This study is a global, multicenter, open-label phase 1b and randomized, double-blinded, 2 part, phase 2 study designed to evaluate the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus panitumumab alone in patients with metastatic colorectal cancer whose tumors are wild-type KRAS status.
This study consisted of 3 parts: Part 1: determination of the tolerable dose of rilotumumab in combination with panitumumab to be administered in Part 2. Part 2: Comparison of the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus that of panitumumab alone. In Part 2, participants were randomized 1:1:1 into 3 cohorts: 6 mg/kg panitumumab plus 10 mg/kg rilotumumab, 6 mg/kg panitumumab plus 12 mg/kg ganitumab, or 6 mg/kg panitumumab and placebo (panitumumab alone cohort). Panitumumab was administered open-label, and rilotumumab and ganitumab were double-blinded. Part 3: Exploratory evaluation of the safety and efficacy of the rilotumumab and ganitumab monotherapy following treatment with panitumumab in Part 2. In Part 3, eligible participants who terminated panitumumab treatment in the Panitumumab Alone arm of Part 2 due to disease progression or intolerability could be randomized 1:1 into 2 double-blind cohorts: 10 mg/kg rilotumumab or 12 mg/kg ganitumab. Participants who permanently discontinued all the investigational products completed a safety follow-up visit 30 days and a follow-up visit 60 days after the last dose of investigational product. Participants were followed for radiographic disease progression and survival every 3 months after the 30-day safety follow-up visit for up to 2 years after the last participant was enrolled in Part 2.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
177
Panitumumab for intravenous infusion
Ganitumab for intravenous infusion
Rilotumumab for intravenous infusion
Placebo intravenous infusion
Part 1: Number of Participants With Dose-limiting Toxicities (DLT)
A DLT is defined as any grade 3 or 4 rilotumumab-related or combination (panitumumab and rilotumumab)-related adverse event or laboratory abnormality that is deemed clinically significant by the investigator
Time frame: 7 weeks
Part 2: Percentage of Participants With an Objective Response
An objective response is defined as a confirmed complete (CR) or partial response (PR) no less than 4 weeks after the criteria for response are first met, determined by the investigator considering the radiologic response of all existing target and non-target lesions, evidence of new lesions, and cytology evaluation (as appropriate) according to the Modified-Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 criteria: CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders. Tumor assessments up to the initiation of another anti-tumor therapy including the Part 3 treatment, if applicable, were used.
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
Duration of Response - Part 2
Time from the confirmed objective response to disease progression per the modified RECIST v1.0 criteria.
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
Time to Response - Part 2
Time from the first dose of investigational product to the date of first confirmed objective response. Calculated only for subject with a confirmed objective response
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
Disease Control Rate - Part 2
The incidence of confirmed objective response or stable disease. Stable disease cannot be established prior to study day 49 (calculated from the date of first dose of investigational product), ie, the earliest protocol scheduled tumor assessment
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
Progression-free Survival (PFS) - Part 2
Time from the first dose of investigational product to the date of disease progression per the modified RECIST v1.0 criteria or death
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
On-treatment Progression-free Survival (PFS) - Part 2
Time from the first dose of investigational product to the date of disease progression per the modified RECIST v1.0 criteria or death during the treatment period (from the first to last dose of investigational product). Radiographic progression within 28 days since last dose of study therapy (last component of combination therapy) up to the initiation of another anti-tumor therapy, including the Part 3 treatment, if applicable, or death within 28 days since last dose of study therapy.
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Up to 56 weeks.
Overall Survival - Part 2
The interval in months from the first dose of investigational product to the date of death.
Time frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.
Cmin, Cmax of Panitumumab
Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval
Time frame: 14 days
Cmin, Cmax, for Rilotumumab
Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval
Time frame: 14 days
Cmin for Panitumumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Cmax for Panitumumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Cmin for Rilotumumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Cmax for Rilotumumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Cmin for Ganitumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Cmax for Ganitumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Total Anti-Panitumumab Antibody Incidence - Part 2
Ratio of the number of subjects with at least one positive antibody result at baseline (or at any post-baseline or long-term follow-up time point) to the number of subjects with at least one immunoassay results at baseline (or at any post-baseline or long term follow-up time point). Measured by either Biacore or ELISA.
Time frame: First dose of any study drug and before 120 days of last dose of study drugs; up to 1 year, eight months
Total Anti-AMG 102 Antibody Incidence - Part 2
Ratio of the number of subjects with at least one positive antibody result at baseline (or at any post-baseline or long-term follow-up time point) to the number of subjects with at least one immunoassay results at baseline (or at any post-baseline or long term follow-up time point). Measured by MSD.
Time frame: First dose of any study drug and before 120 days of last dose of study drugs, up to 1 year, eight months.
Total Anti-AMG 479 Antibody Incidence - Part 2
Ratio of the number of subjects with at least one positive antibody result at baseline (or at any post-baseline or long-term follow-up time point) to the number of subjects with at least one immunoassay results at baseline (or at any post-baseline or long term follow-up time point). Measured by MSD.
Time frame: First dose of any study drug and before 120 days of last dose of study drugs, up to 1 year, eight months.
AUC for Rilotumumab
AUC = area under the drug concentration-time curve during a dosing interval
Time frame: 14 Days
AUC for Panitumumab
AUC = area under the drug concentration-time curve during a dosing interval
Time frame: 14 Days
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