Malignant Solid Tumor
Conditions
Keywords
Advanced Malignant Solid Tumors
Brief summary
The purpose of this study is to assess the effect of concomitant ramucirumab on the pharmacokinetics of docetaxel in participants with advanced malignant solid tumors. Participants who do not complete both Cycle 1, Day 1, and Cycle 2, Day 1 according to schedule will be replaced for the purpose of analysis; these participants may continue to receive study therapy. No dose reductions, delayed or missed doses are allowed during Cycles 1 and 2.
Interventions
BIOLOGICALRamucirumab
ramucirumab 10 milligrams/kilogram (mg/kg) intravenous infusion, administered on Day 1 of 3-week cycle
DRUGDocetaxel
docetaxel 75 milligrams/square meter (mg/m\^2) intravenous infusion administered on Day 1 of each 3-week 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
* Participant has histologic or cytologic documentation of a malignant solid tumor * Participant has an advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available * Participant 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. * Participant has resolution to Grade ≤ 1 (except where otherwise stated in this eligibility criteria) by 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 * Participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 * Participant has adequate hematologic function (absolute neutrophil count \[ANC\] ≥ 1500 cells/liter (cells/L), hemoglobin ≥ 10 grams/deciliter (g/dL), and platelet count ≥ 100,000 cells/microliter (cells/mcL)\]. Blood transfusion is allowed but must be completed 48 hours before study drug administration. * Participant has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal \[x ULN\], aspartate transaminase \[AST\] and alanine transaminase \[ALT\] ≤ 1.5 x ULN) * Participant has serum creatinine ≤ 1.5 x ULN. If serum creatinine \> 1.5 x ULN, the calculated creatinine clearance \[CrCl\] should be ≥ 40 milliliters/minute (mL/min) * Participant's urinary protein is \<2+ on dipstick or routine urinalysis (UA) at study entry * Participant 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 * 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 a known allergy or hypersensitivity to any of the treatment components * 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 therapeutic 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 prior to first dose of study medication * Is receiving concurrent treatment with another anticancer therapy, including chemotherapy, immunotherapy, hormonal therapy (except for androgen deprivation therapy for prostate cancer), 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 despite standard medical management * Has symptomatic congestive heart failure, symptomatic or poorly controlled cardiac arrhythmia, or any other serious, uncontrolled medical disorders, which in the opinion of the investigator would make the participant ineligible for participation in the study * Has known brain or leptomeningeal metastases * Has known positive status for human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome-related illness * Has known active drug or alcohol abuse * 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 the primary cancer is non-small-cell lung cancer (NSCLC), there is radiographic evidence of intratumor cavitation, major blood vessel invasion or encasement by cancer, or proximity of cancer to major airways * Has received prior ramucirumab (IMC-1121B) therapy * Is receiving concomitant therapy with clinically relevant inhibitors or inducers of cytochrome P450 3A4 and 3A5 and/or isoenzymes * 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 |
|---|---|
| Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 1 | Cycle 1: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion |
| Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 2 | Cycle 2: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion |
| Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 1 | Cycle 1: 0, 1, 1.5, 2, 3, 5, 7, 24, 48, and 72 hours post docetaxel infusion |
| Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 2 | Cycle 2: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Docetaxel | Cycle 2: 1 hour prior to ramucirumab infusion, 0, 1, 2, 2.5, 3, 4, 6, 8, 25, 49, 73, 169, 265 and 337 hours post ramucirumab infusion | — |
| Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Docetaxel | Cycle 2: 1 hour prior to ramucirumab infusion, 0, 1, 2, 2.5, 3, 4, 6, 8, 25, 49, 73, 169, 265 and 337 hours post ramucirumab infusion | — |
| Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Cycle 1, Day 1 through Cycle 2, Day 1 and 30 days after last dose of study drug | Participants with treatment-emergent anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilution increase) in immunogenicity titer over baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Cycle 1: docetaxel 75-milligrams/square meter (mg/m\^2) intravenous infusion administered on Day 1 of 3-week cycle
Cycle 2: ramucirumab 10-milligrams/kilogram (mg/kg) intravenous infusion, followed by docetaxel 75-mg/m\^2 intravenous infusion administered on Day 1 of 3-week cycle
Cycle 3 and beyond: ramucirumab and docetaxel administered on Day 1 of each 3-week cycle | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Progressive Disease | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 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 | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 22 |
| serious Total, serious adverse events | 11 / 22 |
Outcome results
Primary
Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 1
Time frame: Cycle 1: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion
Population: All participants who completed Cycle 1, Day 1 and Cycle 2, Day 1 treatment and had sufficient concentration data to calculate docetaxel AUC(0-∞) in Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 1 | 13.7 nanograms*hour/milliliter/milligram | Geometric Coefficient of Variation 40 |
Primary
Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 2
Time frame: Cycle 2: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion
Population: All participants who completed Cycle 1, Day 1 and Cycle 2, Day 1 treatment and had sufficient concentration data to calculate docetaxel AUC(0-∞) in Cycle 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Dose-Normalized Area Under the Concentration Versus Time Curve of Docetaxel From Time Zero to Infinity [AUC(0-∞)] Following a Single Dose in Cycle 2 | 12.8 nanograms*hour/milliliter/milligram | Geometric Coefficient of Variation 30 |
90% CI: [0.84, 1.1]Mixed Models Analysis
Primary
Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 1
Time frame: Cycle 1: 0, 1, 1.5, 2, 3, 5, 7, 24, 48, and 72 hours post docetaxel infusion
Population: All participants who completed Cycle 1, Day 1 and Cycle 2, Day 1 treatment and had sufficient concentration data to calculate docetaxel Cmax in Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 1 | 7.66 nanograms/milliliter/milligram | Geometric Coefficient of Variation 76 |
Primary
Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 2
Time frame: Cycle 2: 0, 1, 1.5, 2, 3, 5, 7, 24, 48 and 72 hours post docetaxel infusion
Population: All participants who completed Cycle 1, Day 1 and Cycle 2, Day 1 treatment and had sufficient concentration data to calculate docetaxel Cmax in Cycle 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Dose-Normalized Maximum Observed Drug Concentration (Cmax) of Docetaxel in Cycle 2 | 8.78 nanograms/milliliter/milligram | Geometric Coefficient of Variation 37 |
90% CI: [0.84, 1.55]Mixed Models Analysis
Secondary
Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies
Participants with treatment-emergent anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilution increase) in immunogenicity titer over baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Time frame: Cycle 1, Day 1 through Cycle 2, Day 1 and 30 days after last dose of study drug
Population: All participants who completed Cycle 1, Day 1 and Cycle 2, Day 1 treatment who had immunogenicity samples collected at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel (Cycle 1) | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Immunogenicity During Study (n=17) | 0 participants |
| Docetaxel (Cycle 1) | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Immunogenicity Post-Treatment (n=5) | 0 participants |
Secondary
Pharmacokinetics: Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Docetaxel
Time frame: Cycle 2: 1 hour prior to ramucirumab infusion, 0, 1, 2, 2.5, 3, 4, 6, 8, 25, 49, 73, 169, 265 and 337 hours post ramucirumab infusion
Population: All enrolled participants who received ramucirumab and had sufficient concentration data to calculate ramucirumab AUC(0-∞) in Cycle 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Area Under the Concentration Versus Time Curve of Ramucirumab From Time Zero to Infinity [AUC(0-∞)] in the Presence of Docetaxel | 42400 micrograms*hour/milliliter (mcg*h/mL) | Geometric Coefficient of Variation 32 |
Secondary
Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Docetaxel
Time frame: Cycle 2: 1 hour prior to ramucirumab infusion, 0, 1, 2, 2.5, 3, 4, 6, 8, 25, 49, 73, 169, 265 and 337 hours post ramucirumab infusion
Population: All enrolled participants who received ramucirumab and had sufficient concentration data to calculate ramucirumab Cmax in Cycle 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Docetaxel (Cycle 1) | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of Ramucirumab in the Presence of Docetaxel | 303.6 micrograms/milliliter (mcg/mL) | Geometric Coefficient of Variation 28 |