Colon Cancer, Colorectal Cancer, Gastrointestinal Cancer, Metastatic Colorectal Cancer, Rectal Cancer
Conditions
Keywords
panitumumab, vectibix, AMG 102, AMG 479, colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, EGFR inhibitor, IGF inhibitor, c-MET inhibitor
Brief summary
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.
Detailed description
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.
Interventions
DRUGPanitumumab
Panitumumab for intravenous infusion
DRUGGanitumab
Ganitumab for intravenous infusion
DRUGRilotumumab
Rilotumumab for intravenous infusion
DRUGPlacebo
Placebo intravenous infusion
Sponsors
NantBioScience, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* metastatic adenocarcinoma of the colon or rectum * wild-type KRAS tumor status * radiographic evidence of disease progression during or following treatment with irinotecan and/or oxaliplatin containing chemotherapy for mCRC * measurable disease \>/= 20 mm per Response Evaluation Criteria In Solid Tumors (RECIST) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * adequate laboratory values
Exclusion criteria
* history of central nervous system (CNS) metastases * history of another primary cancer, unless: * curatively resected non-melanomatous skin cancer * curatively treated cervical carcinoma in situ * other primary solid tumor treated with curative intent and no known active disease present for \>/= 5 years * prior treatment with an anti-epithelial growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR, c-MET), and/or insulin-like growth factor receptor (IGFR) inhibitor * prior treatment with AMG 102 or AMG 479 * prior treatment with chemotherapy or radiotherapy \</= 21 days * prior treatment with targeted therapy \</= 30 days * known allergy or hypersensitivity to panitumumab, AMG 102, or AMG 479 * history of interstitial lung disease * clinically significant cardiovascular disease \</= 1 year * active inflammatory bowel disease * known human immunodeficiency virus (HIV), hepatitis C, or hepatitis B infection * any co-morbid disease or condition that could increase the risk of toxicity * serious or non-healing wound \</= 35 days * any uncontrolled concurrent illness or history of any medical condition that could interfere with the interpretation of the study results * major surgical procedure \</= 35 days or minor surgical procedure \</= 14 days * other investigational procedures or drugs \</= 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | 7 weeks | 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 |
| Part 2: Percentage of Participants With an Objective Response | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | 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 |
| Progression-free Survival (PFS) - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | Time from the first dose of investigational product to the date of disease progression per the modified RECIST v1.0 criteria or death |
| On-treatment Progression-free Survival (PFS) - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Up to 56 weeks. | 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. |
| Overall Survival - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | The interval in months from the first dose of investigational product to the date of death. |
| Cmin, Cmax of Panitumumab | 14 days | Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval |
| Cmin, Cmax, for Rilotumumab | 14 days | Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval |
| Cmin for Panitumumab - Part 2 | Up to 23 weeks | Cmin = minimum drug concentration during a dosing interval |
| Cmax for Panitumumab - Part 2 | Up to 23 weeks | Cmax = maximum observed drug concentration during a dosing interval |
| Duration of Response - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | Time from the confirmed objective response to disease progression per the modified RECIST v1.0 criteria. |
| Cmax for Rilotumumab - Part 2 | Up to 23 weeks | Cmax = maximum observed drug concentration during a dosing interval |
| Cmin for Ganitumab - Part 2 | Up to 23 weeks | Cmin = minimum drug concentration during a dosing interval |
| Cmax for Ganitumab - Part 2 | Up to 23 weeks | Cmax = maximum observed drug concentration during a dosing interval |
| Total Anti-Panitumumab Antibody Incidence - Part 2 | First dose of any study drug and before 120 days of last dose of study drugs; up to 1 year, eight months | 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. |
| Total Anti-AMG 102 Antibody Incidence - Part 2 | First dose of any study drug and before 120 days of last dose of study drugs, up to 1 year, eight months. | 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. |
| Total Anti-AMG 479 Antibody Incidence - Part 2 | First dose of any study drug and before 120 days of last dose of study drugs, up to 1 year, eight months. | 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. |
| AUC for Rilotumumab | 14 Days | AUC = area under the drug concentration-time curve during a dosing interval |
| AUC for Panitumumab | 14 Days | AUC = area under the drug concentration-time curve during a dosing interval |
| Cmin for Rilotumumab - Part 2 | Up to 23 weeks | Cmin = minimum drug concentration during a dosing interval |
| Time to Response - Part 2 | From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. | 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 |
Participant flow
Recruitment details
First patient enrolled 27 October 2008; last patient enrolled 05 February 2010. In Part 1, participants with wild-type KRAS metastatic colorectal cancer received open-label rilotumumab and panitumumab to identify a tolerable dose of rilotumumab for Part 2 of the study. Participants enrolled in Part 1 were not eligible for randomization in Part 2.
Pre-assignment details
In Part 2 participants were randomized in a 1:1:1 ratio to the 3 double-blinded treatment arms. In Part 3, participants randomized to Panitumumab Alone in Part 2 and with disease progression or intolerability were re-randomized 1:1 into 2 double-blind groups. Clinically significant laboratory findings were considered adverse events, so the protocol endpoint Incidence of all AEs and clinical laboratory abnormalities was not analyzed separately but was included in the AE data
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Panitumumab + Rilotumumab Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. | 11 |
| Part 2: Panitumumab Alone Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. | 48 |
| Part 2: Panitumumab + Rilotumumab Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. | 48 |
| Part 2: Panitumumab + Ganitumab Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision. | 46 |
| Part 3: Rilotumumab Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive rilotumumab 10 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision. | 13 |
| Part 3: Ganitumab Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive ganitumab 12 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision. | 11 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 | Death | 8 | 0 | 0 | 0 | 0 | 0 |
| Part 1 | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 2 | Death | 0 | 32 | 35 | 37 | 0 | 0 |
| Part 2 | Lost to Follow-up | 0 | 0 | 3 | 0 | 0 | 0 |
| Part 2 | On-study at time of data cut-off | 0 | 1 | 1 | 1 | 0 | 0 |
| Part 2 | Withdrawal by Subject | 0 | 9 | 5 | 3 | 0 | 0 |
| Part 3 | Death | 0 | 0 | 0 | 0 | 8 | 8 |
| Part 3 | On-study at time of data cut-off | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Part 2: Panitumumab Alone | Part 2: Panitumumab + Rilotumumab | Part 1: Panitumumab + Rilotumumab | Part 2: Panitumumab + Ganitumab | Part 3: Rilotumumab | Part 3: Ganitumab | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1 Participants | NA years | NA years | 56.5 years STANDARD_DEVIATION 13.8 | NA years | NA years | NA years | 56.5 years STANDARD_DEVIATION 13.8 |
| Age, Continuous Part 2 Participants | 55.0 years STANDARD_DEVIATION 12.5 | 62.1 years STANDARD_DEVIATION 7.5 | NA years | 62.0 years STANDARD_DEVIATION 9.7 | NA years | NA years | 59.7 years STANDARD_DEVIATION 10.6 |
| Age, Continuous Part 3 Participants | NA years | NA years | NA years | NA years | 54.8 years STANDARD_DEVIATION 13.9 | 52.0 years STANDARD_DEVIATION 11.3 | 53.5 years STANDARD_DEVIATION 12.6 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White or Caucasian | 45 participants | 47 participants | 11 participants | 45 participants | 13 participants | 10 participants | 171 participants |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 6 Participants | 21 Participants | 3 Participants | 6 Participants | 75 Participants |
| Sex: Female, Male Male | 28 Participants | 29 Participants | 5 Participants | 25 Participants | 10 Participants | 5 Participants | 102 Participants |
| Subjects With Wild-Type KRAS Metastatic Colorectal Cancer | 48 Participants | 48 Participants | 11 Participants | 46 Participants | 13 Participants | 11 Participants | 177 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 11 | 32 / 48 | 35 / 48 | 37 / 46 | 8 / 13 | 8 / 11 |
| other Total, other adverse events | 11 / 11 | 42 / 48 | 47 / 48 | 44 / 46 | 11 / 13 | 9 / 11 |
| serious Total, serious adverse events | 5 / 11 | 11 / 48 | 9 / 48 | 9 / 46 | 6 / 13 | 2 / 11 |
Outcome results
Primary
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
Population: The first 6 DLT evaluable participants, including participants who received at least 2 doses of panitumumab and rilotumumab as scheduled (ie, Week 1 and 3) and have a minimum 28 days follow-up for safety or, have received at least 1 dose of panitumumab and rilotumumab and had a DLT within the first 28 days on study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
Primary
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.
Population: Efficacy analysis set (enrolled participants who received at least one dose of respective investigational product in the corresponding parts of the study) with measurable baseline disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Part 2: Percentage of Participants With an Objective Response | 21 percentage of participants |
| Part 2: Panitumumab + Rilotumumab | Part 2: Percentage of Participants With an Objective Response | 31 percentage of participants |
| Part 2: Panitumumab + Ganitumab | Part 2: Percentage of Participants With an Objective Response | 22 percentage of participants |
Secondary
AUC for Panitumumab
AUC = area under the drug concentration-time curve during a dosing interval
Time frame: 14 Days
Population: PK Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | AUC for Panitumumab | 1200 day•μg/mL |
Secondary
AUC for Rilotumumab
AUC = area under the drug concentration-time curve during a dosing interval
Time frame: 14 Days
Population: PK population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | AUC for Rilotumumab | 2300 day•μg/mL |
Secondary
Cmax for Ganitumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 3 | 240 μg/mL | Standard Deviation 25.3 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 1 | 218 μg/mL | Standard Deviation 30 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 5 | 244 μg/mL | Standard Deviation 29.3 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 7 | 279 μg/mL | Standard Deviation 35.5 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 13 | 274 μg/mL | Standard Deviation 28.1 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Ganitumab - Part 2 | Week 23 | 276 μg/mL | Standard Deviation 22.8 |
Secondary
Cmax for Panitumumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 1 | 114 μg/mL | Standard Deviation 27.7 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 3 | 149 μg/mL | Standard Deviation 31.4 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 5 | 165 μg/mL | Standard Deviation 30.1 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 7 | 166 μg/mL | Standard Deviation 30.8 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 13 | 201 μg/mL | Standard Deviation 26.7 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 23 | 196 μg/mL | Standard Deviation 24.5 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 23 | 207 μg/mL | Standard Deviation 24.9 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 1 | 124 μg/mL | Standard Deviation 26.4 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 7 | 180 μg/mL | Standard Deviation 29.6 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 13 | 199 μg/mL | Standard Deviation 25.7 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 3 | 154 μg/mL | Standard Deviation 29 |
| Part 2: Panitumumab + Rilotumumab | Cmax for Panitumumab - Part 2 | Week 5 | 172 μg/mL | Standard Deviation 32.3 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 3 | 139 μg/mL | Standard Deviation 24.4 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 5 | 150 μg/mL | Standard Deviation 26.5 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 23 | 187 μg/mL | Standard Deviation 22.3 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 7 | 167 μg/mL | Standard Deviation 23.9 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 1 | 118 μg/mL | Standard Deviation 34.7 |
| Part 2: Panitumumab + Ganitumab | Cmax for Panitumumab - Part 2 | Week 13 | 192 μg/mL | Standard Deviation 31.2 |
Secondary
Cmax for Rilotumumab - Part 2
Cmax = maximum observed drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 3 | 316 μg/ml | Standard Deviation 28.4 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 1 | 239 μg/ml | Standard Deviation 29.3 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 5 | 357 μg/ml | Standard Deviation 25 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 7 | 397 μg/ml | Standard Deviation 24.8 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 13 | 453 μg/ml | Standard Deviation 23.7 |
| Part 1: Panitumumab + Rilotumumab | Cmax for Rilotumumab - Part 2 | Week 23 | 421 μg/ml | Standard Deviation 26 |
Secondary
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
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmin, Cmax, for Rilotumumab | Cmax | 306 μg/mL |
| Part 1: Panitumumab + Rilotumumab | Cmin, Cmax, for Rilotumumab | Cmin | 120 μg/mL |
Secondary
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
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmin, Cmax of Panitumumab | Cmin | 42.5 μg/mL |
| Part 1: Panitumumab + Rilotumumab | Cmin, Cmax of Panitumumab | Cmax | 223 μg/mL |
Secondary
Cmin for Ganitumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmin for Ganitumab - Part 2 | Week 3 | 19.8 μg/ml | Standard Deviation 51.6 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Ganitumab - Part 2 | Week 5 | 24.4 μg/ml | Standard Deviation 55.2 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Ganitumab - Part 2 | Week 7 | 28.9 μg/ml | Standard Deviation 54.2 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Ganitumab - Part 2 | Week 13 | 38.8 μg/ml | Standard Deviation 61.6 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Ganitumab - Part 2 | Week 23 | 39.7 μg/ml | Standard Deviation 58.8 |
Secondary
Cmin for Panitumumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 13 | 63.5 μg/mL | Standard Deviation 43 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 7 | 39.9 μg/mL | Standard Deviation 62.2 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 3 | 19.8 μg/mL | Standard Deviation 80.3 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 5 | 34.8 μg/mL | Standard Deviation 58.9 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 23 | 82.1 μg/mL | Standard Deviation 28.2 |
| Part 2: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 7 | 45.2 μg/mL | Standard Deviation 50.4 |
| Part 2: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 3 | 22.8 μg/mL | Standard Deviation 73.5 |
| Part 2: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 5 | 37.9 μg/mL | Standard Deviation 52.5 |
| Part 2: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 13 | 63.4 μg/mL | Standard Deviation 45.2 |
| Part 2: Panitumumab + Rilotumumab | Cmin for Panitumumab - Part 2 | Week 23 | 62.1 μg/mL | Standard Deviation 44.3 |
| Part 2: Panitumumab + Ganitumab | Cmin for Panitumumab - Part 2 | Week 23 | 54.8 μg/mL | Standard Deviation 53.8 |
| Part 2: Panitumumab + Ganitumab | Cmin for Panitumumab - Part 2 | Week 13 | 51.4 μg/mL | Standard Deviation 63.1 |
| Part 2: Panitumumab + Ganitumab | Cmin for Panitumumab - Part 2 | Week 3 | 17.2 μg/mL | Standard Deviation 56.5 |
| Part 2: Panitumumab + Ganitumab | Cmin for Panitumumab - Part 2 | Week 7 | 37.4 μg/mL | Standard Deviation 54.5 |
| Part 2: Panitumumab + Ganitumab | Cmin for Panitumumab - Part 2 | Week 5 | 29.8 μg/mL | Standard Deviation 55.7 |
Secondary
Cmin for Rilotumumab - Part 2
Cmin = minimum drug concentration during a dosing interval
Time frame: Up to 23 weeks
Population: PK population Measure of dispersion is %CV
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Cmin for Rilotumumab - Part 2 | Week 3 | 70.1 μg/mL | Standard Deviation 41.2 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Rilotumumab - Part 2 | Week 5 | 119 μg/mL | Standard Deviation 31.8 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Rilotumumab - Part 2 | Week 7 | 143 μg/mL | Standard Deviation 27.5 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Rilotumumab - Part 2 | Week 13 | 186 μg/mL | Standard Deviation 40.7 |
| Part 1: Panitumumab + Rilotumumab | Cmin for Rilotumumab - Part 2 | Week 23 | 181 μg/mL | Standard Deviation 36.3 |
Secondary
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Disease Control Rate - Part 2 | 56 percentage of participants |
| Part 2: Panitumumab + Rilotumumab | Disease Control Rate - Part 2 | 71 percentage of participants |
| Part 2: Panitumumab + Ganitumab | Disease Control Rate - Part 2 | 61 percentage of participants |
Secondary
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.
Population: Only subjects with confirmed response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Duration of Response - Part 2 | 3.7 Months |
| Part 2: Panitumumab + Rilotumumab | Duration of Response - Part 2 | 5.1 Months |
| Part 2: Panitumumab + Ganitumab | Duration of Response - Part 2 | 3.7 Months |
Secondary
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | On-treatment Progression-free Survival (PFS) - Part 2 | 3.8 Months |
| Part 2: Panitumumab + Rilotumumab | On-treatment Progression-free Survival (PFS) - Part 2 | 5.3 Months |
| Part 2: Panitumumab + Ganitumab | On-treatment Progression-free Survival (PFS) - Part 2 | 5.3 Months |
Secondary
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Overall Survival - Part 2 | NA Months |
| Part 2: Panitumumab + Rilotumumab | Overall Survival - Part 2 | NA Months |
| Part 2: Panitumumab + Ganitumab | Overall Survival - Part 2 | NA Months |
Secondary
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Progression-free Survival (PFS) - Part 2 | 3.7 Months |
| Part 2: Panitumumab + Rilotumumab | Progression-free Survival (PFS) - Part 2 | 5.2 Months |
| Part 2: Panitumumab + Ganitumab | Progression-free Survival (PFS) - Part 2 | 5.3 Months |
Secondary
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.
Population: Only subjects with confirmed response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Time to Response - Part 2 | 1.8 Months |
| Part 2: Panitumumab + Rilotumumab | Time to Response - Part 2 | 1.6 Months |
| Part 2: Panitumumab + Ganitumab | Time to Response - Part 2 | 1.7 Months |
Secondary
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.
Population: Only subjects having AMG-102 treatment in part 2 were measured for antibody incidence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Total Anti-AMG 102 Antibody Incidence - Part 2 | 6.3 percentage of participants |
Secondary
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.
Population: Only subjects having AMG-479 treatment in part 2 were measured for antibody incidence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Total Anti-AMG 479 Antibody Incidence - Part 2 | 17.4 percentage of participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Panitumumab + Rilotumumab | Total Anti-Panitumumab Antibody Incidence - Part 2 | 6.3 percentage of participants |
| Part 2: Panitumumab + Rilotumumab | Total Anti-Panitumumab Antibody Incidence - Part 2 | 18.8 percentage of participants |
| Part 2: Panitumumab + Ganitumab | Total Anti-Panitumumab Antibody Incidence - Part 2 | 17.4 percentage of participants |