Study to Evaluate Mechanisms of Acquired Resistance to Panitumumab

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00891930
• Collaborator: (none)
• Enrollment: 76
• Arm: 1
• Duration (Months): 50

Study Details

Study Description

Brief Summary

This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus oncogene (KRAS) tumor status at the time of initial diagnosis.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Biological: Panitumumab; Biological: Ganitumab; Drug: Irinotecan	Phase 2

Detailed Description

In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2.

In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin-or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance to Panitumumab
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panitumumab Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.	Biological: Panitumumab; Panitumumab 6 mg/kg administered via IV infusion over 60 minutes; Other Names: Vectibix ; Biological: Ganitumab; AMG 479 12 mg/kg adminstered by IV infusion over 60 minutes; Other Names: AMG 479 ; Drug: Irinotecan; Irinotecan starting dose of 180 mg/m² adminstered via IV infusion

Outcome Measures

Primary Outcome Measures

1. Part 1: Emergence of Mutant KRAS [From first dose of study drug until the 2nd biopsy at the time of disease progression/entry into Part 2; median duration of treatment in Part 1 was 16 weeks.]

   Mutation in Kirsten rat sarcoma-2 virus oncogene (KRAS) status was determined by examining KRAS exons 2, 3, and 4. The emergence of mutant KRAS was defined as a change in KRAS mutation status from wild-type at Baseline in KRAS exons 2, 3, and 4 to mutant in any of KRAS exons 2, 3, and 4 at the time of the second biopsy following the radiographic evidence of acquired resistance to panitumumab when given in combination with irinotecan.

2. Part 2: Objective Response Rate (ORR) [From the first dose of study drug in Part 2 until the end of treatment in Part 2; median duration of treatment in Part 2 was 8 weeks.]

   Objective response rate (ORR) is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression (increase in size) of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) and no new lesions.

Secondary Outcome Measures

1. Part 1: Objective Response Rate [From first dose of study drug until the end of treatment in Part 1; median duration of treatment was 16 weeks.]

   Objective response rate is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified RECIST version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions.

2. Progression-free Survival (PFS) [From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.]

   Progression-free survival was defined as the interval from the first dose of study therapy to the earlier date of disease progression (per modified RECIST version 1.0) or death prior to the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in Part 2 where applicable. Participants who had not progressed or died during this period were censored at their last evaluable disease assessment date. Progressive Disease (PD): At least a 20% increase in the size of target or non-target lesions, significant increase in pleural effusions, ascites, or other fluid collections with cytologic proof of malignancy, or any new lesions.

3. Overall Survival (OS) [From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.]

   Overall survival was defined as the time from the first dose of study therapy in Part 1 or Part 2 to the date of death. Participants who had not died by the analysis data cutoff date were censored at their last contact date.

4. Time to Objective Response [From the first dose of study drug until the end of treatment in each Part; median duration of treatment was 16 weeks in Part 1 and 8 weeks in Part 2.]

   Time to objective response was defined as the time from first dose of study drug to the first confirmed objective response. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period.

5. Duration of Response [From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.]

   Duration of response is defined as the time from the first confirmed objective response to the earlier date of disease progression or death. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period.

6. Number of Participants Who Developed Antibodies to Panitumumab [From first dose date to 30 days since the last dose date. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.]

   Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. Postive samples were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay.

7. Number of Participants Who Developed Antibodies to Ganitumab [From first dose of ganitumab until 30 days after last dose; median time frame was 2.4 months.]

   Two validated assays were used to detect the presence of anti-ganitumab antibodies. First, an eletrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding ganitumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against ganitumab.

8. Number of Participants With Adverse Events [From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.]

   The severity of each adverse event (AE) was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (where 1 = Mild [aware of sign or symptom, but easily tolerated]; 2 = Moderate [discomfort enough to cause interference with usual activity]; 3 = severe [incapacitating with inability to work or do usual activity]; 4 = life-threatening; 5 = fatal), with the exception of selected skin toxicities that were graded using a modified version of CTC. Treatment-related adverse events were those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by panitumumab (Part 1) and by panitumumab and/or ganitumab (Part 2). Discontinuation includes AEs leading to discontinuation of panitumumab (Part 1) and panitumumab, ganitumab (Part 2) or removal from the study.

9. Number of Subjects With Worst Post-baseline Grade 3 or Higher Laboratory Toxicities [From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.]

   The severity of laboratory toxicities was graded using CTCAE v3.0.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum;

• Subjects with wild-type KRAS tumor status confirmed by an Amgen approved central laboratory assessment or an experienced local laboratory assessment of archival tumor tissue (preferably from the primary tumor);

• Radiographic evidence of disease progression while on or ≤ 6 months after completion of treatment with irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC;

• Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of treatment with investigational product);

• At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm by spiral CT scan per modified RECIST v1.0. Lesion must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to enrollment. All sites of disease must be evaluated;

• At least 1 tumor (preferably a metastasis or unresected primary tumour) that is amenable to core biopsy, as determined by the clinician who will perform the biopsy;

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

• A life expectancy estimate of ≥ 3 months;

• Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected primary);

• other criteria may apply

Exclusion Criteria:

• History of other primary cancer, unless:

• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician,

• Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease,

• Adequately treated cervical carcinoma in situ without evidence of disease,

• Prostatic intraepithelial neoplasia without evidence of prostate cancer;

• History of prior or concurrent central nervous system (CNS) metastases;

• Prior treatment with anti-EGFR (eg, panitumumab, cetuximab or small molecule inhibitors (eg, erlotinib, gefitinib);

• Prior treatment with monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) or small molecule inhibitors directed against IGF-1R;

• Use of systemic chemotherapy or radiotherapy ≤ 21 days before enrollment. Subjects must have recovered from acute toxicities related to radiotherapy;

• Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrolment;

• Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules ≤ 30 days before enrolment;

• Known allergy or hypersensitivity to any component of panitumumab, irinotecan, or AMG 479;

• Known uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms predisposing to increased irinotecan toxicity;

• History of irinotecan intolerance that may interfere with planned treatment;

• History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan;

• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment;

• Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea (defined as ≥ grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 3.0);

• Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection;

• Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. Core biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or paracentesis is not considered a major or minor surgical procedure; - Other investigational procedures or drugs (ie, participation in another clinical study) ≤ 30 days before enrolment;

• other criteria 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

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00891930
• Other Study ID Numbers: 20070820; 2008-004752-77
• First Posted: May 1, 2009
• Last Update Posted: Feb 8, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Amgen: wild-type KRAS; panitumumab; biomarker; mechanisms of acquired resistance; metastatic colorectal cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Irinotecan; Panitumumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 14 centers in Belgium, France, Germany, Italy and Spain. A total of 100 patients were screened, of whom 76 were enrolled in Part 1 from 05 May 2009 to 27 June 2011.
Pre-assignment Detail	Upon confirmation of eligibility participants were enrolled into Part 1 of the study to receive panitumumab plus irinotecan. Upon radiographically confirmed disease progression, eligible participants proceeded to Part 2 of the study to receive panitumumab plus ganitumab.

Arm/Group Title	Panitumumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Period Title: Part 1: Panitumumab +Irinotecan
STARTED	76
Received Treatment	74
COMPLETED	36
NOT COMPLETED	40
Period Title: Part 1: Panitumumab +Irinotecan
STARTED	36
COMPLETED	5
NOT COMPLETED	31

Baseline Characteristics

Arm/Group Title	Panitumumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Overall Participants	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (9.9)
Sex: Female, Male (Count of Participants)
Female	28 36.8%
Male	48 63.2%
Race/Ethnicity, Customized (participants) [Number]
White or Caucasian	75 98.7%
Other	1 1.3%
Primary Diagnosis (participants) [Number]
Colon Cancer	49 64.5%
Rectal Cancer	27 35.5%

Outcome Measures

1. Primary Outcome

Title	Part 1: Emergence of Mutant KRAS
Description	Mutation in Kirsten rat sarcoma-2 virus oncogene (KRAS) status was determined by examining KRAS exons 2, 3, and 4. The emergence of mutant KRAS was defined as a change in KRAS mutation status from wild-type at Baseline in KRAS exons 2, 3, and 4 to mutant in any of KRAS exons 2, 3, and 4 at the time of the second biopsy following the radiographic evidence of acquired resistance to panitumumab when given in combination with irinotecan.
Time Frame	From first dose of study drug until the 2nd biopsy at the time of disease progression/entry into Part 2; median duration of treatment in Part 1 was 16 weeks.

Outcome Measure Data

Analysis Population Description

KRAS analysis set (participants with known wild-type KRAS tumors from archival tumor sample and who received at least 1 dose of panitumumab and/or irinotecan in Part 1 and with known KRAS status at baseline and at acquired disease resistance to panitumumab in combination with irinotecan (i.e., based on the results of the second biopsy on study).

Arm/Group Title	Part 1: Panitumumab + Irinotecan
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).
Measure Participants	25
Number (95% Confidence Interval) [percentage of participants]	8.00 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Irinotecan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments	Exact test for a single proportion was performed with a null hypothesis of 1%.
	Method	Exact test
	Comments

2. Primary Outcome

Title	Part 2: Objective Response Rate (ORR)
Description	Objective response rate (ORR) is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression (increase in size) of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) and no new lesions.
Time Frame	From the first dose of study drug in Part 2 until the end of treatment in Part 2; median duration of treatment in Part 2 was 8 weeks.

Outcome Measure Data

Analysis Population Description

Tumor Response Evaluable Analysis Set - Part 2 (participants who had radiographically confirmed disease progression on panitumumab and irinotecan in Part 1 and received at least 1 dose of panitumumab and/or ganitumab in Part 2 and with at least 1 baseline uni-dimensionally measurable lesion per the RECIST v1.0 based on investigators' review.

Arm/Group Title	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	36
Number (95% Confidence Interval) [percentage of participants]	0.00 0%

3. Secondary Outcome

Title	Part 1: Objective Response Rate
Description	Objective response rate is defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) measured by the investigator per modified RECIST version 1.0 criteria during the treatment period. Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in size of target lesions and no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease and no new lesions.
Time Frame	From first dose of study drug until the end of treatment in Part 1; median duration of treatment was 16 weeks.

Outcome Measure Data

Analysis Population Description

Tumor Response Evaluable Analysis Set - Part 1 (participants who had known wild-type KRAS tumors from archival tumor sample and who received at least 1 dose of panitumumab and/or irinotecan in Part 1 and with at least one Baseline uni-dimensionally measurable lesion per the RECIST version 1.0 based on investigators' review).

Arm/Group Title	Part 1: Panitumumab + Irinotecan
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).
Measure Participants	74
Number (95% Confidence Interval) [percentage of participants]	21.62 28.4%

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival was defined as the interval from the first dose of study therapy to the earlier date of disease progression (per modified RECIST version 1.0) or death prior to the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in Part 2 where applicable. Participants who had not progressed or died during this period were censored at their last evaluable disease assessment date. Progressive Disease (PD): At least a 20% increase in the size of target or non-target lesions, significant increase in pleural effusions, ascites, or other fluid collections with cytologic proof of malignancy, or any new lesions.
Time Frame	From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 1: participants who had known wild-type KRAS tumors from archival tumor sample and who received at least 1 dose of panitumumab and/or irinotecan. Part 2: participants who had radiographically confirmed disease progression on treatment in Part 1 and received at least 1 dose of panitumumab and/or ganitumab in Part 2.

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	74	36
Median (95% Confidence Interval) [months]	4.6	1.7

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from the first dose of study therapy in Part 1 or Part 2 to the date of death. Participants who had not died by the analysis data cutoff date were censored at their last contact date.
Time Frame	From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 1 and Part 2

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	74	36
Median (95% Confidence Interval) [months]	11.6	7.6

6. Secondary Outcome

Title	Time to Objective Response
Description	Time to objective response was defined as the time from first dose of study drug to the first confirmed objective response. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period.
Time Frame	From the first dose of study drug until the end of treatment in each Part; median duration of treatment was 16 weeks in Part 1 and 8 weeks in Part 2.

Outcome Measure Data

Analysis Population Description

Tumor Response Evaluable Analysis Set - Part 1 and Part 2 participants with an objective response

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	16	0
Median (Full Range) [months]	1.8

7. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined as the time from the first confirmed objective response to the earlier date of disease progression or death. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period.
Time Frame	From the first dose of study drug until the data cut-off date of 30 July 2013. Median time on study follow-up was 48.5 weeks for Part 1 and 32 weeks in Part 2.

Outcome Measure Data

Analysis Population Description

Tumor Response Evaluable Analysis Set - Part 1 and Part 2 participants with an objective response

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	16	0
Median (95% Confidence Interval) [months]	7.7

8. Secondary Outcome

Title	Number of Participants Who Developed Antibodies to Panitumumab
Description	Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. Postive samples were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay.
Time Frame	From first dose date to 30 days since the last dose date. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 1 participants with at least 1 post-baseline immunoassay result.

Arm/Group Title	Panitumumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	25
Binding antibody positive	0 0%
Neutralizing antibody positive	0 0%

9. Secondary Outcome

Title	Number of Participants Who Developed Antibodies to Ganitumab
Description	Two validated assays were used to detect the presence of anti-ganitumab antibodies. First, an eletrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding ganitumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against ganitumab.
Time Frame	From first dose of ganitumab until 30 days after last dose; median time frame was 2.4 months.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 2 particpants with at least 1 post-baseline immunoassay result.

Arm/Group Title	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	15
Binding antibody positive	0 0%
Neutralizing antibody positive	0 0%

10. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	The severity of each adverse event (AE) was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (where 1 = Mild [aware of sign or symptom, but easily tolerated]; 2 = Moderate [discomfort enough to cause interference with usual activity]; 3 = severe [incapacitating with inability to work or do usual activity]; 4 = life-threatening; 5 = fatal), with the exception of selected skin toxicities that were graded using a modified version of CTC. Treatment-related adverse events were those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by panitumumab (Part 1) and by panitumumab and/or ganitumab (Part 2). Discontinuation includes AEs leading to discontinuation of panitumumab (Part 1) and panitumumab, ganitumab (Part 2) or removal from the study.
Time Frame	From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 1 and Part 2

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	74	36
Any adverse event (AE)	74 97.4%	35 NaN
Worst grade of 3	43 56.6%	17 NaN
Worst grade of 4	6 7.9%	1 NaN
Worst grade of 5	6 7.9%	2 NaN
Worst grade of 5 excluding progressive disease	1 1.3%	0 NaN
Serious adverse event (SAE)	26 34.2%	8 NaN
Non-serious AE leading to discontinuation	3 3.9%	1 NaN
SAE leading to discontinuation	8 10.5%	1 NaN
Any treatment-related adverse event (TRAE)	70 92.1%	33 NaN
TRAE worst grade of 3	34 44.7%	7 NaN
TRAE worst grade of 4	3 3.9%	1 NaN
TRAE worst grade of 5	0 0%	0 NaN
TRAE worst grade 5 excluding progressive disease	0 0%	0 NaN
Treatment-related SAE	7 9.2%	1 NaN
Non-serious TRAE leading to discontinuation	0 0%	1 NaN
Serious TRAE leading to discontinuation	1 1.3%	0 NaN

11. Secondary Outcome

Title	Number of Subjects With Worst Post-baseline Grade 3 or Higher Laboratory Toxicities
Description	The severity of laboratory toxicities was graded using CTCAE v3.0.
Time Frame	From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.

Outcome Measure Data

Analysis Population Description

Primary Analysis Set - Part 1 and Part 2

Arm/Group Title	Part 1: Panitumumab + Irinotecan	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).	Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
Measure Participants	74	36
Decreased absolute neutrophil count	3 3.9%	0 NaN
Decreased hemoglobin	3 3.9%	0 NaN
Decreased lymphocytes	3 3.9%	0 NaN
Decreased total neutrophils	2 2.6%	0 NaN
Decreased white blood cells	2 2.6%	0 NaN
Decreased albumin	1 1.3%	0 NaN
Increased alkaline phosphatase	5 6.6%	2 NaN
Increased aspartate aminotransferase	1 1.3%	1 NaN
Decreased calcium	4 5.3%	1 NaN
Increased creatinine	1 1.3%	0 NaN
Decreased glucose	2 2.6%	0 NaN
Increased glucose	1 1.3%	2 NaN
Decreased magnesium	9 11.8%	2 NaN
Increased magnesium	2 2.6%	2 NaN
Decreased phosphorus	2 2.6%	1 NaN
Decreased potassium	7 9.2%	0 NaN
Increased potassium	3 3.9%	0 NaN
Decreased sodium	7 9.2%	0 NaN
Increased total bilirubin	3 3.9%	0 NaN

Adverse Events

Time Frame	From first dose date to 30 days since the last dose date in each part of the study. The median time frame is 4.2 months for Part 1 and 2.4 months for Part 2.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Part-1: Panitumumab + Irinotecan		Part-2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W).		Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W.
All Cause Mortality
	Part-1: Panitumumab + Irinotecan		Part-2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Part-1: Panitumumab + Irinotecan		Part-2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/74 (35.1%)		8/36 (22.2%)
Blood and lymphatic system disorders
Anaemia	2/74 (2.7%)		0/36 (0%)
Leukopenia	1/74 (1.4%)		0/36 (0%)
Neutropenia	2/74 (2.7%)		0/36 (0%)
Cardiac disorders
Cardiac failure	1/74 (1.4%)		0/36 (0%)
Gastrointestinal disorders
Abdominal pain	1/74 (1.4%)		0/36 (0%)
Diarrhoea	6/74 (8.1%)		0/36 (0%)
Ileus	1/74 (1.4%)		0/36 (0%)
Intestinal obstruction	2/74 (2.7%)		0/36 (0%)
Oesophagitis	1/74 (1.4%)		0/36 (0%)
Rectal haemorrhage	1/74 (1.4%)		1/36 (2.8%)
Stomatitis	1/74 (1.4%)		0/36 (0%)
Vomiting	3/74 (4.1%)		0/36 (0%)
General disorders
Asthenia	3/74 (4.1%)		0/36 (0%)
Fatigue	2/74 (2.7%)		0/36 (0%)
General physical health deterioration	5/74 (6.8%)		2/36 (5.6%)
Performance status decreased	1/74 (1.4%)		0/36 (0%)
Pyrexia	0/74 (0%)		1/36 (2.8%)
Hepatobiliary disorders
Cholangitis	2/74 (2.7%)		1/36 (2.8%)
Cholestasis	1/74 (1.4%)		0/36 (0%)
Immune system disorders
Hypersensitivity	1/74 (1.4%)		1/36 (2.8%)
Infections and infestations
Anal abscess	1/74 (1.4%)		0/36 (0%)
Bronchitis	1/74 (1.4%)		0/36 (0%)
Device related infection	2/74 (2.7%)		0/36 (0%)
Gastroenteritis	1/74 (1.4%)		0/36 (0%)
Staphylococcal sepsis	1/74 (1.4%)		0/36 (0%)
Urinary tract infection	1/74 (1.4%)		0/36 (0%)
Investigations
Weight decreased	1/74 (1.4%)		0/36 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/74 (1.4%)		0/36 (0%)
Hypokalaemia	1/74 (1.4%)		0/36 (0%)
Hypomagnesaemia	1/74 (1.4%)		0/36 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/74 (1.4%)		0/36 (0%)
Back pain	1/74 (1.4%)		0/36 (0%)
Bone pain	1/74 (1.4%)		0/36 (0%)
Muscle contracture	1/74 (1.4%)		0/36 (0%)
Myalgia	1/74 (1.4%)		0/36 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colorectal cancer	1/74 (1.4%)		2/36 (5.6%)
Metastases to peritoneum	1/74 (1.4%)		0/36 (0%)
Nervous system disorders
Paresis	1/74 (1.4%)		0/36 (0%)
Syncope	1/74 (1.4%)		0/36 (0%)
Psychiatric disorders
Confusional state	2/74 (2.7%)		0/36 (0%)
Renal and urinary disorders
Renal failure acute	1/74 (1.4%)		0/36 (0%)
Urinary retention	1/74 (1.4%)		0/36 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/74 (1.4%)		0/36 (0%)
Dyspnoea	1/74 (1.4%)		0/36 (0%)
Pulmonary embolism	1/74 (1.4%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Part-1: Panitumumab + Irinotecan		Part-2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/74 (100%)		35/36 (97.2%)
Blood and lymphatic system disorders
Anaemia	11/74 (14.9%)		3/36 (8.3%)
Neutropenia	9/74 (12.2%)		2/36 (5.6%)
Cardiac disorders
Tachycardia	4/74 (5.4%)		0/36 (0%)
Congenital, familial and genetic disorders
Trichomegaly	5/74 (6.8%)		0/36 (0%)
Eye disorders
Conjunctivitis	9/74 (12.2%)		3/36 (8.3%)
Dry eye	4/74 (5.4%)		0/36 (0%)
Gastrointestinal disorders
Abdominal distension	4/74 (5.4%)		0/36 (0%)
Abdominal pain	17/74 (23%)		8/36 (22.2%)
Abdominal pain upper	8/74 (10.8%)		7/36 (19.4%)
Constipation	20/74 (27%)		8/36 (22.2%)
Diarrhoea	54/74 (73%)		8/36 (22.2%)
Dyspepsia	6/74 (8.1%)		2/36 (5.6%)
Haemorrhoids	4/74 (5.4%)		0/36 (0%)
Nausea	38/74 (51.4%)		10/36 (27.8%)
Stomatitis	5/74 (6.8%)		2/36 (5.6%)
Vomiting	28/74 (37.8%)		4/36 (11.1%)
General disorders
Asthenia	39/74 (52.7%)		12/36 (33.3%)
Chest pain	4/74 (5.4%)		0/36 (0%)
Chills	2/74 (2.7%)		3/36 (8.3%)
Fatigue	12/74 (16.2%)		5/36 (13.9%)
General physical health deterioration	6/74 (8.1%)		1/36 (2.8%)
Mucosal inflammation	25/74 (33.8%)		4/36 (11.1%)
Oedema peripheral	5/74 (6.8%)		4/36 (11.1%)
Pyrexia	12/74 (16.2%)		4/36 (11.1%)
Xerosis	7/74 (9.5%)		2/36 (5.6%)
Hepatobiliary disorders
Hepatic pain	2/74 (2.7%)		2/36 (5.6%)
Infections and infestations
Folliculitis	6/74 (8.1%)		2/36 (5.6%)
Infection	0/74 (0%)		2/36 (5.6%)
Nasopharyngitis	4/74 (5.4%)		1/36 (2.8%)
Paronychia	18/74 (24.3%)		7/36 (19.4%)
Urinary tract infection	5/74 (6.8%)		3/36 (8.3%)
Injury, poisoning and procedural complications
Infusion related reaction	2/74 (2.7%)		3/36 (8.3%)
Investigations
Weight decreased	8/74 (10.8%)		1/36 (2.8%)
Metabolism and nutrition disorders
Decreased appetite	28/74 (37.8%)		5/36 (13.9%)
Hypokalaemia	6/74 (8.1%)		0/36 (0%)
Hypomagnesaemia	22/74 (29.7%)		5/36 (13.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/74 (5.4%)		0/36 (0%)
Back pain	9/74 (12.2%)		3/36 (8.3%)
Musculoskeletal chest pain	1/74 (1.4%)		2/36 (5.6%)
Musculoskeletal pain	6/74 (8.1%)		4/36 (11.1%)
Nervous system disorders
Dysgeusia	5/74 (6.8%)		2/36 (5.6%)
Headache	6/74 (8.1%)		0/36 (0%)
Neurotoxicity	4/74 (5.4%)		0/36 (0%)
Paraesthesia	5/74 (6.8%)		0/36 (0%)
Polyneuropathy	5/74 (6.8%)		0/36 (0%)
Psychiatric disorders
Insomnia	8/74 (10.8%)		0/36 (0%)
Renal and urinary disorders
Dysuria	4/74 (5.4%)		2/36 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	8/74 (10.8%)		2/36 (5.6%)
Dysphonia	4/74 (5.4%)		1/36 (2.8%)
Dyspnoea	7/74 (9.5%)		2/36 (5.6%)
Epistaxis	2/74 (2.7%)		3/36 (8.3%)
Oropharyngeal pain	5/74 (6.8%)		1/36 (2.8%)
Productive cough	5/74 (6.8%)		0/36 (0%)
Skin and subcutaneous tissue disorders
Acne	10/74 (13.5%)		2/36 (5.6%)
Alopecia	23/74 (31.1%)		1/36 (2.8%)
Dermatitis acneiform	8/74 (10.8%)		3/36 (8.3%)
Dry skin	24/74 (32.4%)		5/36 (13.9%)
Eczema	1/74 (1.4%)		2/36 (5.6%)
Erythema	5/74 (6.8%)		1/36 (2.8%)
Nail bed inflammation	0/74 (0%)		3/36 (8.3%)
Nail toxicity	4/74 (5.4%)		0/36 (0%)
Palmar-plantar erythrodysaesthesia syndrome	1/74 (1.4%)		3/36 (8.3%)
Pruritus	13/74 (17.6%)		2/36 (5.6%)
Rash	39/74 (52.7%)		15/36 (41.7%)
Skin fissures	19/74 (25.7%)		3/36 (8.3%)
Skin toxicity	14/74 (18.9%)		3/36 (8.3%)
Vascular disorders
Haematoma	4/74 (5.4%)		1/36 (2.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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.