Malignant Solid Tumor
Conditions
Keywords
Advanced Malignant Solid Tumors
Brief summary
The purpose of this study is to investigate whether there are no clinically significant pharmacokinetic effects of concomitant ramucirumab (IMC-1121B) on paclitaxel by investigating the pharmacokinetics (PK) of each in participants with advanced malignant solid tumors. Part A of this study will investigate the potential of concomitant ramucirumab (IMC-1121B) to affect the pharmacokinetics of paclitaxel. Part B of this study will investigate the pharmacokinetics of ramucirumab (IMC-1121B) as monotherapy.
Interventions
BIOLOGICALramucirumab (IMC-1121B)
ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) intravenous infusion, administered on Day 1and Day 15 of each 4-week cycle, unless otherwise specified.
DRUGpaclitaxel
paclitaxel 80 milligrams/square meter (mg/m²) intravenous infusion, administered on Days 1, 8 and 15 of each 4-week cycle, unless otherwise specified.
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
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 refractory to standard therapy or for which no standard therapy is available * Part A only: Has had 0-1 prior taxane-containing treatment regimens (including taxane monotherapy), which must have been completed at least 6 months before the first dose of study medication (prior bevacizumab is allowed) * Part B only: Prior bevacizumab- and taxane-containing treatment regimens (including taxane monotherapy) are allowed, provided these regimens have been completed at least 6 months before the first dose of study medication * Has resolution to Grade ≤ 1 of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy with the exception of peripheral neuropathy, which must not have exceeded Grade 1, by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v 4.0) * Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 - 2 * Has adequate hematologic function. Blood transfusion is allowed but must be completed 48 hours before study drug administration * Has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal \[ULN\], aspartate transaminase \[AST\] and alanine transaminase \[ALT\] ≤ 1.5 x ULN * Has serum creatinine ≤ 1.5 x ULN. If serum creatinine \> 1.5 x ULN, the calculated creatinine clearance (CrCl) should be ≥ 40 milliliter/minute (mL/min) * Urinary protein is \<2+ on dipstick or routine urinalysis (UA) * Must have adequate coagulation function as defined by an international normalized ratio (INR) of ≤ 1.5 and a partial thromboplastin time (PTT) or an activated PTT (aPTT) ≤ 1.5 x ULN * Eligible participants of reproductive potential agree to use adequate method of contraception during the study period and for 12 weeks after the last dose of study medication
Exclusion criteria
* Is receiving concomitant therapy with clinically relevant inhibitors or inducers of cytochrome P450, CYP2C8, CYP3AY and/or isoenzymes * 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 received a monoclonal antibody within 42 days prior to first dose of study medication * Has received radiotherapy within 14 days prior to first dose of study medication * Has received cytotoxic chemotherapy within 21 days (6 weeks for nitrosoureas or mitomycin C) prior to first dose of study medication * Has a cardiac left ventricular ejection fraction (LVEF) not within institutional limits of normal on a multigated acquisition scan (MUGA) or echocardiogram * Is receiving concurrent treatment with another anticancer therapy, including chemotherapy, immunotherapy, hormonal therapy, radiation therapy, chemoembolization, targeted or other investigational anticancer therapy * Is receiving chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet agents. Aspirin use at doses up to 325 milligrams/day (mg/day) and analgesic agents with no or low bleeding risk are permitted * Has a history of uncontrolled hereditary or acquired bleeding or thromboembolic disorders * Has experienced any arterial thromboembolic event, including myocardial infarction (MI), unstable angina stroke or transient ischemic attack (TIA), within 6 months prior to first dose of study medication * Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the 3 months prior to first dose of study medication * Has experienced a Grade 3 or 4 hemorrhagic event within 3 months prior to first dose of study medication * Has experienced peripheral neuropathy ≥ Grade 2 at any time prior to study entry * Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection, Crohn's disease, ulcerative colitis, or chronic diarrhea * History of gastrointestinal perforation and / or fistulae within 6 months prior to randomization * Has an ongoing or active infection requiring treatment with intravenous antibiotics * Has a serious or nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to first dose of study medication * Has uncontrolled hypertension * Has symptomatic congestive heart failure * Has known brain or leptomeningeal disease * Has known positive status for human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome-related illness * Has known active drug or alcohol abuse that would affect participant's ability to comply with study treatment * Has pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen * Has had major surgery within 28 days prior to first dose of study medication or subcutaneous venous access device implantation within 7 days prior to first dose of study medication * Has an elective or planned major surgery during the course of the trial * If a primary cancer is non-small-cell lung cancer (NSCLC), participant has intratumor cavitation, radiologically documented evidence of major blood vessel invasion or encasement by cancer, or proximity of cancer to major airways * Has received prior ramucirumab (IMC-1121B) therapy * The participant has: * cirrhosis at a level of Child-Pugh B (or worse) * cirrhosis (any degree) 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 |
|---|---|---|
| Part B: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] as Monotherapy | Cycle 1: 0,1, 1.5, 2, 5, 7, 24, 48, 72,168, 264, 336, 408, and 504 hours post ramucirumab infusion | Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. |
| Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 1 | Cycle 1: 0, 1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel 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. |
| Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 2 | Cycle 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel 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. |
| Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 1 | Cycle 1: 0,1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion | Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error. |
| Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 2 | Cycle 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel infusion | Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Paclitaxel | Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion | Dose-normalized Cmax was calculated from Cmax divided by the dose. |
| Part A: Immunogenicity of Ramucirumab in Combination With Paclitaxel - Number of Participants With Anti-Ramucirumab Antibodies | -1 hour on Day 1 of Cycle 2, and 30 days after last dose of study drug | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline. |
| Part B: Immunogenicity of Ramucirumab as Monotherapy - Number of Participants With Anti-Ramucirumab Antibodies | 0 hour on Day 1 of Cycle 1, and 30 days after last dose of study drug | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline. |
| Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Paclitaxel | Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion | Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Paclitaxel and Ramucirumab Cycle 1: paclitaxel 80 milligrams/square meter (mg/m²) administered on Day 1 of 2-week cycle.
Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 milligrams/kilogram (mg/kg) administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle. | 24 |
| Part B: Ramucirumab With or Without Paclitaxel Cycle 1: ramucirumab (IMC-1121B) 8 mg/kg administered as monotherapy on Day 1 of 3-week cycle.
Cycle 2 and beyond: ramucirumab (IMC-1121B) 8 mg/kg administered on Day 1 and Day 15, paclitaxel 80 mg/m² administered on Day 1, Day 8 and Day 15 of 4-week cycle.
\*After Cycle 1 (mandatory pharmacokinetic phase) is completed, participants may continue to receive ramucirumab (IMC-1121B) monotherapy or combination therapy with paclitaxel as described in Part A. | 16 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Progressive Disease | 19 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Part A: Paclitaxel and Ramucirumab | Part B: Ramucirumab With or Without Paclitaxel |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 10 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 14 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 23 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 22 Participants | 15 Participants |
| Region of Enrollment United States | 40 Participants | 24 Participants | 16 Participants |
| Sex: Female, Male Female | 22 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 18 Participants | 11 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 24 | 21 / 21 | 8 / 16 | 14 / 15 |
| serious Total, serious adverse events | 1 / 24 | 6 / 21 | 0 / 16 | 6 / 15 |
Outcome results
Primary
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel 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, 1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion
Population: All participants from Part A Cycle 1 and had sufficient concentration data to calculate paclitaxel AUC(0-∞).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 1 | 29 nanograms*hour/milliliter/milligram |
Primary
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 2
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 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel infusion
Population: All participants from Part A Cycle 2 and had sufficient concentration data to calculate paclitaxel AUC(0-∞).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Paclitaxel From Time Zero to Infinity [AUC(0-∞)] in Cycle 2 | 31.67 nanograms*hour/milliliter/milligram |
90% CI: [0.93, 1.29]Mixed Models Analysis
Primary
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 1
Dose-normalized Cmax was calculated from Cmax 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: 0,1, 1.5, 2, 5, 7, 24, 48, 72 and 168 hours post paclitaxel infusion
Population: All participants from Part A Cycle 1 and had sufficient concentration data to calculate paclitaxel cmax.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 1 | 18.84 nanograms/milliliter/milligram |
Primary
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 2
Dose-normalized Cmax was calculated from Cmax 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 2: -1, 0, 1, 1.5, 2, 5, 7, 24, 48, 72, 96, 168, 264 and 336 hours post paclitaxel infusion
Population: All participants from Part A Cycle 2 and had sufficient concentration data to calculate paclitaxel cmax.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Paclitaxel in Cycle 2 | 18.30 nanograms/milliliter/milligram |
90% CI: [0.83, 1.13]Mixed Models Analysis
Primary
Part B: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] as Monotherapy
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose.
Time frame: Cycle 1: 0,1, 1.5, 2, 5, 7, 24, 48, 72,168, 264, 336, 408, and 504 hours post ramucirumab infusion
Population: All participants who received ramucirumab and had sufficient concentration data to calculate ramucirumab AUC(0-∞) in Cycle 1 of Part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part B: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] as Monotherapy | 55.3 micrograms*hour/milliliter/milligram | Geometric Coefficient of Variation 27 |
Secondary
Part A: Immunogenicity of Ramucirumab in Combination With Paclitaxel - Number of Participants With Anti-Ramucirumab Antibodies
Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.
Time frame: -1 hour on Day 1 of Cycle 2, and 30 days after last dose of study drug
Population: All participants from Part A Cycle 2, who received ramucirumab and paclitaxel and had data for anti-ramucirumab antibodies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Immunogenicity of Ramucirumab in Combination With Paclitaxel - Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
Secondary
Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Paclitaxel
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose.
Time frame: Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion
Population: All participants who received ramucirumab and paclitaxel and had sufficient concentration data to calculate ramucirumab AUC(0-∞) in Cycle 2 of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Paclitaxel | 55.4 micrograms*hour/milliliters/milligram | Geometric Coefficient of Variation 27 |
Secondary
Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Paclitaxel
Dose-normalized Cmax was calculated from Cmax divided by the dose.
Time frame: Cycle 2: 0, 1, 2, 2.5, 3, 6, 8, 25, 49, 73, 97, 169, 265 and 337 hours post ramucirumab infusion
Population: All participants who received ramucirumab and paclitaxel and had sufficient concentration data to calculate ramucirumab Cmax in Cycle 2 of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part A: Pharmacokinetics - Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Paclitaxel | 0.384 micrograms/milliliter/milligram | Geometric Coefficient of Variation 31 |
Secondary
Part B: Immunogenicity of Ramucirumab as Monotherapy - Number of Participants With Anti-Ramucirumab Antibodies
Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.
Time frame: 0 hour on Day 1 of Cycle 1, and 30 days after last dose of study drug
Population: All participants from Part B cycle 1, who received ramucirumab and had data for anti-ramucirumab antibodies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Paclitaxel Alone (Cycle 1) | Part B: Immunogenicity of Ramucirumab as Monotherapy - Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |