Metastatic Colorectal Cancer
Conditions
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.
Interventions
BIOLOGICALdalotuzumab
IV infusion
DRUGirinotecan hydrochloride
IV infusion
BIOLOGICALcetuximab
IV infusion
DRUGplacebo
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | Up to 30 days after last dose of study drug (Up to 33 months) | 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. |
| Overall Survival (OS) | Up to 12 weeks after last dose of study drug (Up to 35 months) | 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) | Up to last dose of study drug (Up to 32 months) | 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 Experience an AE of Infusion Site Reaction | Up to 30 days after last dose of study drug (Up to 33 months) | The percentage of participants who experienced an AE of infusion site reaction is presented. |
| Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | Up to 30 days after last dose of study drug (Up to 33 months) | 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 | Up to last dose of study drug (Up to 32 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Every 6 weeks (Up to 32 months) | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) In DB Week 1, participants received cetuximab 400 mg/m\^2 IV loading dose and irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants received cetuximab 250 mg/m\^2 IV Q1W maintenance dose, irinotecan IV Q1W and DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment. | 180 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) In the OL portion of the study, ≥6 participants received 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 received cetuximab 400 mg/m\^2 IV + irinotecan IV. In DB Week 2, participants received cetuximab 250 mg/m\^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants received cetuximab 250 mg/m\^2 IV + irinotecan IV. Starting with DB Week 4, participants received 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. | 8 |
| Dalotuzumab 10 mg/kg Q1W (OL) In the OL portion of the study, ≥6 participants received 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 received cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants received cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB dalotuzumab 10 mg/kg IV Q1W for up to 32 months of treatment. | 10 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) In DB Week 1, participants received cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. In DB Week 2, participants received cetuximab 250 mg/m\^2 IV + irinotecan IV + DB dalotuzumab 15 mg/kg IV. In DB Week 3, participants received cetuximab 250 mg/m\^2 IV + irinotecan IV. Starting with DB Week 4, participants received 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. | 180 |
| Placebo + Cetuximab + Irinotecan (DB) In DB Week 1, participants received cetuximab 400 mg/m\^2 IV + irinotecan IV at their pre-study dosage. Starting with DB Week 2, participants received cetuximab 250 mg/m\^2 IV Q1W + irinotecan IV Q1W + DB normal saline (placebo) IV Q1W for up to 32 months of treatment. | 178 |
| Total | 556 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 20 | 2 | 3 | 13 | 21 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 2 |
| Overall Study | Not Treated | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Other | 4 | 0 | 0 | 4 | 2 |
| Overall Study | Physician Decision | 17 | 0 | 1 | 8 | 9 |
| Overall Study | Progressive Disease | 118 | 5 | 5 | 138 | 130 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Terminated by Sponsor | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 1 | 1 | 16 | 13 |
Baseline characteristics
| Characteristic | 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) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 10.2 | 55.6 Years STANDARD_DEVIATION 16.1 | 64.4 Years STANDARD_DEVIATION 8.9 | 59.4 Years STANDARD_DEVIATION 10.9 | 58.4 Years STANDARD_DEVIATION 11.1 | 59.2 Years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 54 Participants | 3 Participants | 3 Participants | 70 Participants | 62 Participants | 192 Participants |
| Sex: Female, Male Male | 126 Participants | 5 Participants | 7 Participants | 110 Participants | 116 Participants | 364 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 178 / 180 | 8 / 8 | 10 / 10 | 174 / 180 | 172 / 178 |
| serious Total, serious adverse events | 94 / 180 | 5 / 8 | 4 / 10 | 77 / 180 | 75 / 178 |
Outcome results
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.
Time frame: Up to 12 weeks after last dose of study drug (Up to 35 months)
Population: The Intent-to-Treat (ITT) population consisted of all participants who had a wtKRAS tumor genotype. The efficacy analyses were planned for and only included participants from the DB portion of the study. Participants from the OL portion were excluded from the analyses. Participants were counted in the group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Overall Survival (OS) | 10.8 Months |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Overall Survival (OS) | 11.6 Months |
| Placebo + Cetuximab + Irinotecan (DB) | Overall Survival (OS) | 14.0 Months |
p-value: 0.0695% CI: [0.99, 2]Regression, Cox
p-value: 0.1895% CI: [0.89, 1.79]Regression, Cox
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.
Time frame: Up to last dose of study drug (Up to 32 months)
Population: The APaT population consisted of all randomized participants who received ≥1 dose of study drug. Participants were included in the treatment group corresponding to the study drug they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Percentage of Participants Who Discontinue Study Drug Due to an AE | 11.1 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) | Percentage of Participants Who Discontinue Study Drug Due to an AE | 25.0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (OL) | Percentage of Participants Who Discontinue Study Drug Due to an AE | 30.0 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Percentage of Participants Who Discontinue Study Drug Due to an AE | 7.2 Percentage of Participants |
| Placebo + Cetuximab + Irinotecan (DB) | Percentage of Participants Who Discontinue Study Drug Due to an AE | 11.8 Percentage of Participants |
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.
Time frame: Up to 30 days after last dose of study drug (Up to 33 months)
Population: The APaT population consisted of all randomized participants who received ≥1 dose of study drug. Participants were included in the treatment group corresponding to the study drug they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Percentage of Participants Who Experience an AE of Infusion Site Reaction | 0.0 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) | Percentage of Participants Who Experience an AE of Infusion Site Reaction | 12.5 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (OL) | Percentage of Participants Who Experience an AE of Infusion Site Reaction | 0.0 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Percentage of Participants Who Experience an AE of Infusion Site Reaction | 0.0 Percentage of Participants |
| Placebo + Cetuximab + Irinotecan (DB) | Percentage of Participants Who Experience an AE of Infusion Site Reaction | 0.0 Percentage of Participants |
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.
Time frame: Up to 30 days after last dose of study drug (Up to 33 months)
Population: The All Participants as Treated (APaT) population consisted of all randomized participants who received ≥1 dose of study drug. Participants were included in the treatment group corresponding to the study drug they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | 82.8 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) | Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | 100.0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (OL) | Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | 90.0 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | 81.1 Percentage of Participants |
| Placebo + Cetuximab + Irinotecan (DB) | Percentage of Participants Who Have a Clinical or Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 to 5 Toxicity | 75.8 Percentage of Participants |
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.
Time frame: Up to 30 days after last dose of study drug (Up to 33 months)
Population: The APaT population consisted of all randomized participants who received ≥1 dose of study drug. Participants were included in the treatment group corresponding to the study drug they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | 67.8 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (OL) | Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | 100.0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (OL) | Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | 90.0 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | 72.8 Percentage of Participants |
| Placebo + Cetuximab + Irinotecan (DB) | Percentage of Participants Who Have a Drug-related Clinical or Laboratory CTCAE Grade 3 to 5 Toxicity | 61.8 Percentage of Participants |
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.
Time frame: Up to last dose of study drug (Up to 32 months)
Population: The ITT population consisted of all participants who had a wtKRAS tumor genotype. The efficacy analyses were planned for and only included participants from the DB portion of the study. Participants from the OL portion were excluded from the analyses. Participants were counted in the group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | Progression-free Survival (PFS) | 3.9 Months |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | Progression-free Survival (PFS) | 5.4 Months |
| Placebo + Cetuximab + Irinotecan (DB) | Progression-free Survival (PFS) | 5.6 Months |
p-value: 0.0795% CI: [0.98, 1.83]Regression, Cox
p-value: 0.4495% CI: [0.83, 1.55]Regression, Cox
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.
Time frame: Every 6 weeks (Up to 32 months)
Population: The ITT population consisted of all participants who had a wtKRAS tumor genotype. The efficacy analyses were planned for and only included participants from the DB portion of the study. Participants from the OL portion were excluded from the analyses. Participants were counted in the group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 10 mg/kg Q1W (DB) | 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 | 21.6 Percentage of Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Q2W (DB) | 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 | 23.9 Percentage of Participants |
| Placebo + Cetuximab + Irinotecan (DB) | 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 | 26.1 Percentage of Participants |