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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00788957
• Other study ID #: 20060447
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 23, 2008
• Last updated: June 23, 2015
• Start date: October 2008
• Est. completion date: October 2013

Study information

• Verified date: June 2015
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaEuropean Union: European Medicines AgencyUnited States: Food and Drug AdministrationUnited States: Quorom Institutional Review BoardUnited States: Western Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 153
• Est. completion date: October 2013
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colon Cancer
• Colorectal Cancer
• Colorectal Neoplasms
• Gastrointestinal Cancer
• Gastrointestinal Neoplasms
• Metastatic Colorectal Cancer
• Rectal Cancer

Intervention

Drug:
• Panitumumab
Panitumumab for intravenous infusion
• Ganitumab
Ganitumab for intravenous infusion
• Rilotumumab
Rilotumumab for intravenous infusion
• Placebo
Placebo intravenous infusion

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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	7 weeks	Yes
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.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.	No
Secondary	Part 2: Duration of Response	The interval from the first visit of a confirmed objective response to disease progression as defined by the modified RECIST v1.0 criteria. Participants who did not progress by the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and the start of Part 3 dosing where applicable were censored at their last evaluable disease assessment date prior to the end of reporting period. Progressive disease is defined as at least a 20% increase in the size of target lesions, or unequivocal progression of existing non-target lesions, or any new lesions.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.	No
Secondary	Part 2: Time to Response	The interval from the first dose of study therapy to the date of the first confirmed objective response, calculated only for 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.	No
Secondary	Part 2: Percentage of Participants With Disease Control	The percentage of participants with an overall objective response of CR, PR, or stable disease (SD). 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 (PD). SD: Neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase to qualify for PD and no progression of non-target lesions, or the persistence of one or more non-target lesion(s) not qualifying for either CR or PD.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.	No
Secondary	Progression-free Survival	The interval from the first dose of study therapy to the earlier date of disease progression (per modified-RECIST v1.0) or death. Participants who did not progress or die by the analysis data cutoff date were censored at their last evaluable disease assessment date prior to the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in Part 3 where applicable. Participants enrolled into Part 3 or who started a new line of anti-tumor therapy before radiographic progression but subsequently died were considered as having an event with the event date same as the death date.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.	No
Secondary	On-treatment Progression-free Survival	An event is defined as a radiographic progression or death that occurred from the first dose to 28 days since the last dose of study therapy. Participants who did not progress or die during this period were censored at their last evaluable disease assessment before the end of the 28-day period. Participants who received Part 3 treatment before 28 days since their last dose of study drug in Part 2 and did not have radiographic progression or die were censored at their last evaluable disease assessment prior to receiving therapy in Part 3. Radiographic progressions after start of a new anti-tumor therapy, including Part 3 treatment, or after 28 days since the last dose in Part 2 were excluded from the analysis. Participants who died with no prior radiographic disease progression during Part 3 treatment, but within the 28-day period since the last dose in Part 2 were considered as having an event.	From the date of first dose until 28 days after the last dose until the data cut-off date of 23 July 2010. Median time on treatment was 3.7, 4.9 and 5.1 months in each treatment arm respectively.	No
Secondary	Overall Survival	The interval from the first dose of study therapy to the date of death. Participants still alive at the analysis data cutoff date were censored at their last contact date.	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.	No
Secondary	Number of Participants With Adverse Events (AEs)	A serious adverse event (SAE) is defined as an AE that is fatal, life threatening (places the participant at immediate risk of death), requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other significant medical hazard. AEs were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. AEs were assessed by the investigator for the relationship of the AE to each one or more of the investigational products by the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?"	From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively.	Yes
Secondary	Number of Participants With Grade 3 or Higher Laboratory Toxicities	The severity of laboratory toxicities was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.	From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively.	Yes
Secondary	Number of Participants With Antibody Formation to Panitumumab, Rilotumumab and Ganitumab	Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.	From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively.	Yes
Secondary	Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum Drug Concentration (Cmin) for Panitumumab and Rilotumumab		Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.	No
Secondary	Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab		Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.	No
Secondary	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab		Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.	No
Secondary	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).	Pre-dose at Weeks 3, 5, 7, 13 and 23.	No
Secondary	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab		Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.	No
Secondary	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).	Pre-dose at Weeks 3, 5, 7, 13 and 23.	No
Secondary	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab		Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.	No
Secondary	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).	Pre-dose at Weeks 3, 5, 7, 13 and 23.	No

External Links

•   AmgenTrials clinical trials website