A Study to Assess the Pharmacokinetics of Ramucirumab (IMC-1121B) in Combination With FOLFIRI

Study Overview
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Brief Summary
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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.

Official Title
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A Study to Evaluate the Potential of Concomitant Ramucirumab to Affect the Pharmacokinetics of Irinotecan and Its Metabolite SN-38 When Coadministered With Folinic Acid and 5 Fluorouracil in Patients With Advanced Malignant Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Biological: Ramucirumab (IMC-1121B)
* Drug: Irinotecan
* Drug: Folinic acid
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ramucirumab (IMC-1121B) and FOLFIRI<br>Treatment is sequential, Ramucirumab (IMC-1121B) will be administered before FOLFIRI ((Irinotecan + Folinic acid + 5-Fluorouracil). FOLFIRI will be administered each cycle and Ramucirumab (IMC-1121B) will be administered beginning from Cycle 2 (2-week cycle). | Biological: Ramucirumab (IMC-1121B)<br>* 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)<br>* Other names: LY3009806;Drug: Irinotecan<br>* 180 milligrams per square meter (mg/m²) administered IV on Day 1 of each cycle<br>Drug: Folinic acid<br>* 400 mg/m² administered IV on Day 1 of each cycle<br>Drug: 5-Fluorouracil<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. | Up To 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Malignant Solid Tumors