Panitumumab Plus FOLFIRI in First-line Treatment of Metastatic Colorectal Cancer

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00508404
• Collaborator: (none)
• Enrollment: 154
• Arm: 1
• Actual Duration (Months): 61.1

Study Details

Study Description

Brief Summary

To estimate the effect of KRAS mutation status (Wild-type versus Mutant) on objective response rate and other measures of efficacy for patients treated with panitumumab in combination with a chemotherapy regimen of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line therapy for metastatic colorectal cancer (mCRC).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Panitumumab; Drug: FOLFIRI	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 154 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm Multicentre Phase II Study of Panitumumab in Combination With Irinotecan/5-fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer
• Actual Study Start Date: May 9, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 12, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panitumumab plus FOLFIRI Participants received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Drug: Panitumumab; Administered by intravenous infusion; Other Names: Vectibix ; Drug: FOLFIRI; FOLFIRI chemotherapy was initiated on Day 1 of each treatment cycle at the following starting doses: irinotecan 180 mg/m², leucovorin 400 mg/m², 5-fluorouracil bolus 400 mg/m², 5-fluorouracil infusion 2400 mg/m².

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks]

   Objective response rate is defined as the percentage of participants with a best response of complete response or partial response. Disease assessments are based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.

Secondary Outcome Measures

1. Objective Response by 17 Weeks [Up to Week 17]

   The percentage of participants with a best response of complete response or partial response by Week 17. Disease assessments are based on investigator review of scans using modified RECIST V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders.

2. Disease Control Rate [Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks]

   The percentage of participants whose best response was either a complete or partial response or stable disease, based on modified RECIST v1.0 criteria as assessed by the Investigator. Stable diease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD of target lesions and no progression of existing non-target lesions and no new lesions, or, the persistence of 1 or more non-target lesions not qualifying for either CR or PD if no target lesions were identified at Baseline.

3. Duration of Response [Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.]

   Duration of response was calculated only for those participants who had a confirmed complete or partial response, and is defined as the time from first confirmed response to first observed progression. For participants who responded and did not progress by the analysis data cut-off date, duration of response was censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method.

4. Time to Initial Objective Response [Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.]

   Time to response is the time from the date of enrollment to the date of first confirmed complete or partial response. Participants with a best response of stable disease at the analysis data cut-off date were censored at their last assessment of SD and participants with all other categories of best response were censored at the maximum observed time to a first confirmed response among all responders. Time to initial objective response was analyzed using Kaplan-Meier methods.

5. Progression-free Survival [From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.]

   Progression-free survival is the time from the date of enrollment to the date of first observed progression or death, whichever comes first. Participants who were alive and did not progress by the analysis data cut-off date were censored at the last evaluable disease assessment date. Progression-free survival was analyzed using Kaplan-Meier methods.

6. Time to Disease Progression [From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.]

   Time to progression is the time from the enrollment date to the date of first observed progression. For participants who had not progressed by the analysis data cutoff date, time to progressive disease was censored at their last evaluable disease assessment date. Time to disease progression was analyzed using Kaplan-Meier methods.

7. Duration of Stable Disease [Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.]

   Duration of stable disease was calculated only for participants with a best response of stable disease and is defined as the time from enrollment to first observed PD. For participants who did not progress by the analysis data cut-off date, duration of SD was censored at their last evaluable disease assessment date. Duration of stable disease was estimated using Kaplan-Meier methods.

8. Time to Treatment Failure [From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.]

   Time to treatment failure is defined as the time from enrollment to the date the decision was made to end the treatment phase for any reason. For participants who remained in the treatment phase at the analysis data cut-off date, time to treatment failure was censored at the date of their last on-study assessment. Time to treatment failure was analyzed using Kaplan-Meier methods.

9. Time to Disease Relapse Following Surgical Intervention [From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.]

   Calculated only for those participants who underwent surgical intervention, and defined as the time from the date of first post-intervention radiographic disease assessment to the date of first observed PD. Participants with no post-intervention disease assessment had their time to relapse set to zero and censored in the analysis. Participants that had evidence of progression / recurrence at their first post-intervention disease assessment had a time to relapse of zero. For participants who had not progressed by the analysis data cut-off date, time to relapse was censored at the date of their last evaluable disease assessment. Time to relapse was analyzed using Kaplan-Meier metjhods.

10. Resection Rate [From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.]

    The percentage of participants who underwent a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosed with histologically- or cytologically-confirmed metastatic adenocarcinoma of the colon and/or rectum.

• Measurable disease according to modified RECIST guidelines.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

• Paraffin-embedded tissue or unstained tumour slides from primary or metastatic tumour available for central lab analysis.

• Adequate haematologic, renal, hepatic and metabolic function.

Exclusion Criteria:

• Central nervous system metastases.

• Prior systemic therapy for the treatment of metastatic colorectal carcinoma with the exception of adjuvant fluoropyrimidine-based chemotherapy given at least six months prior to initiating study treatment.

• Prior anti-epidermal growth factor receptor (EGFr) antibody therapy (e.g. cetuximab) or treatment with small molecule EGFr tyrosine kinase inhibitors (e.g. erlotinib).

• Prior radiotherapy within 14 days prior to screening, and for which all signs of early radiological toxicity have not abated.

• Significant cardiovascular disease including unstable angina or myocardial infarction within six months before initiating study treatment or a history of ventricular arrhythmia.

• History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computed tomography (CT scan.

• Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as > 4 loose stools per day).

• History of Gilbert's syndrome or dihydropyrimidine deficiency.

• Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection.

• Any investigational agent within 30 days before initiation of study treatment.

• Must not have had a major surgical procedure within 28 days prior to initiation of study treatment.

• Subject who is pregnant or breast-feeding.

• Woman or man of childbearing potential not consenting to use adequate contraceptive precautions during the course of the study and for six months after the last study drug administration for women, and one month for men.

• Other protocol specified criteria and specific details may apply.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Köhne CH, Hofheinz R, Mineur L, Letocha H, Greil R, Thaler J, Fernebro E, Gamelin E, Decosta L, Karthaus M. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol. 2012 Jan;138(1):65-72. doi: 10.1007/s00432-011-1061-6. Epub 2011 Sep 30.
• Thaler J, Karthaus M, Mineur L, Greil R, Letocha H, Hofheinz R, Fernebro E, Gamelin E, Baños A, Köhne CH. Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study. BMC Cancer. 2012 Sep 29;12:438. doi: 10.1186/1471-2407-12-438.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00508404
• Other Study ID Numbers: 20060314; EUDRACT Number 2006-006739-36
• First Posted: Jul 30, 2007
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Colorectal Neoplasms; Panitumumab

Study Results

Participant Flow

Recruitment Details	A total of 169 patients were screened, of whom 154 were enrolled into this study at 36 study centers in Austria, Belgium, France, Germany, and Sweden from 9 May 2007 through 18 June 2008. Results are reported through the primary analysis data cut-off date of 18 June 2009 (12 months after the last patient was enrolled).
Pre-assignment Detail	Participants received a FOLFIRI regimen in combination with panitumumab once every 14 days until diagnosed with radiographic disease progression, at which time the participant was withdrawn from the treatment phase. Participants were to complete a safety follow-up visit 8 weeks after the treatment phase.

Arm/Group Title	Panitumumab Plus FOLFIRI
Arm/Group Description	Participants received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Period Title: Overall Study
STARTED	154
COMPLETED	112
NOT COMPLETED	42

Baseline Characteristics

Arm/Group Title	Panitumumab Plus FOLFIRI
Arm/Group Description	Participants received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Overall Participants	154
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.7 (10.6)
Sex: Female, Male (Count of Participants)
Female	49 31.8%
Male	105 68.2%
Race/Ethnicity, Customized (participants) [Number]
Black or African American	2 1.3%
Hispanic or Latino	1 0.6%
Japanese	1 0.6%
White or Caucasian	150 97.4%
Kirsten Rat Sarcoma-2 Virus (KRAS) Mutation Status (participants) [Number]
Wild-type KRAS	86 55.8%
Mutant KRAS	59 38.3%
Unevaluable KRAS	9 5.8%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	Objective response rate is defined as the percentage of participants with a best response of complete response or partial response. Disease assessments are based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.
Time Frame	Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set (all participants who provided informed consent, enrolled, received at least 1 dose of panitumumab, had evaluable KRAS status data, and with at least 1 unidimensionally measurable lesion per modified RECIST by the local investigator)

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	85	58
Number (95% Confidence Interval) [percentage of participants]	56.47 36.7%	37.93 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.12
	Confidence Interval	(2-Sided) 95%; 1.02 to 4.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio is defined as the odds of having an objective response in the KRAS Wild-type group relative to the odds in the KRAS Mutant group.

2. Secondary Outcome

Title	Objective Response by 17 Weeks
Description	The percentage of participants with a best response of complete response or partial response by Week 17. Disease assessments are based on investigator review of scans using modified RECIST V1.0 criteria. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Participants with no post-baseline assessment were considered non-responders.
Time Frame	Up to Week 17

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	85	58
Number (95% Confidence Interval) [percentage of participants]	49.41 32.1%	34.48 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.86
	Confidence Interval	(2-Sided) 95%; 0.88 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio is defined as the odds of having an objective response in the KRAS Wild-type group relative to the odds in the KRAS Mutant group.

3. Secondary Outcome

Title	Disease Control Rate
Description	The percentage of participants whose best response was either a complete or partial response or stable disease, based on modified RECIST v1.0 criteria as assessed by the Investigator. Stable diease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD of target lesions and no progression of existing non-target lesions and no new lesions, or, the persistence of 1 or more non-target lesions not qualifying for either CR or PD if no target lesions were identified at Baseline.
Time Frame	Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	85	58
Number (95% Confidence Interval) [percentage of participants]	90.59 58.8%	89.66 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.30 to 3.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio is defined as the odds of having an objective response in the KRAS Wild-type group relative to the odds in the KRAS Mutant group.

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response was calculated only for those participants who had a confirmed complete or partial response, and is defined as the time from first confirmed response to first observed progression. For participants who responded and did not progress by the analysis data cut-off date, duration of response was censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method.
Time Frame	Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set with an objective response (CR or PR)

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	48	22
Median (95% Confidence Interval) [months]	13.0	7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.283
	Confidence Interval	(2-Sided) 95%; 0.130 to 0.614
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

5. Secondary Outcome

Title	Time to Initial Objective Response
Description	Time to response is the time from the date of enrollment to the date of first confirmed complete or partial response. Participants with a best response of stable disease at the analysis data cut-off date were censored at their last assessment of SD and participants with all other categories of best response were censored at the maximum observed time to a first confirmed response among all responders. Time to initial objective response was analyzed using Kaplan-Meier methods.
Time Frame	Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	85	58
Median (95% Confidence Interval) [months]	3.8	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.642
	Confidence Interval	(2-Sided) 95%; 0.990 to 2.721
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

6. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival is the time from the date of enrollment to the date of first observed progression or death, whichever comes first. Participants who were alive and did not progress by the analysis data cut-off date were censored at the last evaluable disease assessment date. Progression-free survival was analyzed using Kaplan-Meier methods.
Time Frame	From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set (all participants who provided informed consent, enrolled, received at least 1 dose of panitumumab, and had evaluable KRAS status data)

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	86	59
Median (95% Confidence Interval) [months]	8.9	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.464
	Confidence Interval	(2-Sided) 95%; 0.306 to 0.703
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

7. Secondary Outcome

Title	Time to Disease Progression
Description	Time to progression is the time from the enrollment date to the date of first observed progression. For participants who had not progressed by the analysis data cutoff date, time to progressive disease was censored at their last evaluable disease assessment date. Time to disease progression was analyzed using Kaplan-Meier methods.
Time Frame	From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	86	59
Median (95% Confidence Interval) [months]	11.2	7.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.395
	Confidence Interval	(2-Sided) 95%; 0.252 to 0.618
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

8. Secondary Outcome

Title	Duration of Stable Disease
Description	Duration of stable disease was calculated only for participants with a best response of stable disease and is defined as the time from enrollment to first observed PD. For participants who did not progress by the analysis data cut-off date, duration of SD was censored at their last evaluable disease assessment date. Duration of stable disease was estimated using Kaplan-Meier methods.
Time Frame	Tumor response was assessed at Week 8 and every 8 weeks to Week 48 and 3 monthly thereafter until disease progression; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

KRAS Tumor Response Analysis Set with a best response of SD

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	29	30
Median (95% Confidence Interval) [months]	5.9	6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.756
	Confidence Interval	(2-Sided) 95%; 0.400 to 1.430
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

9. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to treatment failure is defined as the time from enrollment to the date the decision was made to end the treatment phase for any reason. For participants who remained in the treatment phase at the analysis data cut-off date, time to treatment failure was censored at the date of their last on-study assessment. Time to treatment failure was analyzed using Kaplan-Meier methods.
Time Frame	From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	86	59
Median (95% Confidence Interval) [months]	6.9	5.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.710
	Confidence Interval	(2-Sided) 95%; 0.503 to 1.002
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is presented as Wild-type KRAS:Mutant KRAS. A value < 1.0 indicates a lower average event rate and longer time to event for Wild-type KRAS relative to Mutant KRAS.

10. Secondary Outcome

Title	Time to Disease Relapse Following Surgical Intervention
Description	Calculated only for those participants who underwent surgical intervention, and defined as the time from the date of first post-intervention radiographic disease assessment to the date of first observed PD. Participants with no post-intervention disease assessment had their time to relapse set to zero and censored in the analysis. Participants that had evidence of progression / recurrence at their first post-intervention disease assessment had a time to relapse of zero. For participants who had not progressed by the analysis data cut-off date, time to relapse was censored at the date of their last evaluable disease assessment. Time to relapse was analyzed using Kaplan-Meier metjhods.
Time Frame	From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set participants who underwent surgery

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	13	4
Median (95% Confidence Interval) [months]	NA	NA

11. Secondary Outcome

Title	Resection Rate
Description	The percentage of participants who underwent a surgical procedure that resulted in partial reduction or complete eradication of all metastatic disease.
Time Frame	From enrollment until the data cut-off date of 18 June 2009; median follow-up time was 34 weeks.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set

Arm/Group Title	Wild-type KRAS	Mutant KRAS
Arm/Group Description	Participants with wild-type KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.	Participants with mutant KRAS received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
Measure Participants	86	59
Number (95% Confidence Interval) [percentage of participants]	15.12 9.8%	6.78 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wild-type KRAS, Mutant KRAS
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in rates
	Estimated Value	8.34
	Confidence Interval	(2-Sided) 95%; -4.01 to 19.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date. The median time frame is 6.6 months.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Panitumumab Plus FOLFIRI
Arm/Group Description	Participants received 6 mg/kg panitumumab intravenously (IV) once every 14 days in combination with FOLFIRI chemotherapy regimen consisting of irinotecan, infusional 5-fluorouracil, and leucovorin, until diagnosed with radiographic disease progression.
All Cause Mortality
	Panitumumab Plus FOLFIRI
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Panitumumab Plus FOLFIRI
	Affected / at Risk (%)	# Events
Total	84/154 (54.5%)
Blood and lymphatic system disorders
ANAEMIA	2/154 (1.3%)
FEBRILE NEUTROPENIA	1/154 (0.6%)
LEUKOPENIA	1/154 (0.6%)
NEUTROPENIA	6/154 (3.9%)
Cardiac disorders
MYOPERICARDITIS	1/154 (0.6%)
Eye disorders
CONJUNCTIVITIS	1/154 (0.6%)
OCULAR TOXICITY	1/154 (0.6%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/154 (0.6%)
ABDOMINAL PAIN	4/154 (2.6%)
ANAL FISSURE	1/154 (0.6%)
CONSTIPATION	1/154 (0.6%)
DIARRHOEA	21/154 (13.6%)
DIARRHOEA HAEMORRHAGIC	1/154 (0.6%)
DYSPHAGIA	1/154 (0.6%)
FAECALOMA	1/154 (0.6%)
GASTROINTESTINAL INFLAMMATION	1/154 (0.6%)
HAEMATEMESIS	1/154 (0.6%)
ILEUS	3/154 (1.9%)
ILEUS PARALYTIC	2/154 (1.3%)
INTESTINAL OBSTRUCTION	3/154 (1.9%)
INTESTINAL PERFORATION	1/154 (0.6%)
LARGE INTESTINE PERFORATION	1/154 (0.6%)
MELAENA	2/154 (1.3%)
NAUSEA	2/154 (1.3%)
RECTAL HAEMORRHAGE	2/154 (1.3%)
STOMATITIS	2/154 (1.3%)
SUBILEUS	2/154 (1.3%)
VOMITING	6/154 (3.9%)
General disorders
CATHETER RELATED COMPLICATION	4/154 (2.6%)
CHEST PAIN	4/154 (2.6%)
CHILLS	1/154 (0.6%)
DEATH	2/154 (1.3%)
FATIGUE	5/154 (3.2%)
GENERAL PHYSICAL HEALTH DETERIORATION	3/154 (1.9%)
MUCOSAL INFLAMMATION	2/154 (1.3%)
MULTI-ORGAN FAILURE	1/154 (0.6%)
PYREXIA	5/154 (3.2%)
Hepatobiliary disorders
BILIARY DILATATION	1/154 (0.6%)
CHOLECYSTITIS	1/154 (0.6%)
CHOLESTASIS	1/154 (0.6%)
HEPATIC FAILURE	1/154 (0.6%)
HEPATIC LESION	1/154 (0.6%)
Infections and infestations
CATHETER RELATED INFECTION	4/154 (2.6%)
ERYSIPELAS	1/154 (0.6%)
GASTROENTERITIS	2/154 (1.3%)
HERPES SIMPLEX	1/154 (0.6%)
INFECTION	1/154 (0.6%)
INTERVERTEBRAL DISCITIS	1/154 (0.6%)
PARONYCHIA	2/154 (1.3%)
PERITONEAL ABSCESS	1/154 (0.6%)
PNEUMONIA	4/154 (2.6%)
SEPSIS	1/154 (0.6%)
SEPTIC SHOCK	1/154 (0.6%)
SINUSITIS	1/154 (0.6%)
SUBCUTANEOUS ABSCESS	1/154 (0.6%)
URINARY TRACT INFECTION	3/154 (1.9%)
UROSEPSIS	2/154 (1.3%)
Injury, poisoning and procedural complications
FEMUR FRACTURE	1/154 (0.6%)
GASTROINTESTINAL STOMA COMPLICATION	1/154 (0.6%)
HUMERUS FRACTURE	1/154 (0.6%)
IATROGENIC INJURY	1/154 (0.6%)
SPINAL FRACTURE	1/154 (0.6%)
Investigations
WEIGHT DECREASED	2/154 (1.3%)
Metabolism and nutrition disorders
DEHYDRATION	5/154 (3.2%)
ELECTROLYTE IMBALANCE	1/154 (0.6%)
HYPOKALAEMIA	1/154 (0.6%)
HYPONATRAEMIA	1/154 (0.6%)
METABOLIC DISORDER	1/154 (0.6%)
PODAGRA	1/154 (0.6%)
Musculoskeletal and connective tissue disorders
BONE PAIN	1/154 (0.6%)
BURSITIS	1/154 (0.6%)
NECK PAIN	1/154 (0.6%)
OSTEOPOROTIC FRACTURE	1/154 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLORECTAL CANCER METASTATIC	2/154 (1.3%)
Nervous system disorders
HEMIPARESIS	1/154 (0.6%)
INTRACRANIAL VENOUS SINUS THROMBOSIS	1/154 (0.6%)
ISCHAEMIC STROKE	1/154 (0.6%)
TRANSIENT ISCHAEMIC ATTACK	1/154 (0.6%)
VASCULITIS CEREBRAL	1/154 (0.6%)
Renal and urinary disorders
HAEMATURIA	1/154 (0.6%)
HYDRONEPHROSIS	2/154 (1.3%)
PYELOCALIECTASIS	1/154 (0.6%)
RENAL COLIC	1/154 (0.6%)
RENAL FAILURE	1/154 (0.6%)
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA	1/154 (0.6%)
OVARIAN CYST	1/154 (0.6%)
PROSTATITIS	1/154 (0.6%)
Respiratory, thoracic and mediastinal disorders
BRONCHOSPASM	1/154 (0.6%)
DYSPNOEA	2/154 (1.3%)
LARYNGOSPASM	1/154 (0.6%)
PULMONARY EMBOLISM	11/154 (7.1%)
PULMONARY THROMBOSIS	1/154 (0.6%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM	1/154 (0.6%)
ERYTHEMA	1/154 (0.6%)
SKIN FISSURES	2/154 (1.3%)
Vascular disorders
CIRCULATORY COLLAPSE	1/154 (0.6%)
DEEP VEIN THROMBOSIS	4/154 (2.6%)
HYPOTENSION	2/154 (1.3%)
PHLEBITIS	1/154 (0.6%)
THROMBOSIS	3/154 (1.9%)
VENA CAVA THROMBOSIS	2/154 (1.3%)
Other (Not Including Serious) Adverse Events
	Panitumumab Plus FOLFIRI
	Affected / at Risk (%)	# Events
Total	154/154 (100%)
Blood and lymphatic system disorders
ANAEMIA	18/154 (11.7%)
LEUKOPENIA	8/154 (5.2%)
NEUTROPENIA	50/154 (32.5%)
Ear and labyrinth disorders
VERTIGO	13/154 (8.4%)
Eye disorders
CONJUNCTIVITIS	33/154 (21.4%)
DRY EYE	10/154 (6.5%)
LACRIMATION INCREASED	8/154 (5.2%)
Gastrointestinal disorders
ABDOMINAL PAIN	31/154 (20.1%)
ABDOMINAL PAIN UPPER	10/154 (6.5%)
APHTHOUS STOMATITIS	10/154 (6.5%)
CONSTIPATION	46/154 (29.9%)
DIARRHOEA	119/154 (77.3%)
DYSPEPSIA	18/154 (11.7%)
NAUSEA	85/154 (55.2%)
STOMATITIS	39/154 (25.3%)
VOMITING	41/154 (26.6%)
General disorders
ASTHENIA	42/154 (27.3%)
CHEST PAIN	10/154 (6.5%)
FATIGUE	49/154 (31.8%)
MUCOSAL INFLAMMATION	40/154 (26%)
OEDEMA PERIPHERAL	18/154 (11.7%)
PAIN	10/154 (6.5%)
PYREXIA	19/154 (12.3%)
Infections and infestations
NASOPHARYNGITIS	11/154 (7.1%)
PARONYCHIA	37/154 (24%)
RHINITIS	10/154 (6.5%)
URINARY TRACT INFECTION	9/154 (5.8%)
Investigations
WEIGHT DECREASED	21/154 (13.6%)
Metabolism and nutrition disorders
ANOREXIA	34/154 (22.1%)
HYPOKALAEMIA	35/154 (22.7%)
HYPOMAGNESAEMIA	29/154 (18.8%)
Musculoskeletal and connective tissue disorders
BACK PAIN	9/154 (5.8%)
PAIN IN EXTREMITY	9/154 (5.8%)
Nervous system disorders
DYSGEUSIA	15/154 (9.7%)
HEADACHE	9/154 (5.8%)
PARAESTHESIA	9/154 (5.8%)
POLYNEUROPATHY	8/154 (5.2%)
Psychiatric disorders
DEPRESSION	8/154 (5.2%)
INSOMNIA	13/154 (8.4%)
Respiratory, thoracic and mediastinal disorders
COUGH	12/154 (7.8%)
DYSPNOEA	16/154 (10.4%)
EPISTAXIS	18/154 (11.7%)
Skin and subcutaneous tissue disorders
ACNE	55/154 (35.7%)
ALOPECIA	52/154 (33.8%)
DERMATITIS	9/154 (5.8%)
DERMATITIS ACNEIFORM	32/154 (20.8%)
DRY SKIN	61/154 (39.6%)
ERYTHEMA	16/154 (10.4%)
NAIL TOXICITY	9/154 (5.8%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	25/154 (16.2%)
PRURITUS	30/154 (19.5%)
RASH	64/154 (41.6%)
SKIN FISSURES	31/154 (20.1%)
SKIN TOXICITY	18/154 (11.7%)
Vascular disorders
HYPOTENSION	9/154 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

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Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.