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

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

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).

Study Overview

• Status: Completed
• Conditions: Colorectal Carcinoma
• Intervention / Treatment: Biological: Ramucirumab (IMC-1121B); Drug: Irinotecan; Drug: levofolinate; Drug: 5-Fluorouracil (5-FU)

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 277-8577
    • ImClone Investigational Site
  • Osaka, Japan, 569-8686
    • ImClone Investigational Site
  • Shizuoka, Japan, 411-8777
    • ImClone Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FOLFIRI plus Ramucirumab (IMC-1121B)

Biological: Ramucirumab (IMC-1121B); Ramucirumab (IMC-1121B): Intravenous (IV) infusions, 8 milligrams per kilogram (mg/kg) every 2 weeks; Other Names: LY3009806; IMC-1121B; Ramucirumab; Drug: Irinotecan; IV Infusion, 180 milligrams per square meter (mg/m²) every 2 weeks; Drug: levofolinate; IV infusion, 200 mg/m² every 2 weeks; Drug: 5-Fluorouracil (5-FU); 400 mg/m² bolus followed by a 2400 mg/m² continuous infusion, every 2 weeks

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: January 25, 2011
• First Submitted That Met QC Criteria: January 28, 2011
• First Posted (Estimate): January 31, 2011

Study Record Updates

• Last Update Posted (Estimate): October 6, 2014
• Last Update Submitted That Met QC Criteria: October 3, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Rectal Cancer; Colon Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan; Levoleucovorin; Ramucirumab; Antibodies, Monoclonal
• Other Study ID Numbers: 14223; CP12-1029 (Other Identifier: ImClone Systems); 14T-IE-JVBY (Other Identifier: Eli Lilly and Company)