Phase I Study of Dalotuzumab (MK-0646) in Combination With Cetuximab and Irinotecan in Participants With Colorectal Cancer (MK-0646-016)

Phase 1

Completed

• Conditions: Colorectal Cancer
• Interventions: Biological: Dalotuzumab 10 mg/kg; Biological: Cetuximab; Drug: Irinotecan; Biological: Dalotuzumab 15/7.5 mg/kg

• Registration Number: NCT00925015
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

The purposes of this study were to assess the safety, tolerability, pharmacokinetic interactions, and the Human Anti-Human Antibody of dalotuzumab in combination with cetuximab and irinotecan in participants with advanced or metastatic colorectal cancer in Japan.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study Start: 2009-06-17
• Study First Submitted: 2009-06-17
• Study First Submitted QC: 2009-06-18
• Study First Posted: 2009-06-19
• Primary Completion: 2010-07-28
• Study Completion: 2010-12-06
• Results First Submitted: 2017-04-24
• Results First Submitted QC: 2017-04-24
• Results First Posted: 2017-08-02
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-18
• Last Update Posted: 2018-08-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Is 20 years of Age or older
• Has a histologically or cytologically confirmed colorectal cancer
• Has 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 radiological evidence of progression as verified by previous radiologic scans
• Must have adequate organ function

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Exclusion Criteria

• Has had chemotherapy, radiotherapy, or biological therapy within 4 weeks prior to initial dosing on this study or whose toxicities from agents administrated 4 weeks earlier have not resolved to at least grade 1 or baseline
• Has experienced intolerable toxicity to Irinotecan therapy
• Has prior exposure to insulin-like growth factor 1 receptor (IGF-1R) inhibitors or epidermal growth factor receptor (EGFR) inhibitors (e.g. Cetuximab)
• Is concurrently using growth hormone (GH), Or GH inhibitors

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cetux/Irin - Dmab 10 mg/kg	Dalotuzumab 10 mg/kg	After treatment with Cetuximab (Cetux) and Irinotecan (Irin), Dalotuzumab (Dmab) was administered as an intravenous infusion at 10 mg/kg in Cycle 1 on Days 22, 29 and 36; followed in subsequent cycles by treatment with 10 mg/kg on Days 1, 8, 15, 22, 29 and 36. Each cycle was 6 weeks long.
Cetux/Irin - Dmab 10 mg/kg	Cetuximab	After treatment with Cetuximab (Cetux) and Irinotecan (Irin), Dalotuzumab (Dmab) was administered as an intravenous infusion at 10 mg/kg in Cycle 1 on Days 22, 29 and 36; followed in subsequent cycles by treatment with 10 mg/kg on Days 1, 8, 15, 22, 29 and 36. Each cycle was 6 weeks long.
Cetux/Irin - Dmab 10 mg/kg	Irinotecan	After treatment with Cetuximab (Cetux) and Irinotecan (Irin), Dalotuzumab (Dmab) was administered as an intravenous infusion at 10 mg/kg in Cycle 1 on Days 22, 29 and 36; followed in subsequent cycles by treatment with 10 mg/kg on Days 1, 8, 15, 22, 29 and 36. Each cycle was 6 weeks long.
Cetux/Irin - Dmab 15/7.5 mg/kg	Cetuximab	After treatment with Cetux/Irin, Dmab was administered as an intravenous infusion at 15 mg/kg in Cycle 1 on Days 8, 22 and 36; followed in subsequent cycles by treatment with 7.5 mg/kg on Days 8, 22 and 36. Each cycle was 6 weeks long.
Cetux/Irin - Dmab 15/7.5 mg/kg	Irinotecan	After treatment with Cetux/Irin, Dmab was administered as an intravenous infusion at 15 mg/kg in Cycle 1 on Days 8, 22 and 36; followed in subsequent cycles by treatment with 7.5 mg/kg on Days 8, 22 and 36. Each cycle was 6 weeks long.
Cetux/Irin - Dmab 15/7.5 mg/kg	Dalotuzumab 15/7.5 mg/kg	After treatment with Cetux/Irin, Dmab was administered as an intravenous infusion at 15 mg/kg in Cycle 1 on Days 8, 22 and 36; followed in subsequent cycles by treatment with 7.5 mg/kg on Days 8, 22 and 36. Each cycle was 6 weeks long.
Dmab 10 mg/kg - Cetux/Irin (DDI)	Dalotuzumab 10 mg/kg	Dmab was administered in each cycle as an intravenous infusion at 10 mg/kg once weekly on Days 1, 22 and 29; followed by treatment with Cetux/Irin. For Drug-Drug Interaction (DDI). Each cycle was 6 weeks long.
Dmab 10 mg/kg - Cetux/Irin (DDI)	Cetuximab	Dmab was administered in each cycle as an intravenous infusion at 10 mg/kg once weekly on Days 1, 22 and 29; followed by treatment with Cetux/Irin. For Drug-Drug Interaction (DDI). Each cycle was 6 weeks long.
Dmab 10 mg/kg - Cetux/Irin (DDI)	Irinotecan	Dmab was administered in each cycle as an intravenous infusion at 10 mg/kg once weekly on Days 1, 22 and 29; followed by treatment with Cetux/Irin. For Drug-Drug Interaction (DDI). Each cycle was 6 weeks long.

Primary Outcome Measures

Name	Time	Method
Number of Dose-limiting Toxicities (DLTs)	Four weeks of Cycle 1 treatment (up to 28 days)	To be declared a DLT an adverse experience had a causality related to study therapy. DLTs could be adverse experiences possibly, probably, or definitely related to study therapy by the Investigator, and included the following : Grade 4 neutropenia lasting \>= 5 days; Grade 3 or 4 neutropenia with fever \>38.5°C; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity, except inadequately treated diarrhea, nausea and vomiting, rash, hyperglycemia, and transient abnormality of electrolytes. Anemia, infusion reactions, hypersensitivity reactions, and adverse experiences not-related to study therapy did not qualify as DLTs.
Number of Participants With an Adverse Event (AE)	Approximately 4 weeks after last drug treatment (up to Day 293)	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.

Secondary Outcome Measures

Name	Time	Method
Concentration at the End of Infusion (Ceoi) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The Ceoi of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Cmax of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The Cmax of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Steady-state Volume of Distribution (Vss) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The Vss of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Cmax of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8, 24, and 48 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The Cmax of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
T1/2 of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8, 24, and 48 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The T1/2 of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29..
CL of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8, 24, and 48 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The CL of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Vss of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8, 24, and 48 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The Vss of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
AUC0-24 of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8 and 24 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The AUC0-24 of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Number of Participants With Human Anti-Human Antibody (HAHA)	Up to 12 weeks after the last administration of dalotuzumab (up to 349 days)	Sera were collected from participants prior to administration of the first dose of study drug, every 6 weeks during the study period, then 4 weeks, 8 weeks and 12 weeks post-treatment. A sandwich format enzyme-linked immunosorbent assay (ELISA) was used to detect the presence of HAHA in serum.
Apparent Terminal Half-life (T1/2) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The T1/2 of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Tmax of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The Tmax of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Time to Maximum Concentration (Tmax) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone in or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The Tmax of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Maximum Concentration (Cmax) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The Cmax of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Clearance From Plasma (CL) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The CL of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
AUC0-24 of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8 and 24 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The AUC0-24 of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Area Under the Concentration-time Curve From 0-24 Hours Post-dose (AUC0-24) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8 and 24 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The AUC0-24 of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
Area Under the Concentration-time Curve From 0-168 Hours Post-dose (AUC0-168) of Dalotuzumab Following Administration of 10 mg/kg Dalotuzumab Alone or in Combination With Cetuximab / Irinotecan	Cycle 1: Day 1 and Day 22 at predose, 0.5 h after start of infusion, end of infusion, 5, 8, 24, 30, 48, 96 and 168 h after initiation of dalotuzumab infusion	In Cycle 1 Dalotuzumab was administered on Days 1 and 22 as an intravenous infusion at 10 mg/kg. In the same Cycle 1 Cetuximab was administered on Days 8, 15, 22 and 29; and Irinotecan was administered on Days 8 and 22. The AUC0-168 of plasma Dalotuzumab alone was determined on Day 1, and in combination with cetuximab/irinotecan on Day 22.
T1/2 of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The T1/2 of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
CL of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The CL of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Vss of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The Vss of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
AUC0-168 of Cetuximab Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 2, 5, 8, 24, 48, 96 and 168 h after initiation of cetuximab infusion	In Cycle 1 Cetuximab was administered with an initial intravenous infusion of 400 mg/m\^2 on Day 8, followed by subsequent once weekly intravenous infusions of 250 mg/m\^2 on Days 15, 22, 29 and 36. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Irinotecan was administered on Days 1, 22, and 29. The AUC0-168 of plasma Cetuximab was determined alone on Day 15 and in combination with dalotuzumab on Day 29.
Tmax of Irinotecan Following Administration of Cetuximab / Irinotecan Alone, or in Combination With 10 mg/kg Dalotuzumab	Cycle 1: Day 15 and Day 29 at predose, 1, 5, 8, 24, and 48 h after completion of Irinotecan infusion	In Cycle 1 Irinotecan was administered with an intravenous infusion of 150 mg/m\^2 once every other week on Days 1, 15, and 29. In the same Cycle 1 Dalotuzumab 10 mg/kg was administered on Days 22, 29 and 36; and Cetuximab was administered on Days 1, 8, 15, 22, 29 and 36. The Tmax of plasma Irinotecan was determined alone on Day 15 and in combination with dalotuzumab on Day 29.