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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00788957
• Collaborator: (none)
• Enrollment: 153
• Arms: 4
• Duration (Months): 60

Study Details

Study Description

Brief Summary

This study is a global, multicenter, open-label phase 1b and randomized, double-blinded, 2 part, phase 2 study designed to evaluate the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus panitumumab alone in patients with metastatic colorectal cancer whose tumors are wild-type KRAS status.

Condition or Disease	Intervention/Treatment	Phase
Colon Cancer; Colorectal Cancer; Gastrointestinal Cancer; Metastatic Colorectal Cancer; Rectal Cancer	Drug: Panitumumab; Drug: Ganitumab; Drug: Rilotumumab; Drug: Placebo	Phase 1/Phase 2

Detailed Description

This study consisted of 3 parts:

Part 1: determination of the tolerable dose of rilotumumab in combination with panitumumab to be administered in Part 2.

Part 2: Comparison of the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus that of panitumumab alone. In Part 2, participants were randomized 1:1:1 into 3 cohorts: 6 mg/kg panitumumab plus 10 mg/kg rilotumumab, 6 mg/kg panitumumab plus 12 mg/kg ganitumab, or 6 mg/kg panitumumab and placebo (panitumumab alone cohort). Panitumumab was administered open-label, and rilotumumab and ganitumab were double-blinded.

Part 3: Exploratory evaluation of the safety and efficacy of the rilotumumab and ganitumab monotherapy following treatment with panitumumab in Part 2. In Part 3, eligible participants who terminated panitumumab treatment in the Panitumumab Alone arm of Part 2 due to disease progression or intolerability could be randomized 1:1 into 2 double-blind cohorts: 10 mg/kg rilotumumab or 12 mg/kg ganitumab.

Participants who permanently discontinued all the investigational products completed a safety follow-up visit 30 days and a follow-up visit 60 days after the last dose of investigational product. Participants were followed for radiographic disease progression and survival every 3 months after the 30-day safety follow-up visit for up to 2 years after the last participant was enrolled in Part 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Panitumumab + Rilotumumab Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix® ; Drug: Rilotumumab; Rilotumumab for intravenous infusion; Other Names: AMG 102
Active Comparator: Part 2: Panitumumab Alone Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix® ; Drug: Placebo; Placebo intravenous infusion
Experimental: Part 2: Panitumumab + Rilotumumab Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix® ; Drug: Rilotumumab; Rilotumumab for intravenous infusion; Other Names: AMG 102
Experimental: Part 2: Panitumumab + Ganitumab Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Drug: Panitumumab; Panitumumab for intravenous infusion; Other Names: Vectibix® ; Drug: Ganitumab; Ganitumab for intravenous infusion; Other Names: AMG 479

Outcome Measures

Primary Outcome Measures

1. Part 1: Number of Participants With Dose-limiting Toxicities (DLT) [7 weeks]

   A DLT is defined as any grade 3 or 4 rilotumumab-related or combination (panitumumab and rilotumumab)-related adverse event or laboratory abnormality that is deemed clinically significant by the investigator

2. Part 2: Percentage of Participants With an Objective Response [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   An objective response is defined as a confirmed complete (CR) or partial response (PR) no less than 4 weeks after the criteria for response are first met, determined by the investigator considering the radiologic response of all existing target and non-target lesions, evidence of new lesions, and cytology evaluation (as appropriate) according to the Modified-Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 criteria: CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders. Tumor assessments up to the initiation of another anti-tumor therapy including the Part 3 treatment, if applicable, were used.

Secondary Outcome Measures

1. Part 2: Duration of Response [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   The interval 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.

2. Part 2: Time to Response [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   The interval from the first dose of study therapy to the date of the first confirmed objective response, calculated only for participants with an objective response.

3. Part 2: Percentage of Participants With Disease Control [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   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.

4. Progression-free Survival [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   The interval 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.

5. On-treatment Progression-free Survival [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.]

   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.

6. Overall Survival [From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.]

   The interval 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.

7. Number of Participants With Adverse Events (AEs) [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.]

   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?"

8. Number of Participants With Grade 3 or Higher Laboratory Toxicities [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.]

   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.

9. Number of Participants With Antibody Formation to Panitumumab, Rilotumumab and Ganitumab [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.]

   Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.

10. 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.]

11. 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.]

12. 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.]

13. Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab [Pre-dose at Weeks 3, 5, 7, 13 and 23.]

    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

14. 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.]

15. Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab [Pre-dose at Weeks 3, 5, 7, 13 and 23.]

    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

16. 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.]

17. Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab [Pre-dose at Weeks 3, 5, 7, 13 and 23.]

    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

Eligibility Criteria

Criteria

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

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

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

• 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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00788957
• Other Study ID Numbers: 20060447
• First Posted: Nov 11, 2008
• Last Update Posted: Jul 20, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Amgen: panitumumab; vectibix; AMG 102; AMG 479; colon cancer; rectal cancer; colorectal cancer; metastatic colorectal cancer; EGFR inhibitor; IGF inhibitor; c-MET inhibitor
• Additional relevant MeSH terms: Colorectal Neoplasms; Rectal Neoplasms; Colonic Neoplasms; Gastrointestinal Neoplasms; Panitumumab; Rilotumumab

Study Results

Participant Flow

Recruitment Details	First patient enrolled 27 October 2008; last patient enrolled 05 February 2010. In Part 1, participants with wild-type KRAS metastatic colorectal cancer received open-label rilotumumab and panitumumab to identify a tolerable dose of rilotumumab for Part 2 of the study. Participants enrolled in Part 1 were not eligible for randomization in Part 2.
Pre-assignment Detail	In Part 2 participants were randomized in a 1:1:1 ratio to the 3 double-blinded treatment arms. In Part 3, participants randomized to Panitumumab Alone in Part 2 and with disease progression or intolerability were re-randomized 1:1 into 2 double-blind groups. Participants completed a safety follow-up visit 30 days after the last dose of study drug.

Arm/Group Title	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Part 3: Rilotumumab	Part 3: Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive rilotumumab 10 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.	Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive ganitumab 12 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.
Period Title: Part 1
STARTED	11	0	0	0	0	0
COMPLETED	2	0	0	0	0	0
NOT COMPLETED	9	0	0	0	0	0
Period Title: Part 1
STARTED	0	48	48	46	0	0
COMPLETED	0	6	4	5	0	0
NOT COMPLETED	0	42	44	41	0	0
Period Title: Part 1
STARTED	0	0	0	0	13	12
COMPLETED	0	0	0	0	4	1
NOT COMPLETED	0	0	0	0	9	11

Baseline Characteristics

Arm/Group Title	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Total
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Total of all reporting groups
Overall Participants	11	48	48	46	153
Age (years) [Mean (Standard Deviation) ]
Part 1 Participants	56.5 (13.8)	NA (NA)	NA (NA)	NA (NA)	56.5 (13.8)
Part 2 Participants	NA (NA)	55.0 (12.5)	62.1 (7.5)	62.0 (9.7)	59.7 (10.6)
Sex: Female, Male (Count of Participants)
Female	6 54.5%	20 41.7%	19 39.6%	21 45.7%	66 43.1%
Male	5 45.5%	28 58.3%	29 60.4%	25 54.3%	87 56.9%
Race/Ethnicity, Customized (participants) [Number]
White or Caucasian	11 100%	45 93.8%	47 97.9%	45 97.8%	148 96.7%
Black or African American	0 0%	0 0%	1 2.1%	1 2.2%	2 1.3%
Hispanic or Latino	0 0%	1 2.1%	0 0%	0 0%	1 0.7%
Asian	0 0%	1 2.1%	0 0%	0 0%	1 0.7%
Other	0 0%	1 2.1%	0 0%	0 0%	1 0.7%
Primary Tumor Type (participants) [Number]
Colon cancer	6 54.5%	31 64.6%	33 68.8%	28 60.9%	98 64.1%
Rectal cancer	5 45.5%	17 35.4%	15 31.3%	18 39.1%	55 35.9%
Adenocarcinoma Differential of Primary Tumor (participants) [Number]
Well differentiated	0 0%	8 16.7%	7 14.6%	6 13%	21 13.7%
Moderately differentiated	6 54.5%	27 56.3%	27 56.3%	25 54.3%	85 55.6%
Poorly differentiated	5 45.5%	9 18.8%	6 12.5%	11 23.9%	31 20.3%
Undifferentiated	0 0%	0 0%	0 0%	1 2.2%	1 0.7%
Unknown	0 0%	4 8.3%	8 16.7%	3 6.5%	15 9.8%
Months Since Primary Diagnosis (months) [Mean (Standard Deviation) ]
Part 1 Participants	41.7 (29.7)	NA (NA)	NA (NA)	NA (NA)	41.7 (29.7)
Part 2 Participants	NA (NA)	30.3 (18.5)	36.2 (31.8)	34.7 (28.7)	33.7 (26.9)
Months Since Metastatic Disease Diagnosis (months) [Mean (Standard Deviation) ]
Part 1 Participants	29.7 (27.6)	NA (NA)	NA (NA)	NA (NA)	29.7 (27.6)
Part 2 Participants	NA (NA)	21.8 (12.6)	25.8 (27.0)	21.1 (16.0)	22.9 (19.5)

Outcome Measures

1. Primary Outcome

Title	Part 1: Number of Participants With Dose-limiting Toxicities (DLT)
Description	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
Time Frame	7 weeks

Outcome Measure Data

Analysis Population Description

The first 6 DLT evaluable participants, including participants who received at least 2 doses of panitumumab and rilotumumab as scheduled (ie, Week 1 and 3) and have a minimum 28 days follow-up for safety or, have received at least 1 dose of panitumumab and rilotumumab and had a DLT within the first 28 days on study.

Arm/Group Title	Part 1: Panitumumab + Rilotumumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	6
Number [participants]	0 0%

2. Primary Outcome

Title	Part 2: Percentage of Participants With an Objective Response
Description	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.
Time Frame	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Outcome Measure Data

Analysis Population Description

Efficacy analysis set (enrolled participants who received at least one dose of respective investigational product in the corresponding parts of the study) with measurable baseline disease.

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Number [percentage of participants]	21 190.9%	31 64.6%	22 45.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab
	Comments	For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean and 95% credible region are reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean
	Estimated Value	18.5
	Confidence Interval	(2-Sided) 95%; 11.2 to 27.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 2: Panitumumab + Rilotumumab
	Comments	For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean and 95% credible region are reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean
	Estimated Value	29.4
	Confidence Interval	(2-Sided) 95%; 18.3 to 42.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Panitumumab + Ganitumab
	Comments	For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean and 95% credible region are reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean
	Estimated Value	21.1
	Confidence Interval	(2-Sided) 95%; 11.3 to 32.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Rilotumumab
	Comments	The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + rilotumumab compared to panitumumab alone.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean Difference in ORR
	Estimated Value	10.9
	Confidence Interval	(2-Sided) 95%; -2.9 to 26.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Ganitumab
	Comments	The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + ganitumab compared to panitumumab alone.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean Difference in ORR
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -10.6 to 16.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Rilotumumab
	Comments	The posterior distribution of the odds ratio for an ORR was used to assess whether rilotumumab and/or ganitumab in combination with panitumumab has a higher ORR compared to panitumumab alone. A 95% credible region was calculated for the odds ratio. The posterior probability of the odds ratio being > 1 is reported as the P-value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9318
	Comments
	Method	Posterior probability of OR > 1
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean odds ratio (OR)
	Estimated Value	2.003
	Confidence Interval	(2-Sided) 95%; 0.840 to 4.243
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio value greater than 1 implies a higher ORR for the respective combination therapy relative to panitumumab alone.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Ganitumab
	Comments	The posterior distribution of the odds ratio for an ORR was used to assess whether rilotumumab and/or ganitumab in combination with panitumumab has a higher ORR compared to panitumumab alone. A 95% credible region was calculated for the odds ratio. The posterior probability of the odds ratio being > 1 is reported as the P-value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6336
	Comments
	Method	Posterior probability of OR > 1
	Comments
Method of Estimation	Estimation Parameter	Posterior Mean odds ratio (OR)
	Estimated Value	1.281
	Confidence Interval	(2-Sided) 95%; 0.478 to 2.726
	Parameter Dispersion	Type: Value:
	Estimation Comments	An odds ratio value greater than 1 implies a higher ORR for the respective combination therapy relative to panitumumab alone.

3. Secondary Outcome

Title	Part 2: Duration of Response
Description	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.
Time Frame	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Outcome Measure Data

Analysis Population Description

Efficacy analysis set; participants with an objective response of CR or PR.

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	10	15	10
Median (95% Confidence Interval) [months]	3.7	5.1	3.7

4. Secondary Outcome

Title	Part 2: Time to Response
Description	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.
Time Frame	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Outcome Measure Data

Analysis Population Description

Efficacy analysis set; participants with an objective response of CR or PR.

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	10	15	10
Median (95% Confidence Interval) [months]	1.8	1.6	1.7

5. Secondary Outcome

Title	Part 2: Percentage of Participants With Disease Control
Description	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.
Time Frame	From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Outcome Measure Data

Analysis Population Description

Efficacy analysis set

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Number (95% Confidence Interval) [percentage of participants]	56 509.1%	71 147.9%	61 127.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Rilotumumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	15
	Confidence Interval	(2-Sided) 95%; -6 to 34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Ganitumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	5
	Confidence Interval	(2-Sided) 95%; -16 to 25
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Efficacy analysis set

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Median (95% Confidence Interval) [months]	3.7	5.2	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Rilotumumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in median time
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -0.6 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Ganitumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in median time
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -1.6 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	On-treatment Progression-free Survival
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Efficacy analysis set

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Median (95% Confidence Interval) [months]	3.8	5.3	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Rilotumumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in median time
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -0.3 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 1: Panitumumab + Rilotumumab, Part 2: Panitumumab + Ganitumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in median time
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -1.7 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Efficacy analysis set

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Median (95% Confidence Interval) [months]	NA	NA	NA

9. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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?"
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Safety analysis set (all enrolled participants who received at least 1 dose of investigational product).

Arm/Group Title	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	11	48	48	46
Any adverse event	11 100%	45 93.8%	48 100%	46 100%
Worst grade of 3	8 72.7%	19 39.6%	28 58.3%	25 54.3%
Worst grade of 4	1 9.1%	3 6.3%	6 12.5%	4 8.7%
Worst grade of 5	1 9.1%	1 2.1%	4 8.3%	4 8.7%
Serious adverse event	5 45.5%	10 20.8%	9 18.8%	10 21.7%
AE leading to study drug / study discontinuation	4 36.4%	4 8.3%	9 18.8%	7 15.2%
Treatment-related adverse event (TRAE)	10 90.9%	43 89.6%	47 97.9%	45 97.8%
TRAE worst grade of 3	7 63.6%	11 22.9%	26 54.2%	20 43.5%
TRAE worst grade of 4	0 0%	3 6.3%	6 12.5%	4 8.7%
TRAE worst grade of 5	0 0%	0 0%	0 0%	0 0%
Serious treatment-related adverse event	2 18.2%	1 2.1%	2 4.2%	2 4.3%
TRAE leading to study drug / study discontinuation	3 27.3%	2 4.2%	4 8.3%	2 4.3%

10. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Laboratory Toxicities
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Safety analysis set (all enrolled participants who received at least 1 dose of investigational product).

Arm/Group Title	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	11	48	48	46
Increased Alanine Amino Transferase	0 0%	1 2.1%	0 0%	2 4.3%
Decreased Albumin	0 0%	1 2.1%	3 6.3%	0 0%
Increased Alkaline Phosphatase	1 9.1%	2 4.2%	3 6.3%	5 10.9%
Increased Aspartate Amino Transferase	0 0%	0 0%	0 0%	4 8.7%
Decreased Calcium	0 0%	3 6.3%	1 2.1%	2 4.3%
Increased Calcium	1 9.1%	0 0%	1 2.1%	2 4.3%
Increased Creatinine	0 0%	0 0%	0 0%	1 2.2%
Decreased Glucose	0 0%	0 0%	0 0%	0 0%
Increased Glucose	1 9.1%	0 0%	2 4.2%	0 0%
Decreased Magnesium	0 0%	1 2.1%	2 4.2%	8 17.4%
Increased Magnesium	0 0%	4 8.3%	2 4.2%	2 4.3%
Decreased Phosphorus	0 0%	1 2.1%	4 8.3%	1 2.2%
Decreased Potassium	1 9.1%	1 2.1%	1 2.1%	0 0%
Increased Potassium	0 0%	0 0%	1 2.1%	0 0%
Decreased Sodium	0 0%	3 6.3%	2 4.2%	3 6.5%
Increased Sodium	0 0%	0 0%	1 2.1%	0 0%
Increased Total Bilirubin	0 0%	3 6.3%	0 0%	5 10.9%
Increased Uric Acid	1 9.1%	1 2.1%	2 4.2%	1 2.2%
Decreased Absolute Neutrophil Count	0 0%	1 2.1%	1 2.1%	2 4.3%
Decreased Hemoglobin	1 9.1%	2 4.2%	1 2.1%	0 0%
Decreased Lymphocytes	1 9.1%	3 6.3%	2 4.2%	1 2.2%
Decreased Platelets	0 0%	0 0%	0 0%	1 2.2%
Decreased Total Neutrophils	0 0%	1 2.1%	1 2.1%	2 4.3%
Decreased White Blood Cells	0 0%	0 0%	0 0%	0 0%

11. Secondary Outcome

Title	Number of Participants With Antibody Formation to Panitumumab, Rilotumumab and Ganitumab
Description	Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Safety analysis set participants with at least one post-baseline immunoassay result.

Arm/Group Title	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	8	40	44	43
Anti-panitumumab antibodies	0 0%	3 6.3%	3 6.3%	4 8.7%
Anti-rilotumumab antibodies	0 0%	NA NaN	3 6.3%	NA NaN
Anti-ganitumab antibodies	NA NaN	NA NaN	NA NaN	2 4.3%

12. Secondary Outcome

Title	Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum Drug Concentration (Cmin) for Panitumumab and Rilotumumab
Time Frame	Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.

Outcome Measure Data

Analysis Population Description

Part 1 participants for whom intensive pharmacokinetic samples after the third dose (Week 5) were available.

Arm/Group Title	Panitumumab	Rilotumumab
Arm/Group Description	Pharmacokinetics of panitumumab in Part 1 participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Pharmacokinetics of rilotumumab in Part 1 participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	6	6
Cmax (n=6, 6)	227 (37.23)	346 (88.58)
Cmin (n=5, 4)	61.1 (32.93)	124 (35.22)

13. Secondary Outcome

Title	Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab
Time Frame	Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.

Outcome Measure Data

Analysis Population Description

Part 1 participants for whom intensive pharmacokinetic samples after the third dose (Week 5) were available.

Arm/Group Title	Panitumumab	Rilotumumab
Arm/Group Description	Pharmacokinetics of panitumumab in Part 1 participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Pharmacokinetics of rilotumumab in Part 1 participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	5	4
Mean (Standard Deviation) [day*μg/ml]	1420 (386.24)	2560 (675.84)

14. Secondary Outcome

Title	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab
Time Frame	Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Week 1 (n=43, 42, 44)	114 (31.58)	124 (32.74)	118 (40.95)
Week 3 (n=38, 37, 38)	149 (46.79)	154 (44.66)	139 (33.92)
Week 5 (n=35, 35, 35)	165 (49.67)	172 (55.56)	150 (39.75)
Week 7 (n=30, 35, 29)	166 (51.13)	180 (53.28)	167 (39.91)
Week 13 (n=16, 17, 21)	201 (53.67)	199 (51.14)	192 (59.90)
Week 23 (n=10, 10, 9)	196 (48.02)	207 (51.54)	187 (41.70)

15. Secondary Outcome

Title	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab
Description	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).
Time Frame	Pre-dose at Weeks 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48	48	46
Week 3 (n=39, 36, 36)	19.8 (15.90)	22.8 (16.76)	17.2 (9.72)
Week 5 (n=35, 34, 35)	34.8 (20.50)	37.9 (19.90)	29.8 (16.60)
Week 7 (n=29, 32, 31)	39.9 (24.82)	45.2 (22.78)	37.4 (20.38)
Week 13 (n=16, 17, 20)	63.5 (27.31)	63.4 (28.66)	51.4 (32.43)
Week 23 (n=8, 9, 9)	82.1 (23.15)	62.1 (27.51)	54.8 (29.48)

16. Secondary Outcome

Title	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab
Time Frame	Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab + Rilotumumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48
Week 1 (n=43)	239 (70.03)
Week 3 (n=37)	316 (89.74)
Week 5 (n=38)	357 (89.25)
Week 7 (n=37)	397 (98.46)
Week 13 (n=18)	453 (107.36)
Week 23 (n=17)	421 (109.46)

17. Secondary Outcome

Title	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab
Description	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).
Time Frame	Pre-dose at Weeks 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab + Rilotumumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	48
Week 3 (n=38)	70.1 (28.88)
Week 5 (n=34)	119 (37.84)
Week 7 (n=33)	143 (39.33)
Week 13 (n=19)	186 (75.70)
Week 23 (n=17)	181 (65.70)

18. Secondary Outcome

Title	Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab
Time Frame	Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	46
Week 1 (n=40)	218 (65.4)
Week 3 (n=42)	240 (60.72)
Week 5 (n=38)	244 (71.49)
Week 7 (n=35)	279 (99.05)
Week 13 (n=22)	274 (76.99)
Week 23 (n=16)	276 (62.93)

19. Secondary Outcome

Title	Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab
Description	Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).
Time Frame	Pre-dose at Weeks 3, 5, 7, 13 and 23.

Outcome Measure Data

Analysis Population Description

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Arm/Group Title	Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Measure Participants	46
Week 3 (n=39)	19.8 (10.22)
Week 5 (n=39)	24.4 (13.47)
Week 7 (n=37)	28.9 (15.66)
Week 13 (n=22)	38.8 (23.90)
Week 23 (n=16)	39.7 (23.34)

Adverse Events

Time Frame	From the first dose date to 33 days after the last dose of study drug, up to the data cutoff date of 23 July 2010. 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.
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 + Rilotumumab		Part 2: Panitumumab Alone		Part 2: Panitumumab + Rilotumumab		Part 2: Panitumumab + Ganitumab
Arm/Group Description	Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.		Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.		Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.		Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
All Cause Mortality
	Part 1: Panitumumab + Rilotumumab		Part 2: Panitumumab Alone		Part 2: Panitumumab + Rilotumumab		Part 2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Panitumumab + Rilotumumab		Part 2: Panitumumab Alone		Part 2: Panitumumab + Rilotumumab		Part 2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)		11/48 (22.9%)		9/48 (18.8%)		9/46 (19.6%)
Blood and lymphatic system disorders
Anaemia	1/11 (9.1%)		2/48 (4.2%)		0/48 (0%)		0/46 (0%)
Cardiac disorders
Arrhythmia supraventricular	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Gastrointestinal disorders
Abdominal pain	0/11 (0%)		2/48 (4.2%)		0/48 (0%)		2/46 (4.3%)
Ascites	0/11 (0%)		1/48 (2.1%)		1/48 (2.1%)		2/46 (4.3%)
Constipation	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Diarrhoea	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Intestinal obstruction	1/11 (9.1%)		1/48 (2.1%)		1/48 (2.1%)		0/46 (0%)
Small intestinal obstruction	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Upper gastrointestinal haemorrhage	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
General disorders
Fatigue	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		1/46 (2.2%)
General physical health deterioration	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Pyrexia	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Infections and infestations
Pneumonia	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Sepsis	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Staphylococcal sepsis	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Injury, poisoning and procedural complications
Hip fracture	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Investigations
Eastern cooperative oncology group performance status worsened	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Metabolism and nutrition disorders
Hypoalbuminaemia	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Hypoglycaemia	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Hypomagnesaemia	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Colorectal cancer	0/11 (0%)		0/48 (0%)		3/48 (6.3%)		1/46 (2.2%)
Metastases to central nervous system	0/11 (0%)		2/48 (4.2%)		0/48 (0%)		1/46 (2.2%)
Metastases to liver	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Neoplasm	0/11 (0%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Colorectal cancer metastatic	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Nervous system disorders
Cerebrovascular accident	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Loss of consciousness	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Renal and urinary disorders
Renal failure acute	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Urinary retention	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/11 (0%)		1/48 (2.1%)		1/48 (2.1%)		0/46 (0%)
Pleural effusion	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Respiratory failure	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Skin and subcutaneous tissue disorders
Rash	0/11 (0%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Dermatitis acneiform	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Vascular disorders
Deep vein thrombosis	0/11 (0%)		1/48 (2.1%)		1/48 (2.1%)		0/46 (0%)
Capillary leak syndrome	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Panitumumab + Rilotumumab		Part 2: Panitumumab Alone		Part 2: Panitumumab + Rilotumumab		Part 2: Panitumumab + Ganitumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/11 (100%)		42/48 (87.5%)		47/48 (97.9%)		44/46 (95.7%)
Blood and lymphatic system disorders
Anaemia	1/11 (9.1%)		7/48 (14.6%)		2/48 (4.2%)		1/46 (2.2%)
Thrombocytopenia	0/11 (0%)		0/48 (0%)		3/48 (6.3%)		3/46 (6.5%)
Cardiac disorders
Tachycardia	2/11 (18.2%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Ear and labyrinth disorders
Ear pain	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Hypoacusis	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Otorrhoea	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Tinnitus	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Eye disorders
Conjunctivitis	1/11 (9.1%)		0/48 (0%)		6/48 (12.5%)		3/46 (6.5%)
Dry eye	2/11 (18.2%)		0/48 (0%)		2/48 (4.2%)		1/46 (2.2%)
Eye irritation	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		2/46 (4.3%)
Keratitis	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Gastrointestinal disorders
Abdominal pain	2/11 (18.2%)		7/48 (14.6%)		5/48 (10.4%)		3/46 (6.5%)
Abdominal pain upper	1/11 (9.1%)		1/48 (2.1%)		5/48 (10.4%)		2/46 (4.3%)
Constipation	6/11 (54.5%)		11/48 (22.9%)		5/48 (10.4%)		6/46 (13%)
Diarrhoea	4/11 (36.4%)		5/48 (10.4%)		7/48 (14.6%)		11/46 (23.9%)
Dry mouth	0/11 (0%)		1/48 (2.1%)		0/48 (0%)		3/46 (6.5%)
Gingival bleeding	0/11 (0%)		0/48 (0%)		3/48 (6.3%)		0/46 (0%)
Nausea	4/11 (36.4%)		8/48 (16.7%)		4/48 (8.3%)		3/46 (6.5%)
Stomatitis	2/11 (18.2%)		1/48 (2.1%)		4/48 (8.3%)		6/46 (13%)
Vomiting	2/11 (18.2%)		7/48 (14.6%)		3/48 (6.3%)		5/46 (10.9%)
Abdominal discomfort	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Anal inflammation	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Cheilitis	2/11 (18.2%)		1/48 (2.1%)		0/48 (0%)		1/46 (2.2%)
Dyspepsia	1/11 (9.1%)		2/48 (4.2%)		1/48 (2.1%)		1/46 (2.2%)
Dysphagia	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		2/46 (4.3%)
Gingival pain	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Peritoneal haemorrhage	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
General disorders
Asthenia	3/11 (27.3%)		7/48 (14.6%)		4/48 (8.3%)		6/46 (13%)
Chills	0/11 (0%)		0/48 (0%)		0/48 (0%)		3/46 (6.5%)
Fatigue	4/11 (36.4%)		10/48 (20.8%)		4/48 (8.3%)		8/46 (17.4%)
Infusion related reaction	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		4/46 (8.7%)
Mucosal inflammation	3/11 (27.3%)		3/48 (6.3%)		6/48 (12.5%)		5/46 (10.9%)
Oedema peripheral	2/11 (18.2%)		6/48 (12.5%)		9/48 (18.8%)		1/46 (2.2%)
Pyrexia	0/11 (0%)		4/48 (8.3%)		2/48 (4.2%)		2/46 (4.3%)
Oedema	1/11 (9.1%)		0/48 (0%)		2/48 (4.2%)		0/46 (0%)
Face oedema	1/11 (9.1%)		2/48 (4.2%)		0/48 (0%)		0/46 (0%)
Facial pain	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
General physical health deterioration	1/11 (9.1%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Inflammation	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Hepatobiliary disorders
Hepatic pain	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Immune system disorders
Drug hypersensitivity	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Infections and infestations
Paronychia	4/11 (36.4%)		7/48 (14.6%)		15/48 (31.3%)		9/46 (19.6%)
Infection	1/11 (9.1%)		0/48 (0%)		2/48 (4.2%)		0/46 (0%)
Urinary tract infection	1/11 (9.1%)		2/48 (4.2%)		2/48 (4.2%)		1/46 (2.2%)
Anogenital warts	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Candidiasis	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		1/46 (2.2%)
Pneumonia	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Skin bacterial infection	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Staphylococcal infection	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Vulvovaginal mycotic infection	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Injury, poisoning and procedural complications
Contrast media reaction	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Eye injury	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Procedural vomiting	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Investigations
Aspartate aminotransferase increased	0/11 (0%)		3/48 (6.3%)		1/48 (2.1%)		2/46 (4.3%)
Weight decreased	0/11 (0%)		2/48 (4.2%)		1/48 (2.1%)		5/46 (10.9%)
Weight increased	0/11 (0%)		3/48 (6.3%)		1/48 (2.1%)		2/46 (4.3%)
Blood calcium decreased	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Blood magnesium decreased	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		1/46 (2.2%)
Blood potassium decreased	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Blood pressure increased	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Body temperature increased	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Breath sounds abnormal	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Platelet count decreased	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/11 (18.2%)		8/48 (16.7%)		10/48 (20.8%)		9/46 (19.6%)
Hyperglycaemia	0/11 (0%)		4/48 (8.3%)		1/48 (2.1%)		6/46 (13%)
Hypoalbuminaemia	0/11 (0%)		1/48 (2.1%)		4/48 (8.3%)		1/46 (2.2%)
Hypocalcaemia	1/11 (9.1%)		0/48 (0%)		3/48 (6.3%)		2/46 (4.3%)
Hypokalaemia	2/11 (18.2%)		5/48 (10.4%)		6/48 (12.5%)		4/46 (8.7%)
Hypomagnesaemia	1/11 (9.1%)		10/48 (20.8%)		13/48 (27.1%)		19/46 (41.3%)
Dehydration	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Hypercalcaemia	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/11 (0%)		4/48 (8.3%)		4/48 (8.3%)		1/46 (2.2%)
Back pain	2/11 (18.2%)		3/48 (6.3%)		4/48 (8.3%)		0/46 (0%)
Muscle spasms	2/11 (18.2%)		2/48 (4.2%)		3/48 (6.3%)		4/46 (8.7%)
Muscular weakness	0/11 (0%)		3/48 (6.3%)		0/48 (0%)		0/46 (0%)
Pain in extremity	1/11 (9.1%)		2/48 (4.2%)		3/48 (6.3%)		1/46 (2.2%)
Intervertebral disc protrusion	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Musculoskeletal pain	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Myopathy	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pyogenic granuloma	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Nervous system disorders
Headache	1/11 (9.1%)		6/48 (12.5%)		0/48 (0%)		1/46 (2.2%)
Lethargy	0/11 (0%)		1/48 (2.1%)		3/48 (6.3%)		2/46 (4.3%)
Dizziness	1/11 (9.1%)		2/48 (4.2%)		1/48 (2.1%)		1/46 (2.2%)
Neuropathy peripheral	1/11 (9.1%)		2/48 (4.2%)		1/48 (2.1%)		0/46 (0%)
Paraesthesia	1/11 (9.1%)		1/48 (2.1%)		0/48 (0%)		1/46 (2.2%)
Polyneuropathy	2/11 (18.2%)		2/48 (4.2%)		0/48 (0%)		1/46 (2.2%)
Psychiatric disorders
Anxiety	0/11 (0%)		4/48 (8.3%)		0/48 (0%)		2/46 (4.3%)
Depression	0/11 (0%)		4/48 (8.3%)		0/48 (0%)		0/46 (0%)
Insomnia	3/11 (27.3%)		5/48 (10.4%)		5/48 (10.4%)		4/46 (8.7%)
Renal and urinary disorders
Oliguria	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Reproductive system and breast disorders
Genital tract inflammation	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/11 (18.2%)		1/48 (2.1%)		3/48 (6.3%)		3/46 (6.5%)
Epistaxis	2/11 (18.2%)		1/48 (2.1%)		7/48 (14.6%)		2/46 (4.3%)
Cough	1/11 (9.1%)		2/48 (4.2%)		2/48 (4.2%)		2/46 (4.3%)
Oropharyngeal pain	2/11 (18.2%)		1/48 (2.1%)		2/48 (4.2%)		1/46 (2.2%)
Hiccups	1/11 (9.1%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Nasal congestion	1/11 (9.1%)		1/48 (2.1%)		0/48 (0%)		0/46 (0%)
Nasal oedema	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Pharyngeal inflammation	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Skin and subcutaneous tissue disorders
Acne	0/11 (0%)		0/48 (0%)		4/48 (8.3%)		5/46 (10.9%)
Dermatitis acneiform	6/11 (54.5%)		16/48 (33.3%)		17/48 (35.4%)		12/46 (26.1%)
Dry skin	4/11 (36.4%)		7/48 (14.6%)		11/48 (22.9%)		10/46 (21.7%)
Erythema	3/11 (27.3%)		3/48 (6.3%)		4/48 (8.3%)		5/46 (10.9%)
Nail disorder	2/11 (18.2%)		0/48 (0%)		3/48 (6.3%)		0/46 (0%)
Pruritus	5/11 (45.5%)		12/48 (25%)		10/48 (20.8%)		13/46 (28.3%)
Rash	4/11 (36.4%)		25/48 (52.1%)		28/48 (58.3%)		22/46 (47.8%)
Skin fissures	3/11 (27.3%)		8/48 (16.7%)		7/48 (14.6%)		12/46 (26.1%)
Dermatitis	1/11 (9.1%)		1/48 (2.1%)		2/48 (4.2%)		0/46 (0%)
Hypertrichosis	3/11 (27.3%)		2/48 (4.2%)		0/48 (0%)		1/46 (2.2%)
Pain of skin	3/11 (27.3%)		2/48 (4.2%)		0/48 (0%)		1/46 (2.2%)
Eczema	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		1/46 (2.2%)
Hirsutism	1/11 (9.1%)		2/48 (4.2%)		1/48 (2.1%)		1/46 (2.2%)
Ingrowing nail	1/11 (9.1%)		0/48 (0%)		1/48 (2.1%)		0/46 (0%)
Koilonychia	2/11 (18.2%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Palmar-plantar erythrodysaesthesia syndrome	1/11 (9.1%)		1/48 (2.1%)		1/48 (2.1%)		2/46 (4.3%)
Skin hyperpigmentation	1/11 (9.1%)		1/48 (2.1%)		0/48 (0%)		1/46 (2.2%)
Skin oedema	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)
Vascular disorders
Hypertension	3/11 (27.3%)		1/48 (2.1%)		2/48 (4.2%)		2/46 (4.3%)
Capillary leak syndrome	1/11 (9.1%)		0/48 (0%)		0/48 (0%)		0/46 (0%)

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.