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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: IMC-A12
* Biological: cetuximab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-A12<br>Administered every 2 weeks | Biological: IMC-A12<br>* 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.<br>* Other names: LY3012217;|
| Experimental: IMC-A12 + cetuximab<br>Administered every 2 weeks | Biological: IMC-A12<br>* 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.<br>* Other names: LY3012217;Biological: cetuximab<br>* Participants will receive cetuximab 500 milligrams/square meter (mg/m²) intravenous over 2 hours every 2 weeks.<br>* Other names: Erbitux®;|
| Experimental: IMC-A12 + cetuximab [Kirsten rat sarcoma (K-ras) wild-type]<br>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<br>* 10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.<br>* Other names: LY3012217;Biological: cetuximab<br>* Participants will receive cetuximab 500 milligrams/square meter (mg/m²) intravenous over 2 hours every 2 weeks.<br>* Other names: Erbitux®;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | Randomization/treatment to measured PD up to 28.3 weeks | 
| Overall Survival (OS) | 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. | Randomization/treatment to date of death from any cause up to 26.9 months | 
| Duration of Stable Disease (SD) | 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 from randomization/treatment to first date of PD up to 28.3 weeks | 
| Duration of Overall Response | 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 of response to time of measured PD or death up to 161 days | 
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | 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. | Randomization/treatment up to 26.9 months | 
| Number of Participants Reporting Treatment-Emergent Severe Adverse Events | 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. | Randomization/treatment up to 26.9 months | 
| 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) | 
| 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) | 
| 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) | 
| Percentage of Participants With Complete Response (CR) or Partial Response (PR, Response Rate) in Participants With Kirsten Rat Sarcoma (K-ras) Mutations | The response rate in participants with K-ras mutations was not collected for analysis. | Treatment up to 26.9 months | 
| Expression of Type I Insulin-Like Growth Factor Receptors (IGF-IR) |  | Randomization/treatment up to 26.9 months | 
| Expression of IGF Binding Proteins (IGFBP2, IGFBP3) |  | Randomization/treatment up to 26.9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer with Disease Progression, Failed prior to Anti-EGFr Therapy