irinotecan in treating participants with wild type KRAS (wtKRAS) metastatic colorectal cancer (CRC) compared to cetuximab and irinotecan alone. The primary study hypothesis is that administration of dalotuzumab in combination with cetuximab and irinotecan to participants with metastatic CRC expressing the wtKRAS genotype improves Overall Survival OR Progression-free Survival compared to participants treated with cetuximab and irinotecan alone.

Detailed Description

Dalotuzumab is a humanized monoclonal antibody (mAb) that targets the insulin-like growth factor type 1 receptor-1 (IGF-1R). Dalotuzumab may act through inhibition of insulin-like growth factor-1 (IGF-1)-mediated cell signaling to cause reductions in tumor growth and spread antibody dependent cell-mediated cytotoxicity. In preclinical studies, dalotuzumab improved the activity of an anti-epidermal growth factor receptor (EGFR) mAb and the activity of erlotinib, a small molecule inhibitor of EGFR. All eligible participants will receive cetuximab 400 mg/m^2 infusion over 120 minutes followed by weekly infusions of cetuximab 250 mg/m^2 over 60-120 minutes along with irinotecan infusion over 30-90 minutes. Dosage of irinotecan will be the same as most recent pre-study therapy. Participants will then be assigned to one of three treatment double-blind arms.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Colorectal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

558 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dalotuzumab 10 mg/kg Q1W (DB)

Arm Type

Experimental

Arm Description

Arm Title

Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL)

Arm Type

Experimental

Arm Description

Arm Title

Dalotuzumab 10 mg/kg Q1W (OL)

Arm Type

Experimental

Arm Description

Arm Title

Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB)

Arm Type

Experimental

Arm Description

Arm Title

Placebo + Cetuximab + Irinotecan (DB)

Arm Type

Active Comparator

Arm Description

Intervention Type

Biological

Intervention Name(s)

dalotuzumab

Other Intervention Name(s)

MK-0646

Intervention Description

IV infusion

Intervention Type

Drug

Intervention Name(s)

irinotecan hydrochloride

Other Intervention Name(s)

CAMPTOSAR®

Intervention Description

IV infusion

Intervention Type

Biological

Intervention Name(s)

cetuximab

Other Intervention Name(s)

ERBITUX®

Intervention Description

IV infusion

Intervention Type

Drug

Intervention Name(s)

placebo

Other Intervention Name(s)

placebo to dalotuzumab, normal saline solution

Intervention Description

IV infusion

Primary Outcome Measure Information:

Title

Overall Survival (OS)

Description

Time Frame

Up to 12 weeks after last dose of study drug (Up to 35 months)

Title

Progression-free Survival (PFS)

Description

Time Frame

Up to last dose of study drug (Up to 32 months)

Title

Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity

Description

Time Frame

Up to 30 days after last dose of study drug (Up to 33 months)

Title

Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity

Description

Time Frame

Up to 30 days after last dose of study drug (Up to 33 months)

Title

Percentage of Participants Who Discontinue Study Drug Due to an AE

Description

Time Frame

Up to last dose of study drug (Up to 32 months)

Title

Percentage of Participants Who Experience an AE of Infusion Site Reaction

Description

The percentage of participants who experienced an AE of infusion site reaction is presented.

Time Frame

Up to 30 days after last dose of study drug (Up to 33 months)

Secondary Outcome Measure Information:

Title

Overall Response Rate (ORR) of Dalotuzumab in Combination With Cetuximab + Irinotecan Versus ORR of Cetuximab + Irinotecan Alone in Participants With Wild Type of Colorectal Cancer

Description

Time Frame

Every 6 weeks (Up to 32 months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participant must have confirmed wtKRAS CRC. Participant must have previously failed both irinotecan and oxaliplatin containing regimens, and should have progressed on or within 3 months of completing their last line of therapy with objective evidence of progression as verified by previous radiologic scans. Exclusion Criteria: Participant has had cancer treatment within 2 weeks before the first dose of study drug(s) or if the side effects from the drugs have not gone down to a certain level 2 weeks before the first dose of study drugs. Participant has had a bad side effect to irinotecan therapy. Participant has human immunodeficiency virus (HIV). Participant has Hepatitis B or C. Participant is pregnant or breast feeding or planning to have a child while on this study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Merck Sharp & Dohme LLC

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Citations:

PubMed Identifier

26405092

Citation

Sclafani F, Kim TY, Cunningham D, Kim TW, Tabernero J, Schmoll HJ, Roh JK, Kim SY, Park YS, Guren TK, Hawkes E, Clarke SJ, Ferry D, Frodin JE, Ayers M, Nebozhyn M, Peckitt C, Loboda A, Mauro DJ, Watkins DJ. A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer. J Natl Cancer Inst. 2015 Sep 23;107(12):djv258. doi: 10.1093/jnci/djv258. Print 2015 Dec.

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Study of Dalotuzumab (MK-0646) in Combination With Cetuximab and Irinotecan in Metastatic Colorectal Cancer (MK-0646-004)

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