Solid Tumors
Conditions
Keywords
Advanced Malignant Solid Tumors
Brief summary
The purpose of this study is to assess the effect of concomitant ramucirumab (IMC-1121B) on the pharmacokinetics of irinotecan and its metabolite SN-38 when coadministered with folinic acid and 5-fluorouracil, in participants with advanced malignant solid tumors resistant to standard therapy or for which no standard therapy is available.
Interventions
BIOLOGICALRamucirumab (IMC-1121B)
Ramucirumab (IMC-1121B) 8 milligrams per kilogram (mg/kg), administered as an intravenous (IV) infusion on Day 1 of each 2-week cycle (except Cycle 1)
DRUGIrinotecan
180 milligrams per square meter (mg/m²) administered IV on Day 1 of each cycle
DRUGFolinic acid
400 mg/m² administered IV on Day 1 of each cycle
DRUG5-Fluorouracil
400 mg/m² bolus over 2 to 4 minutes administered IV on Day 1 of each cycle, followed by 2400 mg/m² administered IV over 46 to 48 hours on Days 1 and 2 of each cycle
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologic or cytologic documentation of a malignant solid tumor * Has an advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available * Has resolution to Grade ≤1, per the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v. 4.0), of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Has adequate hematologic, coagulation, and hepatic function * Has serum creatinine ≤ 1.5 x upper limit of normal (ULN) * Urinary protein is \<2+ on dipstick or routine urinalysis (UA) at study entry * Women with childbearing potential must have a negative serum or urine pregnancy test * Eligible participants of reproductive potential (both sexes) agree to use adequate method of contraception during the study period and for 12 weeks after the last dose of study medication
Exclusion criteria
* Has received a therapeutic monoclonal antibody within the last 42 days * Has received cytotoxic chemotherapy within the last 21 days * Has received radiotherapy within the last 14 days * Are currently enrolled in, or discontinued within the last 14 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the last 3 months * Has an uncontrolled illness, including, but not limited to uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders * Has experienced any arterial thromboembolic event within the last 6 months * Has known leptomeningeal disease or brain metastases or uncontrolled spinal cord compression * Has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy * Has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness * Has received a prior organ or transplantation * Has undergone major surgery within the last 28 days * Has had a serious nonhealing wound, ulcer, or bone fracture within the last 28 days * Has an elective or planned major surgery to be performed during the course of the trial * Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection, Crohn's disease, ulcerative colitis, or chronic diarrhea * Has experienced a Grade 3 or higher bleeding event within the last 3 months * Has a known history or clinical evidence of Gilbert's Syndrome, or is known to have any of the following genotypes: uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1)\*6/\*6, UGT1A1\*28/\*28, or UGT1A1\*6/\*28 * Has received clinically relevant inhibitors or inducers of cytochrome P (CYP) 450 CYP3A4/5 or CYP2C9 and/or isoenzymes within the last 3 weeks * Has cirrhosis at a level of Child-Pugh B (or worse), or cirrhosis and a history of hepatic encephalopathy, or ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Dose-Normalized AUC(0-∞) of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Cycle 2: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion | Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error. |
| Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1 | Cycle 1: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion | Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error. |
| Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Irinotecan and Its Metabolite SN-38 in Cycle 1 | Cycle 1: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion | Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error. |
| Pharmacokinetics: Dose-Normalized Cmax of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Cycle 2: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion | Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Cmax of Ramucirumab (IMC-1121B) | Cycle 2: -2, -1, -0.5, 0, 2, 3, 4, 5, 8, 10, 25, 48, 72, 96, 168, 264, 336 hours post-ramucirumab (IMC-1121B) infusion | — |
| Number of Participants With Treatment Emergent Anti-Drug Antibodies (TE-ADA) | Up To 2 Years | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab (IMC-1121B) and FOLFIRI Treatment is sequential. Ramucirumab (IMC-1121B) was administered before FOLFIRI (Irinotecan + Folinic acid + 5-Fluorouracil) during Cycles 2+
Ramucirumab (IMC-1121B): 8 mg/kg administered as IV infusion on Day 1 of each 2-week cycle (except Cycle 1)
Irinotecan: 180 mg/m² administered IV on Day 1 of each 2-week cycle
Folinic acid: 400 mg/m² administered IV on Day 1 of each 2-week cycle
5-Fluorouracil: 400 mg/m² bolus over 2 to 4 minutes administered IV on Day 1 of each 2-week cycle, followed by 2400 mg/m² administered IV over 46 to 48 hours on Days 1 and 2 of each cycle | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Ramucirumab (IMC-1121B) and FOLFIRI |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 29 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 29 |
| serious Total, serious adverse events | 11 / 29 |
Outcome results
Primary
Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Time frame: Cycle 1: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion
Population: All participants in DDI population (who completed the required treatment in Cycle 1, Day 1 and Cycle 2, Day 1) and had sufficient concentration data to calculate irinotecan and its metabolite SN-38 AUC(0-∞) in Cycle 1.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1 | Irinotecan | 22.12 nanograms*hour/milliliter/milligram |
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Irinotecan and Its Metabolite SN-38 From Time Zero to Infinity [AUC(0-∞)] in Cycle 1 | Metabolite SN-38 | 0.81 nanograms*hour/milliliter/milligram |
Primary
Pharmacokinetics: Dose-Normalized AUC(0-∞) of Irinotecan and Its Metabolite SN-38 in Cycle 2
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Time frame: Cycle 2: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion
Population: All participants in DDI population (who completed the required treatment in Cycle 1, Day 1 and Cycle 2, Day 1) and had sufficient concentration data to calculate irinotecan and its metabolite SN-38 AUC(0-∞) in Cycle 2.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized AUC(0-∞) of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Irinotecan | 20.56 nanograms*hour/milliliter/milligram |
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized AUC(0-∞) of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Metabolite SN-38 | 0.77 nanograms*hour/milliliter/milligram |
90% CI: [0.83, 1.05]Mixed Models Analysis
90% CI: [0.88, 1.04]Mixed Models Analysis
Primary
Pharmacokinetics: Dose-Normalized Cmax of Irinotecan and Its Metabolite SN-38 in Cycle 2
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Time frame: Cycle 2: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion
Population: All participants in DDI population (who completed the required treatment in Cycle 1, Day 1 and Cycle 2, Day 1) and had sufficient concentration data to calculate irinotecan and its metabolite SN-38 Cmax in Cycle 2.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Cmax of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Irinotecan | 3.31 nanograms/milliliter/milligram |
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Cmax of Irinotecan and Its Metabolite SN-38 in Cycle 2 | Metabolite SN-38 | 0.05 nanograms/milliliter/milligram |
90% CI: [0.97, 1.12]Mixed Models Analysis
90% CI: [0.85, 1.12]Mixed Models Analysis
Primary
Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Irinotecan and Its Metabolite SN-38 in Cycle 1
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Time frame: Cycle 1: 0, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 22, 25, 28, 31, 34, 48, 72, 96 and 168 hours post-irinotecan infusion
Population: All participants in DDI population (who completed the required treatment in Cycle 1, Day 1 and Cycle 2, Day 1) and had sufficient concentration data to calculate irinotecan and its metabolite SN-38 Cmax in Cycle 1.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Irinotecan and Its Metabolite SN-38 in Cycle 1 | Irinotecan | 3.18 nanograms/milliliter/milligram |
| FOLFIRI (Cycle 1) | Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Irinotecan and Its Metabolite SN-38 in Cycle 1 | Metabolite SN-38 | 0.05 nanograms/milliliter/milligram |
Secondary
Number of Participants With Treatment Emergent Anti-Drug Antibodies (TE-ADA)
Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group.
Time frame: Up To 2 Years
Population: All participants with both baseline and at least one post baseline ADA assessments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FOLFIRI (Cycle 1) | Number of Participants With Treatment Emergent Anti-Drug Antibodies (TE-ADA) | 0 Participants |
Secondary
Pharmacokinetics: Cmax of Ramucirumab (IMC-1121B)
Time frame: Cycle 2: -2, -1, -0.5, 0, 2, 3, 4, 5, 8, 10, 25, 48, 72, 96, 168, 264, 336 hours post-ramucirumab (IMC-1121B) infusion
Population: All participants who received study drug and had sufficient concentration data to calculate ramucirumab (IMC-1121B) Cmax in Cycle 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FOLFIRI (Cycle 1) | Pharmacokinetics: Cmax of Ramucirumab (IMC-1121B) | 201.6 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 31 |