Colorectal Carcinoma
Conditions
Keywords
Colon Cancer, Rectal Cancer
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).
Interventions
BIOLOGICALRamucirumab (IMC-1121B)
Ramucirumab (IMC-1121B): Intravenous (IV) infusions, 8 milligrams per kilogram (mg/kg) every 2 weeks
DRUGIrinotecan
IV Infusion, 180 milligrams per square meter (mg/m²) every 2 weeks
DRUGlevofolinate
IV infusion, 200 mg/m² every 2 weeks
DRUG5-Fluorouracil (5-FU)
400 mg/m² bolus followed by a 2400 mg/m² continuous infusion, every 2 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
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; 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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%. |
| 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)] | — |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Japan
Participant flow
Pre-assignment details
Eight (8) participants signed the informed consent.
Participants by arm
| Arm | Count |
|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) 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. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | FOLFIRI Plus Ramucirumab (IMC-1121B) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 - Fully active | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 - Ambulatory, restricted strenuous activity | 3 participants |
| Race/Ethnicity, Customized Asian | 6 participants |
| Region of Enrollment Japan | 6 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
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.
Time frame: Day 1, Cycle 1 through Day 1, Cycle 3 (1 cycle=14 days)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants That Experienced Any Dose-Limiting Toxicities (DLT) During the DLT Assessment Period | 1 participants |
Primary
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.
Time frame: Baseline to end of study (up to 49.3 weeks) plus 37 day follow-up
Population: Safety population: Participants who received any quantity of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events | Related TEAE | 6 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events | Related SAE | 0 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events | Related Grade ≥3 TEAE | 3 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Ramucirumab Drug-Related Adverse Events or Serious Adverse Events | Related AE leading to discontinuation | 2 participants |
Secondary
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).
Time frame: Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Population: Participants who received any quantity of study medication and had evaluable AUC data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Area Under the Curve (AUC) of Ramucirumab | Day 1, Cycle 1 (n=4) | 1600 micrograms*day/milliliter (mcg*day/mL) | Geometric Coefficient of Variation 15 |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Area Under the Curve (AUC) of Ramucirumab | Day 1, Cycle 5 (n=2) | 1690 micrograms*day/milliliter (mcg*day/mL) | Geometric Coefficient of Variation 38 |
Secondary
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.
Time frame: Every 8 weeks until PD (up to 49 weeks)
Population: Safety population: Participants who received any quantity of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] | Complete Response (CR) | 0 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] | Partial Response (PR) | 1 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] | Stable Disease (SD) | 4 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Best Overall Response [Anti-Tumor Activity of FOLFIRI Plus Ramucirumab (IMC-1121B)] | Progressive Disease (PD) | 1 participants |
Secondary
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.
Time frame: Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Population: Participants who received any quantity of study medication and had evaluable CL data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Clearance (CL) of Ramucirumab | Day 1, Cycle 1 (n=4) | 11.4 milliliters per hour (mL/hr) | Geometric Coefficient of Variation 26 |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Clearance (CL) of Ramucirumab | Day 1, Cycle 5 (n=2) | 10.4 milliliters per hour (mL/hr) | Geometric Coefficient of Variation 61 |
Secondary
Half Life (t1/2) of Ramucirumab
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)
Population: Participants who received any quantity of study medication and had evaluable t1/2 data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Half Life (t1/2) of Ramucirumab | Day 1, Cycle 1 (n=6) | 7.38 days | Geometric Coefficient of Variation 19 |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Half Life (t1/2) of Ramucirumab | Day 1, Cycle 5 (n=2) | 8.55 days | Geometric Coefficient of Variation 2 |
Secondary
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.
Time frame: Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Population: Participants who received any quantity of study medication and had evaluable Cmax data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Maximum Concentration (Cmax) of Ramucirumab | Day 1, Cycle 1 (n=6) | 245 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 6 |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Maximum Concentration (Cmax) of Ramucirumab | Day 1, Cycle 5 (n=2) | 267 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 11 |
Secondary
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)]
Population: Participants who received any quantity of study medication and had evaluable immunogenicity data at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity) | Day 1, Cycle 5 (n=5) | 0 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity) | Day 1, Cycle 6 (n=1) | 0 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity) | Day 1, Cycle 7 (n=3) | 0 participants |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Number of Participants With Serum Anti-IMC-1121B Antibodies (Immunogenicity) | Day 1, Cycle 9 (n=4) | 0 participants |
Secondary
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.
Time frame: Day 1, Cycle 1 and Day 1, Cycle 5 (1 cycle=14 days)
Population: Participants who received any quantity of study medication and had evaluable Vss data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Steady State Volume of Distribution (Vss) of Ramucirumab | Day 1, Cycle 1 (n=4) | 2.51 Liters (L) | Geometric Coefficient of Variation 25 |
| FOLFIRI Plus Ramucirumab (IMC-1121B) | Steady State Volume of Distribution (Vss) of Ramucirumab | Day 1, Cycle 5 (n=2) | 3.06 Liters (L) | Geometric Coefficient of Variation 56 |