A Study of IMC-1121B (Ramucirumab) in Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test how long participants with colorectal cancer live without progressive disease when being treated with IMC-1121B (ramucirumab) and the modified FOLFOX-6 chemotherapy.

Detailed Description
-----------------
The purpose of this study is to evaluate the progression-free survival (PFS) in participants with metastatic colorectal cancer when treated with the monoclonal antibody IMC-1121B (ramucirumab) in combination with the modified FOLFOX-6 [folinic acid (FA) + fluorouracil (5-FU) + oxaliplatin, mFOLFOX-6] chemotherapy regimen as first-line therapy.

Official Title
-----------------
An Open Label, Multicenter, Phase 2 Study Evaluating the Safety and Efficacy of IMC-1121B in Combination With 5-FU/FA and Oxaliplatin (Modified FOLFOX-6) as First-line Therapy in Patients With Metastatic Colorectal Cancer

Conditions
-----------------
Colorectal Carcinoma

Intervention / Treatment
-----------------
* Biological: IMC-1121B (ramucirumab)
* Drug: Oxaliplatin
* Drug: Folinic acid
* Drug: 5-FU
* Drug: 5-FU


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant must have histologically confirmed adenocarcinoma of the colon or rectum that is locally-advanced or metastatic and unresectable The participant has at least one unidimensionally-measurable target lesion [≥ 2 centimeters (cm) with conventional techniques or ≥ 1 cm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), as defined by Response Evaluation Criteria in Solid Tumors (RECIST)]; target lesion(s) must not lie within an irradiated area. Participants with locally advanced rectal carcinoma who have undergone previous radiation must have documented evidence of disease progression in the pelvis in order to participate The participant is age ≥ 18 years The participant has a life expectancy of ≥ 6 months The participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 at study entry The participant has adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥ 1500/microliter (μL), hemoglobin ≥ 10 grams/deciliter (g/dL), and platelets ≥ 100,000/μL The participant has adequate hepatic function as defined by: total bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN (or 5.0 x ULN in the case of liver metastases), and serum albumin ≥ lower limit of normal (LLN) institutional range or (if < LLN) within 10% of the LLN The participant has adequate renal function as defined by a serum creatinine ≤ 1.5 x ULN, or creatinine clearance (measured via 24-hour urine collection) ≥ 60 milliliters/minute (mL/min) The participant's urinary protein ≤ 1+ on dipstick or routine urinalysis [(UA); if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine for protein must demonstrate < 1000 milligrams (mg) of protein in 24 hours to allow participation in the study] The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight (LMW) heparin and if on warfarin, must have an INR between 2 and 3 and no active bleeding or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices) The participant has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI-CTCAE v 3.0) of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy with the exception of peripheral neuropathy which must have resolved to Grade 0 The participant agrees to use adequate contraception during the study period and for 8 weeks after the last dose of study treatment The participant has provided signed informed consent Exclusion Criteria: The participant has received prior systemic chemotherapy for locally-advanced unresectable or metastatic colorectal cancer (CRC). Prior adjuvant chemotherapy is allowed if disease progression has been documented > 6 months after the end of the last cycle of adjuvant chemotherapy or > 12 months after the end of the last cycle of adjuvant oxaliplatin-containing regimens The participant has documented and/or symptomatic brain or leptomeningeal metastases The participant has participated in clinical studies of non-approved experimental agents or procedures within 12 weeks of study entry The participant has received previous therapy with monoclonal antibodies The participant has received previous therapy with any agent that targets vascular endothelial growth factor (VEGF) or VEGF receptor-2 (VEGFR-2) (including multi-targeted tyrosine kinase inhibitors) The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator The participant is on chronic non-topical corticosteroid treatment for > 6 months at doses > 10 mg/day of prednisolone or equivalent before study entry, which in the opinion of the investigator could compromise the participant or the study The participant has a known dihydropyrimidine dehydrogenase (DPD) deficiency The participant has a known allergy to any of the treatment components The participant has an acute or subacute intestinal obstruction The participant has uncontrolled or poorly controlled hypertension on a standard regimen of anti-hypertensive therapy The participant has a concurrent active malignancy other than adequately treated nonmelanomatous skin cancer, other noninvasive carcinoma, or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that he/she has been disease free for > 3 years The participant, if female, is pregnant Has had prior autologous or allogeneic organ or tissue transplantation Has interstitial pneumonia or interstitial fibrosis of the lung, which in the opinion of the investigator could compromise the participant or the study Has pleural effusion or ascites that causes > Grade 1 dyspnea Has psychological, familial, sociological, or geographical conditions which do not permit adequate study follow-up, compliance with the protocol, or signature of Informed Consent Has undergone major surgery within 28 days prior to the first dose of study medication, or subcutaneous venous access device placement within 7 days prior to the first dose of study medication

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-1121B (ramucirumab) + mFOLFOX-6<br>This regimen will be repeated every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. | Biological: IMC-1121B (ramucirumab)<br>* 8 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) infusions every 2 weeks<br>* Other names: LY3009806;Drug: Oxaliplatin<br>* 85 milligrams/square meter (mg/m²) intravenous infusion over 2 hours on Day 1<br>Drug: Folinic acid<br>* 400 mg/m² intravenous infusion over 2 hours on Day 1<br>Drug: 5-FU<br>* 400 mg/m² intravenous bolus injection over 2-4 minutes, immediately following folinic acid infusion<br>Drug: 5-FU<br>* 2400 mg/m² intravenous continuous infusion over 46 hours immediately following bolus 5-FU on Days 1 and 2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was defined as the time from date of first dose to the first observation of progression of disease (PD) or death due to any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions and/or unequivocal progression of non-target lesion and/or new lesion. For participants who had no PD or death or had started new therapeutic anticancer treatment, PFS was censored at their last radiographic tumor assessment. | First dose to measured progressive disease or death due to any cause up to 28.1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response or Partial Response [Objective Response Rate (ORR)] | ORR is the percentage of participants with a confirmed complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is 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 lesion. ORR is calculated as a total number of participants with CR or PR from the start of study treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100. | First dose to date of objective progressive disease up to 23.8 months | 
| Overall Survival (OS) | OS was defined as the time from first dose to the date of death due to any cause. For participants who were alive or were lost to follow-up, OS was censored on the last date the participant was known to be alive. | First dose to death due to any cause up to 28.1 months | 
| Duration of Response | The duration of response was defined as the time from first objective status assessment of complete response (CR) or partial response (PR) to the first time of progression or death as a result of any cause. CR or PR is classified by the investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is 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 lesion. | Time of response to time of measured progressive disease up to 22.2 months | 
| Number of Participants With IMC-1121B (Ramucirumab)-Related Adverse Events (AEs) | Data presented are the number of participants who experienced AEs of any grade and AEs of Grade ≥3 based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v 3.0), that were considered to be related to IMC-1121B (ramucirumab) by the investigators. A summary of serious AEs (SAEs) and all other non-serious AEs regardless of causality, is located in the Reported Adverse Events module. | First dose to 25.2 months | 
| Number of Participants With IMC-1121B (Ramucirumab)-Related Severe Adverse Events (SAEs) | Data presented are the number of participants who experienced SAEs, adverse events (AEs) resulting in death and AEs leading to discontinuation of treatment, that were considered to be related to IMC-1121B (ramucirumab) by the investigators. A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | First dose to 25.2 months | 
| Maximum Concentration (Cmax) at Day 1 of Cycle 1 | Due to sparse pharmacokinetic schedule, Cmax was not calculated. | Baseline, 1, 168, and 336 hours post infusion on Day 1 (Cycle 1) | 
| Area Under the Concentration (AUC) at Day 1 of Cycle 1 | Due to sparse pharmacokinetic schedule, AUC was not calculated. | Baseline, 1, 168, and 336 hours post infusion on Day 1 (Cycle 1) | 
| Half-Life (t1/2) at Day 1 of Cycle 1 | Due to sparse pharmacokinetic schedule, t1/2 was not calculated. | Baseline, 1, 168, and 336 hours post infusion on Day 1 (Cycle 1) | 
| Clearance (CL) at Day 1 of Cycle 1 | Due to sparse pharmacokinetic schedule, CL was not calculated. | Baseline, 1, 168, and 336 hours post infusion on Day 1 (Cycle 1) | 
| Steady State Volume of Distribution (Vss) at Day 1 of Cycle 1 | Due to sparse pharmacokinetic schedule, Vss was not calculated. | Baseline, 1, 168, and 336 hours post infusion Day 1 (Cycle 1) | 
| Maximum Concentration (Cmax) at Day 1 of Cycles 5, 9, 13, 17, and 21 | Due to sparse pharmacokinetic schedule, Cmax was not calculated. | Baseline and 1 hour post infusion on Day 1 (Cycles 5, 9, 13, 17, and 21) | 
| Area Under the Concentration (AUC) at Day 1 of Cycles 5, 9, 13, 17, and 21 | Due to sparse pharmacokinetic schedule, AUC was not calculated. | Baseline and 1 hour post infusion on Day 1 (Cycles 5, 9, 13, 17, and 21) | 
| Half-Life (t1/2) at Day 1 of Cycles 5, 9, 13, 17, and 21 | Due to sparse pharmacokinetic schedule, t1/2 was not calculated. | Baseline and 1 hour post infusion on Day 1 (Cycles 5, 9, 13, 17, and 21) | 
| Clearance (CL) at Day 1 of Cycles 5, 9, 13, 17, and 21 | Due to sparse pharmacokinetic schedule, CL was not calculated. | Baseline and 1 hour post infusion on Day 1 (Cycles 5, 9, 13, 17, and 21) | 
| Steady State Volume of Distribution (Vss) at Day 1 of Cycles 5, 9, 13, 17, and 21 | Due to sparse pharmacokinetic schedule, Vss was not calculated. | Baseline and 1 hour post infusion on Day 1 (Cycles 5, 9, 13, 17, and 21) | 
| Serum Anti-IMC-1121B (Immunogenicity) at Day 1 | Data presented are the number of participants with treatment emergent anti-IMC-112B antibodies. | Day 1 (Cycles 1, 5, 9, and 30-day follow-up) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal carcinoma, CRC, Colon Cancer