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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: dalotuzumab
* Drug: irinotecan hydrochloride
* Biological: cetuximab
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dalotuzumab 10 mg/kg Q1W (DB)<br>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. | Biological: dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;Drug: irinotecan hydrochloride<br>* IV infusion<br>* Other names: CAMPTOSAR®;Biological: cetuximab<br>* IV infusion<br>* Other names: ERBITUX®;|
| Experimental: Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL)<br>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. | Biological: dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;Drug: irinotecan hydrochloride<br>* IV infusion<br>* Other names: CAMPTOSAR®;Biological: cetuximab<br>* IV infusion<br>* Other names: ERBITUX®;|
| Experimental: Dalotuzumab 10 mg/kg Q1W (OL)<br>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. | Biological: dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;Drug: irinotecan hydrochloride<br>* IV infusion<br>* Other names: CAMPTOSAR®;Biological: cetuximab<br>* IV infusion<br>* Other names: ERBITUX®;|
| Experimental: Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB)<br>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. | Biological: dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;Drug: irinotecan hydrochloride<br>* IV infusion<br>* Other names: CAMPTOSAR®;Biological: cetuximab<br>* IV infusion<br>* Other names: ERBITUX®;|
| Active Comparator: Placebo + Cetuximab + Irinotecan (DB)<br>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. | Drug: irinotecan hydrochloride<br>* IV infusion<br>* Other names: CAMPTOSAR®;Biological: cetuximab<br>* IV infusion<br>* Other names: ERBITUX®;Drug: placebo<br>* IV infusion<br>* Other names: normal saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 12 weeks after last dose of study drug (Up to 35 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. | Up to last dose of study drug (Up to 32 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. | Up to 30 days after last dose of study drug (Up to 33 months) | 
| 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. | Up to 30 days after last dose of study drug (Up to 33 months) | 
| Percentage of Participants Who Discontinue Study Drug Due to an AE | 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. The percentage of participants who discontinued study drug due to an AE is presented. | Up to last dose of study drug (Up to 32 months) | 
| 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. | Up to 30 days after last dose of study drug (Up to 33 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 6 weeks (Up to 32 months) |