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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01286818
• Collaborator: (none)
• Enrollment: 6
• Locations: 3
• Arm: 1
• Duration (Months): 12.9
• Patients Per Site: 2
• Patients Per Site Per Month: 0.2

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Carcinoma	Biological: Ramucirumab (IMC-1121B); Drug: Irinotecan; Drug: levofolinate; Drug: 5-Fluorouracil (5-FU)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Feb 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

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: IMC-1121B Ramucirumab LY3009806 ; 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

Outcome Measures

Primary Outcome Measures

1. Number of Participants That Experienced Any Dose-Limiting Toxicities (DLT) During the DLT Assessment Period [Day 1, Cycle 1 through Day 1, Cycle 3 (1 cycle=14 days)]

   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.

2. Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events [Baseline to end of study (up to 49.3 weeks) plus 37 day follow-up]

   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

1. 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)]]

2. Maximum Concentration (Cmax) of Ramucirumab [Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)]

   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.

3. Area Under the Curve (AUC) of Ramucirumab [Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)]

   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).

4. Half Life (t1/2) of Ramucirumab [Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)]

   t1/2 is the time required for the plasma/serum concentration to decrease 50%.

5. Clearance (CL) of Ramucirumab [Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)]

   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.

6. Steady State Volume of Distribution (Vss) of Ramucirumab [Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)]

   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.

7. Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] [Every 8 weeks until PD (up to 49 weeks)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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; UGT1A128/28 or UGT1A16/*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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Chiba		Japan	277-8577
2	ImClone Investigational Site	Osaka		Japan	569-8686
3	ImClone Investigational Site	Shizuoka		Japan	411-8777

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: 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), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01286818
• Other Study ID Numbers: 14223; CP12-1029; 14T-IE-JVBY
• First Posted: Jan 31, 2011
• Last Update Posted: Oct 6, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Eli Lilly and Company: Colon Cancer; Rectal Cancer
• Additional relevant MeSH terms: Carcinoma; Colorectal Neoplasms; Leucovorin; Fluorouracil; Irinotecan; Ramucirumab; Antibodies, Monoclonal; Levoleucovorin

Study Results

Participant Flow

Pre-assignment Detail	Eight (8) participants signed the informed consent.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Period Title: Overall Study
STARTED	6
Completed DLT Assessment Period	5
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 66.7%
>=65 years	2 33.3%
Sex: Female, Male (Count of Participants)
Female	2 33.3%
Male	4 66.7%
Race/Ethnicity, Customized (participants) [Number]
Asian	6 100%
Region of Enrollment (participants) [Number]
Japan	6 100%
Eastern Cooperative Oncology Group (ECOG) performance status (participants) [Number]
0 - Fully active	3 50%
1 - Ambulatory, restricted strenuous activity	3 50%

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

DLT population: All enrolled participants who either completed the first 3 administrations of study medication or discontinued study medication due to a DLT during the DLT assessment period (Day 1, Cycle 1 through Day 1, Cycle 3).

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	6
Number [participants]	1 16.7%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety population: Participants who received any quantity of study medication.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	6
Related TEAE	6 100%
Related SAE	0 0%
Related Grade ≥3 TEAE	3 50%
Related AE leading to discontinuation	2 33.3%

3. Secondary Outcome

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)]

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable immunogenicity data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	5
Day 1, Cycle 5 (n=5)	0 0%
Day 1, Cycle 6 (n=1)	0 0%
Day 1, Cycle 7 (n=3)	0 0%
Day 1, Cycle 9 (n=4)	0 0%

4. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable Cmax data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	6
Day 1, Cycle 1 (n=6)	245 (6)
Day 1, Cycle 5 (n=2)	267 (11)

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable AUC data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	4
Day 1, Cycle 1 (n=4)	1600 (15)
Day 1, Cycle 5 (n=2)	1690 (38)

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable t1/2 data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	6
Day 1, Cycle 1 (n=6)	7.38 (19)
Day 1, Cycle 5 (n=2)	8.55 (2)

7. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable CL data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	4
Day 1, Cycle 1 (n=4)	11.4 (26)
Day 1, Cycle 5 (n=2)	10.4 (61)

8. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Participants who received any quantity of study medication and had evaluable Vss data at the specified time points.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	4
Day 1, Cycle 1 (n=4)	2.51 (25)
Day 1, Cycle 5 (n=2)	3.06 (56)

9. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety population: Participants who received any quantity of study medication.

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
Measure Participants	6
Complete Response (CR)	0 0%
Partial Response (PR)	1 16.7%
Stable Disease (SD)	4 66.7%
Progressive Disease (PD)	1 16.7%

Adverse Events

Arm/Group Title	FOLFIRI Plus Ramucirumab (IMC-1121B)
Arm/Group Description	Ramucirumab (IMC-1121B): Intravenous (IV) infusion, 8 milligrams per kilogram (mg/kg) every 2 weeks. Then 1-hour observation followed by chemotherapy with irinotecan, levofolinate, and 5-fluorouracil (FOLFIRI) according to manufacturer's standards. Irinotecan: IV infusion, 180 milligrams per square meter (mg/m^2) every 2 weeks. Levofolinate: IV infusion, 200 mg/m^2 every 2 weeks. 5-fluorouracil (5-FU): 400 mg/m^2 bolus followed by a 2400 mg/m^2 continuous infusion, every 2 weeks. Antiemetic premedication recommended according to manufacturer's standards but not required prior to ramucirumab drug product infusion. Participants who did not experience unacceptable toxicities during dose limiting toxicity (DLT) assessment period (Day 1, Cycle 1 through Day 1, Cycle 3) who met criteria for treatment continuation received additional cycles of study medication until disease progression, unacceptable toxicity, protocol noncompliance, withdrawal of consent, or Sponsor/investigator decision.
All Cause Mortality
	FOLFIRI Plus Ramucirumab (IMC-1121B)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	FOLFIRI Plus Ramucirumab (IMC-1121B)
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	FOLFIRI Plus Ramucirumab (IMC-1121B)
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
ANAEMIA	1/6 (16.7%)	3
NEUTROPENIA	5/6 (83.3%)	34
THROMBOCYTOPENIA	4/6 (66.7%)	11
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/6 (16.7%)	2
ABDOMINAL PAIN	2/6 (33.3%)	3
CHEILITIS	1/6 (16.7%)	2
DIARRHOEA	5/6 (83.3%)	12
GINGIVITIS	1/6 (16.7%)	1
LOWER GASTROINTESTINAL HAEMORRHAGE	1/6 (16.7%)	3
MOUTH HAEMORRHAGE	1/6 (16.7%)	1
NAUSEA	3/6 (50%)	34
PERIODONTAL DISEASE	2/6 (33.3%)	2
STOMATITIS	5/6 (83.3%)	12
VOMITING	4/6 (66.7%)	22
General disorders
FACE OEDEMA	1/6 (16.7%)	1
FATIGUE	3/6 (50%)	5
FEELING ABNORMAL	1/6 (16.7%)	1
INFUSION RELATED REACTION	1/6 (16.7%)	1
MALAISE	2/6 (33.3%)	23
OEDEMA	1/6 (16.7%)	1
OEDEMA PERIPHERAL	2/6 (33.3%)	4
Infections and infestations
NASOPHARYNGITIS	1/6 (16.7%)	1
UPPER RESPIRATORY TRACT INFECTION	1/6 (16.7%)	2
URINARY TRACT INFECTION	1/6 (16.7%)	1
Injury, poisoning and procedural complications
SKIN INJURY	1/6 (16.7%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	1/6 (16.7%)	1
ASPARTATE AMINOTRANSFERASE INCREASED	1/6 (16.7%)	1
BLOOD ALKALINE PHOSPHATASE INCREASED	1/6 (16.7%)	1
BLOOD CREATININE INCREASED	1/6 (16.7%)	1
WEIGHT DECREASED	1/6 (16.7%)	2
WHITE BLOOD CELL COUNT DECREASED	1/6 (16.7%)	3
Metabolism and nutrition disorders
DECREASED APPETITE	4/6 (66.7%)	36
DEHYDRATION	1/6 (16.7%)	2
HYPERURICAEMIA	1/6 (16.7%)	1
HYPOALBUMINAEMIA	1/6 (16.7%)	3
HYPOPROTEINAEMIA	1/6 (16.7%)	2
Musculoskeletal and connective tissue disorders
BACK PAIN	1/6 (16.7%)	1
BONE PAIN	1/6 (16.7%)	1
Nervous system disorders
HEADACHE	1/6 (16.7%)	1
PRESYNCOPE	1/6 (16.7%)	2
Psychiatric disorders
INSOMNIA	1/6 (16.7%)	1
Renal and urinary disorders
PROTEINURIA	2/6 (33.3%)	10
Reproductive system and breast disorders
UTERINE HAEMORRHAGE	1/2 (50%)	2
Respiratory, thoracic and mediastinal disorders
EPISTAXIS	3/6 (50%)	6
HICCUPS	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
ALOPECIA	2/6 (33.3%)	2
DRY SKIN	1/6 (16.7%)	1
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	1/6 (16.7%)	1
RASH MACULO-PAPULAR	1/6 (16.7%)	2
Vascular disorders
HYPERTENSION	1/6 (16.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.