Back to resultsA Study of Irinotecan, Levofolinate, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (IMC-1121B)
Primary Purpose
Colorectal Carcinoma
Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Ramucirumab (IMC-1121B)
Irinotecan
levofolinate
5-Fluorouracil (5-FU)
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Carcinoma focused on measuring Colon Cancer, Rectal Cancer
Eligibility Criteria
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
Sites / Locations
- ImClone Investigational Site
- ImClone Investigational Site
- ImClone Investigational Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
FOLFIRI plus Ramucirumab (IMC-1121B)
Arm Description
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity)
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.
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).
Half Life (t1/2) of Ramucirumab
t1/2 is the time required for the plasma/serum concentration to decrease 50%.
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.
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.
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.
Full Information
NCT ID
NCT01286818
First Posted
January 25, 2011
Last Updated
October 3, 2014
Sponsor
Eli Lilly and Company
1. Study Identification
Unique Protocol Identification Number
NCT01286818
Brief Title
A Study of Irinotecan, Levofolinate, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (IMC-1121B)
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2014
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
March 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Carcinoma
Keywords
Colon Cancer, Rectal Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
FOLFIRI plus Ramucirumab (IMC-1121B)
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
Ramucirumab (IMC-1121B)
Other Intervention Name(s)
IMC-1121B, Ramucirumab, LY3009806
Intervention Description
Ramucirumab (IMC-1121B): Intravenous (IV) infusions, 8 milligrams per kilogram (mg/kg) every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Intervention Description
IV Infusion, 180 milligrams per square meter (mg/m²) every 2 weeks
Intervention Type
Drug
Intervention Name(s)
levofolinate
Intervention Description
IV infusion, 200 mg/m² every 2 weeks
Intervention Type
Drug
Intervention Name(s)
5-Fluorouracil (5-FU)
Intervention Description
400 mg/m² bolus followed by a 2400 mg/m² continuous infusion, every 2 weeks
Primary Outcome Measure Information:
Title
Number of Participants That Experienced Any Dose-Limiting Toxicities (DLT) During the DLT Assessment Period
Description
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.
Time Frame
Day 1, Cycle 1 through Day 1, Cycle 3 (1 cycle=14 days)
Title
Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events
Description
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.
Time Frame
Baseline to end of study (up to 49.3 weeks) plus 37 day follow-up
Secondary Outcome Measure Information:
Title
Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity)
Time Frame
Day 1 of Cycle 5 (Week 9), Cycle 6 (Week 11), Cycle 7 (Week 13), and Cycle 9 (Week 17) [(1 cycle=14 days)]
Title
Maximum Concentration (Cmax) of Ramucirumab
Description
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.
Time Frame
Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Title
Area Under the Curve (AUC) of Ramucirumab
Description
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).
Time Frame
Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Title
Half Life (t1/2) of Ramucirumab
Description
t1/2 is the time required for the plasma/serum concentration to decrease 50%.
Time Frame
Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Title
Clearance (CL) of Ramucirumab
Description
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.
Time Frame
Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Title
Steady State Volume of Distribution (Vss) of Ramucirumab
Description
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.
Time Frame
Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Title
Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)]
Description
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.
Time Frame
Every 8 weeks until PD (up to 49 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
ImClone Investigational Site
City
Chiba
ZIP/Postal Code
277-8577
Country
Japan
Facility Name
ImClone Investigational Site
City
Osaka
ZIP/Postal Code
569-8686
Country
Japan
Facility Name
ImClone Investigational Site
City
Shizuoka
ZIP/Postal Code
411-8777
Country
Japan
12. IPD Sharing Statement
Learn more about this trial
A Study of Irinotecan, Levofolinate, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (IMC-1121B)
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