Panitumumab Combination Study With Rilotumumab or Ganitumab in Wild-type Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS) Metastatic Colorectal Cancer (mCRC)

Phase 1

Completed

• Conditions: Colorectal Cancer; Metastatic Colorectal Cancer; Rectal Cancer; Gastrointestinal Cancer; Colon Cancer
• Interventions: Drug: Ganitumab; Drug: Panitumumab; Drug: Rilotumumab; Drug: Placebo

• Registration Number: NCT00788957
• Lead Sponsor: NantBioScience, Inc.

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.

Study Timeline

• Study First Submitted: 2008-10-23
• Study Start: 2008-10-27
• Study First Submitted QC: 2008-11-10
• Study First Posted: 2008-11-11
• Primary Completion: 2010-07-23
• Study Completion: 2010-07-23
• Disposition First Submitted: 2014-03-26
• Disposition First Submitted QC: 2014-03-26
• Disposition First Posted: 2014-04-22
• Results First Submitted: 2015-03-24
• Results First Submitted QC: 2015-06-23
• Results First Posted: 2015-07-20
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-12
• Last Update Posted: 2024-08-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 177

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Panitumumab + Rilotumumab	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.
Part 2: Panitumumab + Ganitumab	Placebo	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.
Part 3: Ganitumab	Placebo	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.
Part 3: Rilotumumab	Placebo	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.
Part 2: Panitumumab + Rilotumumab	Placebo	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.
Part 3: Rilotumumab	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.
Part 3: Ganitumab	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.
Part 1: Panitumumab + Rilotumumab	Panitumumab	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.
Part 2: Panitumumab Alone	Panitumumab	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Part 2: Panitumumab + Rilotumumab	Panitumumab	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.
Part 2: Panitumumab + Ganitumab	Panitumumab	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.
Part 2: Panitumumab + Ganitumab	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.
Part 2: Panitumumab + Rilotumumab	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.

Primary Outcome Measures

Name	Time	Method
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.
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

Secondary Outcome Measures

Name	Time	Method
Cmax for Rilotumumab - Part 2	Up to 23 weeks	Cmax = maximum observed drug concentration during a dosing interval
Cmin, Cmax of Panitumumab	14 days	Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval
Cmax for Ganitumab - 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.
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
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.
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
Cmin for Rilotumumab - Part 2	Up to 23 weeks	Cmin = minimum 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
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
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.
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
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.
AUC for Panitumumab	14 Days	AUC = area under the drug concentration-time curve 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.
Cmin for Ganitumab - Part 2	Up to 23 weeks	Cmin = minimum drug concentration during a dosing interval
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