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

Metastatic Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00614393
• Other study ID #: 0646-004
• Secondary ID: 2007_529
• Status: Completed
• Phase: Phase 2
• Start date: December 24, 2007
• Est. completion date: March 7, 2012

Study information

• Verified date: July 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 558
• Est. completion date: March 7, 2012
• Est. primary completion date: June 1, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Biological:
• dalotuzumab
IV infusion

Drug:
• irinotecan hydrochloride
IV infusion

Biological:
• cetuximab
IV infusion

Drug:
• placebo
IV infusion

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & Publications (1)

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, Frödin 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)