A Study of Irinotecan, Levofolinate, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (IMC-1121B)

Study Overview
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Brief Summary
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The primary objective of this study is to investigate the safety and tolerability of the anti-vascular endothelial growth factor receptor-2 (anti-VEGFR-2) monoclonal antibody Ramucirumab (IMC-1121B) in combination with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) in Japanese participants with advanced colorectal carcinoma (CRC).

Official Title
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A Phase 1b Study of Irinotecan, Levofolinate, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (IMC-1121B) Drug Product in Japanese Subjects With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine

Conditions
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Colorectal Carcinoma

Intervention / Treatment
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* Biological: Ramucirumab (IMC-1121B)
* Drug: Irinotecan
* Drug: levofolinate
* Drug: 5-Fluorouracil (5-FU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is Japanese Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has histologically or cytologically confirmed CRC Has metastatic disease that is not amenable to potentially curative resection Has received no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted) Has received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and has experienced disease progression during first-line therapy, or disease progression within 6 months after the last dose of first-line therapy, or discontinued part or all of first-line therapy due to toxicity and experienced disease progression within 6 months after the last dose of first-line therapy. Participants must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy in order to enroll. Has adequate hepatic, renal, hematologic, and coagulation function The participant's urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate <1000 milligrams (mg) of protein in 24 hours to allow participation in the study Exclusion Criteria: Has received bevacizumab within 28 days prior to study registration Has received chemotherapy within 21 days prior to study registration Has received any previous systemic therapy (other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine) for first-line treatment of metastatic CRC The participant experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event; Grade 4 hypertension; Grade 4 proteinuria; a Grade 3-4 bleeding event; or bowel perforation Has received wide-field (full-dose pelvic) radiotherapy within 28 days prior to study registration Has undergone major surgery within 28 days or subcutaneous venous access device placement within 7 days prior to study registration Has elective or planned surgery to be conducted during the trial Has a history of deep vein thrombosis or pulmonary embolism within the past 12 months Has experienced any arterial thrombotic event within the past 12 months Participant is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents Participant is receiving chronic therapy with nonsteroidal anti-inflammatory agents [Aspirin up to 325 milligrams per day (mg/day) permitted] Has a significant bleeding disorder or has had a significant (Grade 3 or higher) bleeding event within 3 months prior to registration date Has a history of gastrointestinal perforation and/or fistulae within 6 months prior to registration date Has symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia Has uncontrolled arterial hypertension despite standard medical management Has a serious or nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to study registration Has an acute/subacute bowel obstruction or history of clinically significant chronic diarrhea Has a history of inflammatory bowel disease or Crohn's disease requiring medical intervention within 12 months prior to registration date The participant has either peptic ulcer disease associated with a bleeding event or known active diverticulitis Has an active infection requiring antibiotic, antifungal, or antiviral therapy Has known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness Has known leptomeningeal or brain metastases or uncontrolled spinal cord compression Has a known history of Gilbert's Syndrome, or is known to have any of the following genotypes: uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*6/*6; UGT1A1*28/*28 or UGT1A1*6/*28 Has previous or concurrent malignancy, except for basal or squamous cell skin cancer and/or in situ carcinoma, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFIRI plus Ramucirumab (IMC-1121B)<br> | Biological: Ramucirumab (IMC-1121B)<br>* Ramucirumab (IMC-1121B): Intravenous (IV) infusions, 8 milligrams per kilogram (mg/kg) every 2 weeks<br>* Other names: LY3009806;Drug: Irinotecan<br>* IV Infusion, 180 milligrams per square meter (mg/m²) every 2 weeks<br>Drug: levofolinate<br>* IV infusion, 200 mg/m² every 2 weeks<br>Drug: 5-Fluorouracil (5-FU)<br>* 400 mg/m² bolus followed by a 2400 mg/m² continuous infusion, every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Any Dose-Limiting Toxicities (DLT) During the DLT Assessment Period | DLTs were adverse events (AEs) possibly related to study drug that met the National Cancer Institute's Common Terminology Criteria for AEs (NCI CTCAE, version 4.03): Grade 4 neutropenia ≥7 days or ≥Grade 3 with bacteremia or sepsis; Absolute neutrophil count <1.0x10^9/Liters with fever ≥38.3°Celsius requiring intravenous antibiotic therapy; Grade 4 thrombocytopenia or ≥Grade 3 with bleeding requiring platelet transfusion; ≥Grade 3 altered coagulation tests and no anticoagulation; ≥Grade 4 or uncontrolled hypertension; ≥Grade 3 non-hematologic toxicity (except non-clinically significant Grade 3 events like electrolyte abnormality, hypersensitivity, and arthralgia/myalgia); urine protein >3 grams/24 hours; study drug-related toxicity causing Cycle 3, Day 1 treatment delay until Day 44 or later. Grade 3 or Grade 4 infusion-related reaction (hypersensitivity) due to ramucirumab or FOLFIRI, not a DLT. | Day 1, Cycle 1 through Day 1, Cycle 3 (1 cycle=14 days) | 
| Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events | Data are presented for the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade ≥3 TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered to be related to ramucirumab. Events related to Irinotecan, Levofolinate, and 5-fluorouracil (5-FU) were reported separately. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section. | Baseline to end of study (up to 49.3 weeks) plus 37 day follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity) |  | Day 1 of Cycle 5 (Week 9), Cycle 6 (Week 11), Cycle 7 (Week 13), and Cycle 9 (Week 17) [(1 cycle=14 days)] | 
| Maximum Concentration (Cmax) of Ramucirumab | The Cmax of ramucirumab in serum on Day 1, Cycle 1 and on Day 1, Cycle 5, which was also considered Cmax at steady state (Cmax,ss), is reported. | Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days) | 
| Area Under the Curve (AUC) of Ramucirumab | Reported for Day 1, Cycle 1 is AUC from time 0 extrapolated to infinity [AUC(0-inf)] and for Day 1, Cycle 5 is AUC over the dosing interval at steady state AUC(tau,ss). | Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days) | 
| Half Life (t1/2) of Ramucirumab | t1/2 is the time required for the plasma/serum concentration to decrease 50%. | Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days) | 
| Clearance (CL) of Ramucirumab | The total body CL of ramucirumab on Day 1, Cycle 1 and on Day 1, Cycle 5, which was also considered CL at steady state (CLss), is reported. | Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days) | 
| Steady State Volume of Distribution (Vss) of Ramucirumab | Vss is the theoretical volume in which the total amount of study drug would need to be uniformly distributed during steady state to produce the same concentration as it is in plasma/serum. | Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days) | 
| Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] | Best overall response evaluated using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. Complete Response (CR): disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 millimeters (mm). Partial Response (PR): at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Progressive Disease (PD): an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). In addition, the sum must have demonstrated an absolute increase of at least 5 mm (the appearance of 1 or more new lesions was considered progression). Stable Disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. | Every 8 weeks until PD (up to 49 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colon Cancer, Rectal Cancer