Study Using IMC-A12 (Cixutumumab) With or Without Cetuximab in Participants With Metastatic Colorectal Cancer Who Have Failed a Treatment Regimen That Consisted of a Prior Anti-EGFR Therapy

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00503685
• Collaborator: (none)
• Enrollment: 65
• Locations: 4
• Arms: 3
• Duration (Months): 21
• Patients Per Site: 16.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Participants with metastatic Colorectal Cancer (mCRC) who have progressed on a prior Anti-epidermal growth factor receptor (EGFR) regimen randomized to receive IMC-A12 monotherapy or combination therapy with cetuximab to assess response, survival, durations of response, safety and tolerability as well as pharmacodynamics of IMC-A12 and cetuximab

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: IMC-A12; Biological: cetuximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Clinical Trial of IMC-A12, as a Single Agent or in Combination With Cetuximab, in Patients With Metastatic Colorectal Cancer With Disease Progression on Prior Anti-EGFR Therapy
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IMC-A12 Administered every 2 weeks	Biological: IMC-A12; 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.; Other Names: Cixutumumab LY3012217
Experimental: IMC-A12 + cetuximab Administered every 2 weeks	Biological: IMC-A12; 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.; Other Names: Cixutumumab LY3012217 ; Biological: cetuximab; Participants will receive cetuximab 500 milligrams/square meter (mg/m²) intravenous over 2 hours every 2 weeks.; Other Names: Erbitux®
Experimental: IMC-A12 + cetuximab [Kirsten rat sarcoma (K-ras) wild-type] Participants who have experienced confirmed partial response (PR) or stable disease (SD) ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression are enrolled in this arm.	Biological: IMC-A12; 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.; Other Names: Cixutumumab LY3012217 ; Biological: cetuximab; Participants will receive cetuximab 500 milligrams/square meter (mg/m²) intravenous over 2 hours every 2 weeks.; Other Names: Erbitux®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)] [Start of randomization/treatment to date of objective progressive disease (PD) up to 28.3 weeks]

   ORR is the percentage of participants with a confirmed CR or PR, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR is calculated as a total number of participants with CR or PR from start of the treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [Randomization/treatment to measured PD up to 28.3 weeks]

   PFS was defined as the duration from the date of randomization/treatment to the date of PD or death from any cause. PD was determined using RECIST criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the cutoff date. Participants who began a new antitumor treatment before evidence of PD were categorized as PD.

2. Overall Survival (OS) [Randomization/treatment to date of death from any cause up to 26.9 months]

   OS is defined as the duration from the date of randomization/treatment to the date of death from any cause. Participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive.

3. Duration of Stable Disease (SD) [Time from randomization/treatment to first date of PD up to 28.3 weeks]

   The duration of SD is measured from the date of randomization/treatment until the date of PD. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. RECIST criteria version 1.0 was used to asses PR and PD. PR is ≥30% decrease in sum of longest diameter of target lesions. PD is ≥20% increase in sum of longest diameter of target lesions and/or a new lesion. Participants who had no PD or death at the time of the data inclusion cutoff, duration of SD was censored at their last tumor assessment prior to the cutoff date.

4. Duration of Overall Response [Time of response to time of measured PD or death up to 161 days]

   The duration of overall response (CR or PR) was defined as the time from first objective status assessment of CR or PR to the first time of PD or death due to any cause. CR, PR and PD were determined using RECIST criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions; PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of overall response was censored at their last tumor assessment prior to the cutoff date. Duration of overall response was not analyzed due to low number of participants with CR or PR.

5. Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) [Randomization/treatment up to 26.9 months]

   Data presented are the number of participants who experienced nonserious adverse events (AEs) during the study including the 30-day follow-up. A summary of serious AEs (SAEs) and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

6. Number of Participants Reporting Treatment-Emergent Severe Adverse Events [Randomization/treatment up to 26.9 months]

   Data presented are the number of participants who experienced serious adverse events (SAEs) or death during the study including the 30-day follow-up. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

7. Maximum Concentration (Cmax) [Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)]

8. Minimum Concentration (Cmin) [Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)]

9. Area Under Serum Concentration (AUC) [Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)]

10. Percentage of Participants With Complete Response (CR) or Partial Response (PR, Response Rate) in Participants With Kirsten Rat Sarcoma (K-ras) Mutations [Treatment up to 26.9 months]

    The response rate in participants with K-ras mutations was not collected for analysis.

11. Expression of Type I Insulin-Like Growth Factor Receptors (IGF-IR) [Randomization/treatment up to 26.9 months]

12. Expression of IGF Binding Proteins (IGFBP2, IGFBP3) [Randomization/treatment up to 26.9 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria

• The participant has histologically or cytologically-confirmed colorectal cancer with metastatic disease documented on diagnostic imaging studies

• The participant has measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded), measuring ≥ 2 centimeter (cm) on conventional measurement techniques or ≥ 1 cm on spiral computed tomography (CT) scan

• The participant has clinical documentation of disease progression during treatment or within 6 weeks after receiving the last dose of a therapeutic regimen for metastatic disease containing an anti-EGFR-component (cetuximab or panitumumab). Toxicity or planned treatment break will not be regarded as adequate evidence of disease progression and such participants will not be eligible for this trial

• The participant has received at least one prior standard and/or investigational regimen for metastatic disease

• The participant is age ≥ 18 years

• The participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 (Karnofsky ≥ 80%

• The participant has adequate hematologic function as defined by an absolute neutrophil count ≥ 1500/microliter (μL), hemoglobin ≥ 9 grams/deciliter (g/dL), and a platelet count ≥ 100,000/μL

• The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 x the upper limit of normal (ULN), and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the ULN (or ≤ 5 x the ULN in the presence of known liver metastases)

• The participant has adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x the ULN. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin, and if on warfarin must have an INR between 2 and 3 and have no active bleeding or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or invading the rectal lumen, or known varices)

• The participant has adequate renal function as defined by serum creatinine ≤ 1.5 x the institutional ULN or creatinine clearance ≥ 60 milliliters/minute (mL/min) for participants with creatinine levels above the ULN, as well as urine protein ≤ 1+ on urine dipstick or routine urinalysis [(UA), if urine dipstick/routine UA indicates ≥ 2+ protein, a 24-hour urine collection for protein must demonstrate < 1000 milligrams (mg) of protein in 24 hours to allow participation in the study]

• The participant has fasting serum glucose < 120 milligrams/deciliter (mg/dL) or below the ULN

• The participant has a life expectancy of > 3 months

• Because the teratogenicity of IMC-A12 (cixutumumab) is not known, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation

• The participant has the ability to understand and the willingness to sign a written informed consent document

• The participant has a tumor that is K-ras wild-type (absence of mutations at codon 12 or 13, as determined by the DxS K-ras Mutation Kit [polymerase chain reaction (PCR)-based analysis]).

• The participant experienced either a confirmed partial response or stable disease of ≥ 24 weeks duration during prior treatment with a cetuximab- or panitumumab-containing regimen except for participants with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) promoter polymorphism, for example, Gilbert syndrome, confirmed by genotyping or Invader®UGT1A1 Molecular Assay prior to enrollment. Participants enrolled with Gilbert Syndrome must have a total bilirubin ≤ 3 x ULN. If the participant has liver metastases, total bilirubin must be ≤ 3 x ULN.

Exclusion Criteria

• The participant has received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or has not recovered from adverse events due to agents administered more than 4 weeks earlier. Neurotoxicity, if present, must have recovered to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 3.0 grade ≤ 2.

• The participant is receiving any other investigational agent(s).

• The participant has a history of treatment with other agents targeting the insulin-like growth factor receptor (IGFR).

• The participant has known brain or leptomeningeal metastases.

• The participant has a history of primary central nervous system tumors, seizures not well controlled with standard medical therapy, or history of stroke within 6 months prior to randomization.

• The participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab or IMC-A12 (cixutumumab).

• The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within normal range (fasting glucose < 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition.

• The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• The participant is pregnant or lactating.

• The participant is known to be positive for infection with the human immunodeficiency virus.

• The participant is receiving therapy with immune modulators such as cyclosporine or tacrolimus.

• The participant has a history of another primary cancer, with the exception of: a) curatively resected nonmelanomatous skin cancer; b) curatively treated cervical carcinoma in-situ; or c) other primary solid tumor curatively resected treated with no known active disease present and no treatment administered for the last 3 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Los Angeles	California	United States	90095
2	ImClone Investigational Site	New Haven	Connecticut	United States	06520
3	ImClone Investigational Site	Buffalo	New York	United States	14263
4	ImClone Investigational Site	New York	New York	United States	10021

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Chair: E-mail: ClinicalTrials@ ImClone.com, Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00503685
• Other Study ID Numbers: 13936; CP02-0657; CP13-0605; I5A-IE-JAEL
• First Posted: Jul 19, 2007
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by Eli Lilly and Company: Metastatic Colorectal Cancer with Disease Progression; Failed prior to Anti-EGFr Therapy
• Additional relevant MeSH terms: Colorectal Neoplasms; Disease Progression; Cetuximab

Study Results

Participant Flow

Pre-assignment Detail	Participants with progressive disease (PD) or death are considered having completed study.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 milligrams/kilogram (mg/kg) IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 milligrams/square meter (mg/m²) intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with Kirsten rat sarcoma (K-ras) wild-type who experienced confirmed partial response (PR) or stable disease (SD) ≥ 24 weeks on a prior anti-epidermal growth factor receptor (EGFR)-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Period Title: Overall Study
STARTED	23	22	20
Received at Least 1 Dose of Study Drug	23	21	20
COMPLETED	23	19	18
NOT COMPLETED	0	3	2

Baseline Characteristics

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)	Total
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Total of all reporting groups
Overall Participants	23	21	20	64
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59.3 (8.94)	62.6 (12.40)	61.7 (7.89)	60.5 (9.84)
Sex: Female, Male (Count of Participants)
Female	14 60.9%	9 42.9%	10 50%	33 51.6%
Male	9 39.1%	12 57.1%	10 50%	31 48.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8.7%	3 14.3%	2 10%	7 10.9%
Not Hispanic or Latino	21 91.3%	18 85.7%	18 90%	57 89.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	17 73.9%	17 81%	17 85%	51 79.7%
Black	4 17.4%	2 9.5%	2 10%	8 12.5%
Asian	1 4.3%	1 4.8%	1 5%	3 4.7%
Hispanic	1 4.3%	0 0%	0 0%	1 1.6%
Unknown or Not Reported	0 0%	1 4.8%	0 0%	1 1.6%
Region of Enrollment (Count of Participants)
United States	23 100%	21 100%	20 100%	64 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)]
Description	ORR is the percentage of participants with a confirmed CR or PR, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR is calculated as a total number of participants with CR or PR from start of the treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100.
Time Frame	Start of randomization/treatment to date of objective progressive disease (PD) up to 28.3 weeks

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	23	21	20
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	4.8 22.9%	0.0 0%

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the duration from the date of randomization/treatment to the date of PD or death from any cause. PD was determined using RECIST criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the cutoff date. Participants who began a new antitumor treatment before evidence of PD were categorized as PD.
Time Frame	Randomization/treatment to measured PD up to 28.3 weeks

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of study drug. The number of participants censored was 0 for IMC-A12 group, 1 for IMC-A12 + cetuximab group and 1 for IMC-A12 + cetuximab (K-ras wild-type) group.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	23	21	20
Median (95% Confidence Interval) [weeks]	5.9	6.1	9.4

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the duration from the date of randomization/treatment to the date of death from any cause. Participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive.
Time Frame	Randomization/treatment to date of death from any cause up to 26.9 months

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of study drug. The number of participants censored was 5 for IMC-A12 group, 4 for IMC-A12 + cetuximab group and 11 for IMC-A12 + cetuximab (K-ras wild-type) group.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	23	21	20
Median (95% Confidence Interval) [months]	5.7	4.5	10.9

4. Secondary Outcome

Title	Duration of Stable Disease (SD)
Description	The duration of SD is measured from the date of randomization/treatment until the date of PD. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. RECIST criteria version 1.0 was used to asses PR and PD. PR is ≥30% decrease in sum of longest diameter of target lesions. PD is ≥20% increase in sum of longest diameter of target lesions and/or a new lesion. Participants who had no PD or death at the time of the data inclusion cutoff, duration of SD was censored at their last tumor assessment prior to the cutoff date.
Time Frame	Time from randomization/treatment to first date of PD up to 28.3 weeks

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of the study drug and achieved SD or better. The number of participants censored was 0 for IMC-A12 group, 0 for IMC-A12 + cetuximab group and 1 for IMC-A12 + cetuximab (K-ras wild-type) group.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	3	3	12
Median (95% Confidence Interval) [weeks]	11.1	15.4	11.6

5. Secondary Outcome

Title	Duration of Overall Response
Description	The duration of overall response (CR or PR) was defined as the time from first objective status assessment of CR or PR to the first time of PD or death due to any cause. CR, PR and PD were determined using RECIST criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions; PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of overall response was censored at their last tumor assessment prior to the cutoff date. Duration of overall response was not analyzed due to low number of participants with CR or PR.
Time Frame	Time of response to time of measured PD or death up to 161 days

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. Duration of Response for CR or PR data was not collected for analysis due to N=0 CR and N=1 PR.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

6. Secondary Outcome

Title	Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)
Description	Data presented are the number of participants who experienced nonserious adverse events (AEs) during the study including the 30-day follow-up. A summary of serious AEs (SAEs) and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Randomization/treatment up to 26.9 months

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	23	21	20
Count of Participants [Participants]	18 78.3%	19 90.5%	20 100%

7. Secondary Outcome

Title	Number of Participants Reporting Treatment-Emergent Severe Adverse Events
Description	Data presented are the number of participants who experienced serious adverse events (SAEs) or death during the study including the 30-day follow-up. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Randomization/treatment up to 26.9 months

Outcome Measure Data

Analysis Population Description

All randomized/enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	23	21	20
SAEs	7 30.4%	6 28.6%	4 20%
Death Due to PD	1 4.3%	0 0%	0 0%
Death Due to SAE	0 0%	1 4.8%	0 0%

8. Secondary Outcome

Title	Maximum Concentration (Cmax)
Time Frame	Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

9. Secondary Outcome

Title	Minimum Concentration (Cmin)
Time Frame	Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

10. Secondary Outcome

Title	Area Under Serum Concentration (AUC)
Time Frame	Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

11. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR, Response Rate) in Participants With Kirsten Rat Sarcoma (K-ras) Mutations
Description	The response rate in participants with K-ras mutations was not collected for analysis.
Time Frame	Treatment up to 26.9 months

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. Response rate data was not collected for analysis due to N=0 CR and N=1 PR.

Arm/Group Title	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0

12. Secondary Outcome

Title	Expression of Type I Insulin-Like Growth Factor Receptors (IGF-IR)
Time Frame	Randomization/treatment up to 26.9 months

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. No data collected for analysis.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

13. Secondary Outcome

Title	Expression of IGF Binding Proteins (IGFBP2, IGFBP3)
Time Frame	Randomization/treatment up to 26.9 months

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. No data collected for analysis.

Arm/Group Title	IMC-A12	IMC-A12 + Cetuximab	IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.	Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0

Adverse Events

Arm/Group Title	IMC-A12		IMC-A12 + Cetuximab		IMC-A12 + Cetuximab (K-ras Wild-type)
Arm/Group Description	Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.		Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.		Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm. Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent.
All Cause Mortality
	IMC-A12		IMC-A12 + Cetuximab		IMC-A12 + Cetuximab (K-ras Wild-type)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	IMC-A12		IMC-A12 + Cetuximab		IMC-A12 + Cetuximab (K-ras Wild-type)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/23 (30.4%)		6/21 (28.6%)		4/20 (20%)
Blood and lymphatic system disorders
Anaemia	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Thrombocytopenia	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Abdominal pain	2/23 (8.7%)	3	0/21 (0%)	0	1/20 (5%)	1
Abdominal pain upper	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Constipation	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Haematemesis	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Nausea	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Small intestinal obstruction	1/23 (4.3%)	1	0/21 (0%)	0	1/20 (5%)	1
Vomiting	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
General disorders
Asthenia	2/23 (8.7%)	2	0/21 (0%)	0	0/20 (0%)	0
Disease progression	2/23 (8.7%)	2	1/21 (4.8%)	1	0/20 (0%)	0
Fatigue	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Infusion related reaction	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Pyrexia	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Hepatobiliary disorders
Bile duct obstruction	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Cholangitis	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Infections and infestations
Bacteraemia	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Pneumonia	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Sepsis	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Urinary tract infection	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Injury, poisoning and procedural complications
Fall	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Post procedural bile leak	0/23 (0%)	0	1/21 (4.8%)	3	0/20 (0%)	0
Investigations
Aspartate aminotransferase increased	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Blood alkaline phosphatase increased	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Blood bilirubin increased	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/23 (4.3%)	1	1/21 (4.8%)	1	0/20 (0%)	0
Hyperglycaemia	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Back pain	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Pain in extremity	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Nervous system disorders
Headache	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Renal and urinary disorders
Acute prerenal failure	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Renal failure acute	0/23 (0%)	0	1/21 (4.8%)	1	0/20 (0%)	0
Ureteric obstruction	1/23 (4.3%)	1	0/21 (0%)	0	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/23 (4.3%)	1	0/21 (0%)	0	1/20 (5%)	1
Pleural effusion	0/23 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	IMC-A12		IMC-A12 + Cetuximab		IMC-A12 + Cetuximab (K-ras Wild-type)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/23 (78.3%)		19/21 (90.5%)		20/20 (100%)
Blood and lymphatic system disorders
Anaemia	1/23 (4.3%)	1	2/21 (9.5%)	3	0/20 (0%)	0
Gastrointestinal disorders
Abdominal pain	3/23 (13%)	3	2/21 (9.5%)	2	1/20 (5%)	1
Abdominal pain upper	2/23 (8.7%)	2	2/21 (9.5%)	2	1/20 (5%)	1
Constipation	4/23 (17.4%)	4	2/21 (9.5%)	2	2/20 (10%)	2
Diarrhoea	2/23 (8.7%)	2	4/21 (19%)	6	4/20 (20%)	5
Nausea	3/23 (13%)	4	6/21 (28.6%)	9	3/20 (15%)	3
Stomatitis	1/23 (4.3%)	1	1/21 (4.8%)	1	3/20 (15%)	3
Vomiting	2/23 (8.7%)	3	3/21 (14.3%)	5	4/20 (20%)	4
General disorders
Fatigue	7/23 (30.4%)	9	8/21 (38.1%)	11	8/20 (40%)	9
Mucosal inflammation	0/23 (0%)	0	2/21 (9.5%)	2	0/20 (0%)	0
Pyrexia	3/23 (13%)	3	2/21 (9.5%)	2	1/20 (5%)	1
Infections and infestations
Paronychia	0/23 (0%)	0	1/21 (4.8%)	2	2/20 (10%)	3
Investigations
Blood bilirubin increased	2/23 (8.7%)	3	1/21 (4.8%)	1	0/20 (0%)	0
Weight decreased	4/23 (17.4%)	5	2/21 (9.5%)	3	0/20 (0%)	0
Metabolism and nutrition disorders
Anorexia	3/23 (13%)	3	3/21 (14.3%)	5	5/20 (25%)	7
Decreased appetite	2/23 (8.7%)	2	3/21 (14.3%)	3	1/20 (5%)	1
Hypokalaemia	0/23 (0%)	0	3/21 (14.3%)	4	0/20 (0%)	0
Hypomagnesaemia	0/23 (0%)	0	4/21 (19%)	10	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	3/23 (13%)	4	2/21 (9.5%)	3	1/20 (5%)	1
Myalgia	0/23 (0%)	0	1/21 (4.8%)	1	2/20 (10%)	2
Nervous system disorders
Dizziness	3/23 (13%)	3	2/21 (9.5%)	4	1/20 (5%)	1
Dysgeusia	2/23 (8.7%)	2	2/21 (9.5%)	2	2/20 (10%)	2
Headache	1/23 (4.3%)	1	2/21 (9.5%)	2	6/20 (30%)	6
Respiratory, thoracic and mediastinal disorders
Cough	0/23 (0%)	0	2/21 (9.5%)	2	1/20 (5%)	1
Dyspnoea	7/23 (30.4%)	7	3/21 (14.3%)	4	1/20 (5%)	1
Dyspnoea exertional	0/23 (0%)	0	2/21 (9.5%)	2	0/20 (0%)	0
Epistaxis	1/23 (4.3%)	1	2/21 (9.5%)	2	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform	0/23 (0%)	0	12/21 (57.1%)	19	9/20 (45%)	14
Dry skin	0/23 (0%)	0	3/21 (14.3%)	3	7/20 (35%)	7
Nail disorder	0/23 (0%)	0	1/21 (4.8%)	1	2/20 (10%)	2
Pruritus	0/23 (0%)	0	2/21 (9.5%)	2	4/20 (20%)	5
Rash	0/23 (0%)	0	3/21 (14.3%)	4	1/20 (5%)	1
Rash macular	0/23 (0%)	0	1/21 (4.8%)	1	6/20 (30%)	7
Vascular disorders
Hypertension	0/23 (0%)	0	0/21 (0%)	0	2/20 (10%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.