A Study of Ramucirumab or Icrucumab in Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if participants with metastatic colorectal cancer live longer without their cancer progressing when treated with standard chemotherapy, standard chemotherapy plus ramucirumab, or standard chemotherapy plus icrucumab.

Detailed Description
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The purpose of this study is to evaluate the progression-free survival (PFS) in participants with metastatic colorectal cancer when treated with 1 of 3 modified FOLFOX-6 (folinic acid [FA] + fluorouracil [5-FU] + oxaliplatin [mFOLFOX-6])-based regimens, as second-line therapy. During 2010, there has been an identified shortage of injectable folinic acid (FA) in the United States. Levo-folinic acid (LFA) will be allowed as a substitute for FA in the mFOLFOX-6 chemotherapy regimen in circumstances in which FA is not available, to facilitate continuity of participant care.

Official Title
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An Open-label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of 5 FU/FA and Oxaliplatin (Modified FOLFOX 6) in Combination With Ramucirumab or IMC-18F1 or Without Investigational Therapy as Second Line Therapy in Patients With Metastatic Colorectal Cancer Following Disease Progression on First Line Irinotecan-based Therapy

Conditions
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Colon Cancer, Rectal Cancer

Intervention / Treatment
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* Biological: Ramucirumab
* Biological: Icrucumab
* Drug: mFOLFOX-6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease progression on an irinotecan-based first-line chemotherapy regimen (ie FOLFIRI or CAPIRI [capecitabine + irinotecan], with or without bevacizumab) Age ≥ 18 years Life expectancy of ≥ 6 months Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 at study entry Agrees to adequate contraception during the study period and for 12 weeks after the last dose of study medication Provided signed informed consent Exclusion Criteria: Has received prior oxaliplatin-based chemotherapy for locally advanced unresectable or metastatic Colorectal Cancer (CRC) (Prior oxaliplatin-based adjuvant chemotherapy is allowed if the last dose of oxaliplatin was administered > 12 months prior to randomization) Has documented and/or symptomatic brain or leptomeningeal metastases Has an ongoing or active infection, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders On chronic non-topical corticosteroid treatment. A participant discontinuing such treatment > 3 months prior to randomization is eligible Has uncontrolled or poorly controlled hypertension on a standard regimen of antihypertensive therapy Has a concurrent active malignancy. A participant with previous history of malignancy is eligible, provided that he/she has been disease free for > 3 years If female, is pregnant (confirmed by serum beta human chorionic gonadotropin [βHCG] test) or lactating Has received a prior autologous or allogeneic organ or tissue transplantation Has undergone major surgery within 28 days prior to randomization Has had a serious nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization Has an elective or planned major surgery to be performed during the course of the trial Has a history of inflammatory bowel disease requiring pharmacological and/or surgical intervention in the 12 months prior to randomization

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 |
| --- | --- |
| Active Comparator: mFOLFOX-6<br>mFOLFOX-6 | Drug: mFOLFOX-6<br>* Oxaliplatin: 85 milligram per square meter (mg/m²) IV every 2 weeks (Q2W) FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable). 5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W<br>|
| Experimental: mFOLFOX-6 + Ramucirumab<br>mFOLFOX-6 + Ramucirumab | Biological: Ramucirumab<br>* 8 mg/kg IV Q2W<br>* Other names: LY3009806;Drug: mFOLFOX-6<br>* Oxaliplatin: 85 milligram per square meter (mg/m²) IV every 2 weeks (Q2W) FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable). 5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W<br>|
| Experimental: mFOLFOX-6 + Icrucumab<br>mFOLFOX-6 + Icrucumab | Biological: Icrucumab<br>* 15 mg/kg IV Q2W<br>* Other names: LY3012212;Drug: mFOLFOX-6<br>* Oxaliplatin: 85 milligram per square meter (mg/m²) IV every 2 weeks (Q2W) FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable). 5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from baseline until the date of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1), or death from any cause, whichever was first. Participants who die without a reported prior progression will be considered to have progressed on the day of their death. Participants who did not progress, are lost to follow-up, or have missed two or more scheduled tumor assessments will be censored at the day of their last radiographic tumor assessment, if there are no post-baseline tumor measurements for a randomized and treated participant, the participant will be censored at the date of randomization. If death or progressive disease (PD) occurs after 2 or more missing radiographic visits, censoring will occur at the date of the last radiographic visit prior to the last visit. | Baseline until Disease Progression or Death from Any Cause (Up to 95 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | The ORR is the percentage of participants with Complete Response (CR, the disappearance of target lesions and any pathological lymph nodes [target or non-target] taking as reference the baseline sum of diameters in response to treatment) or Partial Response (PR, at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters in response to treatment) according to RECIST v1.1 from the start of the treatment until disease progression. | Baseline until Disease Progression (Up to 95 Weeks) | 
| Overall Survival (OS) | Overall survival is defined as the time from baseline to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive. | Baseline Until Death from Any Cause (Up to 163 Weeks) | 
| Duration of Response (DoR) | DoR was measured from the time measurement criteria are first met for Complete Response or Partial Response or until the first date that the criteria for disease progression or death from any cause. whichever is first recorded. As defined according to RECIST v1.1, CR is the disappearance of all non-nodal target lesions, and PR is the short axes of any target lymph nodes reduced to < 10 mm and at least a 30% decrease in the sum of the diameters of target lesions including the short axes of any target lymph nodes.) | Criteria First Met for CR or PR until Disease Progression or Death from Any Cause (Up to 95 Weeks) | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) at Cycle 5 | Maximum concentration (1 hour post end of infusion, Cmax) is the concentration measured in serum. | Cycle 5, 1 Hour Post End of Infusion | 
| Pharmacokinetics (PK): Trough Serum Concentrations (Ctrough) at Cycle 5 | Trough (prior to infusion, Ctrough) concentrations measured in serum. | Cycle 5, Prior to Infusion | 
| Maximum Concentration (Cmax) at Day 8 | Maximum concentration (Cmax) is the maximum peak concentration measured in blood plasma after drug infusion. | Day 8 (cycles 1 and 5) | 
| Maximum Concentration (Cmax) at Day 15 | Cmax is the maximum peak concentration measured in blood plasma after drug infusion. | Day 15 (Cycles 1 and 5) | 
| Minimum Concentration (Cmin) at Day 1 | Cmin is the minimum peak concentration measured in blood plasma after drug infusion. | Day 1 (cycles 1, 5, 9, and 13) | 
| Minimum Concentration (Cmin) at Day 4 | Cmin is the minimum peak concentration measured in blood plasma after drug infusion. | Day 4 (cycles 1 and 5) | 
| Minimum Concentration (Cmin) at Day 8 | Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion. | Day 8 (cycles 1 and 5) | 
| Minimum Concentration (Cmin) at Day 15 | Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion. | Day 15 (cycles 1 and 5) | 
| Number of Participants With Serum Ramucirumab Antibody Assessment | A sample will be considered positive for anti-Ramucirumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-Ramucirumab antibody level seen in healthy untreated individuals. | 31 Weeks | 
| Serum Anti-Icrucumab Antibody Assessment | A sample will be considered positive for anti-icrucumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-icrucumab antibody level seen in healthy untreated individuals. | 31 Weeks | 
| Number of Participants With Adverse Events | A summary of serious AEs (SAEs) and all other non-serious AEs regardless of causality, is located in the Reported Adverse Events module. | Baseline up to 165 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colonic Neoplasms, Rectal Neoplasms, Adenocarcinoma, Antibodies, Monoclonal