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

A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in Combination With Panitumumab Versus Panitumumab Alone in Subject With Wild-Type KRAS Metastatic Colorectal Cancer

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer; Colorectal Cancer; Rectal Cancer; Colon Cancer; Gastrointestinal Cancer
• Intervention / Treatment: Drug: Placebo; Drug: Panitumumab; Drug: Rilotumumab; Drug: Ganitumab

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 Type: Interventional
• Enrollment (Actual): 177
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix®; Drug: Rilotumumab; Rilotumumab for intravenous infusion; Other Names: AMG 102
Active Comparator: 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.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix®
Experimental: 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.	Drug: Placebo; Placebo intravenous infusion; Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix®; Drug: Rilotumumab; Rilotumumab for intravenous infusion; Other Names: AMG 102
Experimental: 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.	Drug: Placebo; Placebo intravenous infusion; Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix®; Drug: Ganitumab; Ganitumab for intravenous infusion; Other Names: AMG 479
Experimental: 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.	Drug: Placebo; Placebo intravenous infusion; Drug: Rilotumumab; Rilotumumab for intravenous infusion; Other Names: AMG 102
Experimental: 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.	Drug: Placebo; Placebo intravenous infusion; Drug: Ganitumab; Ganitumab for intravenous infusion; Other Names: AMG 479

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response - Part 2	Time from the confirmed objective response to disease progression per the modified RECIST v1.0 criteria.	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	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	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	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.	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.	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	14 days
Cmin, Cmax, for Rilotumumab	Cmin = minimum drug concentration during a dosing interval; Cmax = maximum observed drug concentration during a dosing interval	14 days
Cmin for Panitumumab - Part 2	Cmin = minimum drug concentration during a dosing interval	Up to 23 weeks
Cmax for Panitumumab - Part 2	Cmax = maximum observed drug concentration during a dosing interval	Up to 23 weeks
Cmin for Rilotumumab - Part 2	Cmin = minimum drug concentration during a dosing interval	Up to 23 weeks
Cmax for Rilotumumab - Part 2	Cmax = maximum observed drug concentration during a dosing interval	Up to 23 weeks
Cmin for Ganitumab - Part 2	Cmin = minimum drug concentration during a dosing interval	Up to 23 weeks
Cmax for Ganitumab - Part 2	Cmax = maximum observed drug concentration during a dosing interval	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.	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.	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.	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	14 Days
AUC for Panitumumab	AUC = area under the drug concentration-time curve during a dosing interval	14 Days

Collaborators and Investigators

• Sponsor: NantBioScience, Inc.
• Investigators: Study Director: MD, Amgen

Publications and helpful links

General Publications

• Peeters M, Kafatos G, Taylor A, Gastanaga VM, Oliner KS, Hechmati G, Terwey JH, van Krieken JH. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015 Sep;51(13):1704-13. doi: 10.1016/j.ejca.2015.05.017. Epub 2015 Jun 3.
• Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, Davidenko I, Stephenson J, Elez E, Prenen H, Deng H, Tang R, McCaffery I, Oliner KS, Chen L, Gansert J, Loh E, Smethurst D, Tabernero J. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res. 2014 Aug 15;20(16):4240-50. doi: 10.1158/1078-0432.CCR-13-2752. Epub 2014 Jun 11.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2008
• Primary Completion (Actual): July 23, 2010
• Study Completion (Actual): July 23, 2010

Study Registration Dates

• First Submitted: October 23, 2008
• First Submitted That Met QC Criteria: November 10, 2008
• First Posted (Estimated): November 11, 2008

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: July 12, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: colorectal cancer; rectal cancer; colon cancer; metastatic colorectal cancer; EGFR inhibitor; panitumumab; AMG 479; AMG 102; c-MET inhibitor; vectibix; IGF inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Gastrointestinal Neoplasms; Colonic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Panitumumab; Rilotumumab
• Other Study ID Numbers: 20060447