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The purpose of this study was to determine the metabolism and elimination of 14C-lenvatinib in participants with advanced solid tumors or lymphomas, who were unsuitable for, or had failed, existing therapies.
The study comprised of two phases, the Study Phase and Extension Phase. Participants received 14C-lenvatinib on Day 1 of the Study Phase. Thereafter participants were given daily oral doses of 24 mg of lenvatinib over a 28 day cycle. During the Study Phase, participants received an initial single dose of 14C-lenvatinib oral patient dosing solution containing 24 mg of lenvatinib as anhydrous free base and radioactivity of 100 mCi (3.7 MBq) on Day 1, followed by collection of blood, urine and feces samples for pharmacokinetic analysis between Day 1 and Day 8, with a discharge visit on Day 8. Participants then entered the Extension Phase of the study to continue to receive once daily oral administration of non-radiolabeled lenvatinib at a dose of 24 mg. Each 28-day dosing period will be considered one treatment cycle.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lenvatinib 24 mg | Experimental | Participants with advanced solid tumors or lymphomas, who are unsuitable for, or had failed, existing therapies. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lenvatinib | Drug | Study phase dosing: participants received an initial single dose of radiolabelled 14C-lenvatinib oral patient dosing solution containing 24 mg of lenvatinib as anhydrous free base and radioactivity of 3.7 millibecquerel (MBq) on Day 1. Extension phase dosing: 24 mg of 14C-lenvatinib: 2 x 10mg, and 4 x 1mg or 1 x 4mg tablets once-daily, continuously in each 28-day cycle during extension phase. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Individual blood/plasma concentration-time data were analyzed using 'non-compartmental' analysis. Cmax was determined from visual inspection of the individual blood/plasma concentration-time profile and was summarized as the Geometric Mean and percent coefficient of variation for the Geometric Mean (CV%) for all participants and expressed as nanograms/milliliter (ng/mL). | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Time of Maximum Plasma Concentration (Tmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Individual blood/plasma concentration-time data were analyzed using 'non-compartmental' analysis. Tmax was determined from visual inspection of the individual blood/plasma concentration-time profile and was summarized as the Geometric Mean (CV%) for all participants and expressed as hours. | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Terminal Phase Rate Constant (λz) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The terminal phase rate constant represents the rate at which study drug was eliminated from the body and was determined by log-linear regression of the plasma concentrations against time in the terminal phase and was summarized as the Geometric Mean (CV%) for all participants and expressed as 1/hours. | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades (for both increasing and decreasing severity) and SAEs; regular monitoring of hematology, blood chemistry, and urine values; results of physical examinations, regular measurement of vital sign measurements, and 12-lead electrocardiogram (ECG), as detailed in the Schedule of Visits and Procedures. The relationship of AEs to treatment was based on investigator judgment. Details of AEs and SAEs are provided in the reported adverse event section. |
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INCLUSION CRITERIA
EXCLUSION CRITERIA
Participants with brain or subdural metastases, unless they had completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs and/or symptoms of brain metastases those were stable for at least 4 weeks.
Participants with meningeal carcinomatosis
Any of the following values for laboratory parameters:
Uncontrolled infections
Significant cardiovascular impairment (history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable ischemic heart disease including a myocardial infarction within six months of study start, or serious cardiac arrhythmia)
Participants with marked baseline prolongation of QT/QT interval corrected for heart rate (QTc) interval (QTc interval greater than or equal to 500 msec) using the Fridericia method
Any treatment with an investigational drug within the last 30 days
Women who were pregnant or breast-feeding; women of childbearing potential with a positive pregnancy test at screening or no pregnancy test. Women of child-bearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator (including two forms of contraception, one of which must be a barrier method). Perimenopausal women who were amenorrheic for at least 12 months to be considered of non-child-bearing potential. Fertile males with female partners of child-bearing potential who were not willing to use contraception, or whose female partners were not using adequate contraceptive protection, were excluded.
Proteinuria greater than 1+ on bedside testing
History of gastrointestinal malabsorption
Surgery within four weeks of start of study treatment
Bleeding or thrombotic disorders or use of an anticoagulant, such as warfarin, with a therapeutic INR. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and low molecular weight heparin (LMWH) were permissible but when used with caution.
Poorly controlled hypertension (defined as a change in hypertensive therapy within three months of study start) or participants diagnosed with hypertension (defined as a repeat blood pressure measurement of 160/90 mmHg or higher) at screening
Previous lenvatinib therapy
History of alcoholism, drug addiction, psychiatric or psychological condition, or social situation which, in the opinion of the investigator, would impair study compliance
History of allergic reactions attributed to compounds of similar chemical or biological composition to lenvatinib
Other significant disease or disorder that, in the Investigator's opinion, would exclude the participant from the study
Legal incapacity
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amsterdam | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22309776 | Background | Dubbelman AC, Rosing H, Thijssen B, Gebretensae A, Lucas L, Chen H, Shumaker R, Schellens JH, Beijnen JH. Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Mar 1;887-888:25-34. doi: 10.1016/j.jchromb.2012.01.004. Epub 2012 Jan 20. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Study Phase |
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| Terminal Exponential Half-life (t1/2) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The terminal phase t1/2 is the time required to divide the plasma concentration of study drug by two after reaching pseudo-equilibrium, and not the time required to eliminate half of the administered dose of study drug. The t1/2 during the apparent terminal disposition phase was calculated at 0.693/λz and was summarized as the Geometric Mean (CV%) for all participants and expressed as hours. | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time t (AUC(0-t)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The AUC(0-t) was calculated by the combination of linear/log (from Tmax) trapezoidal rule where 't' is the time of last quantifiable plasma concentration following dosing. AUC(0-t) was summarized as the Geometric Mean (CV%) for all participants and expressed in nanograms·hour/milliliter (ng·hr/mL). | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC(0-inf)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The AUC(0-inf) was calculated as AUC(0-t) + Ct/λz where Ct is the last measurable concentration and was summarized as the Geometric Mean (CV%) for all participants and expressed in ng·hr/mL. | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Percentage of Area Under the Plasma Concentration Curve Extrapolated to Infinity (%AUC(Extra)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. %AUC(extra) was calculated as [(AUC(0-inf) - AUC(0-t)/AUC(0-inf) ]*100 and was summarized as the Geometric Mean (CV%) for all participants and expressed in (ng·hr/mL). | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Apparent Clearance (CL/F) of Lenvatinib From Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The CL/F for parent lenvatinib only was calculated as Dose/[AUC(0-inf)] and was summarized as the Geometric Mean (CV%) for all participants and expressed in L/hr. | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Apparent Terminal Volume of Distribution in the Terminal Phase of Lenvatinib (Vz/F) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Vz/F for lenvatinib only was calculated as Dose/[(λz)·(AUC(0-inf))] and was summarized as the Geometric Mean (CV%) for all participants and expressed in liters (L). | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
| Renal Clearance of Lenvatinib (CLr) | CLr was determined based on the interval amount and cumulative amount of the analyte excreted in the urine divided by its corresponding AUC over the same collection interval. Aeurine(0-t)/AUC(0-t), where t is the last measurable concentration, was calculated for lenvatinib only and was summarized as the Geometric Mean (CV%) for all participants and expressed in L/hr. | Pre-dose, post-dose at 0-6, 6-12, 12-18, 18-24, 24-30, 30-36, 36-42, 42-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours |
| Percentage Recovery of 14^C- Lenvatinib Related Material in the Urine | Urine samples were collected at specific time points, then analyzed for the amount of 14^C- lenvatinib related material. The total radioactive dose of 14^C-lenvatinib excreted in urine (Aeurine%) was calculated from the time of dosing to the last quantifiable measurement. If radioactivity levels were still present at the end of the Study Phase, sampling continued until each sample contained less than 1% of the total radioactive dose. Percentage recovery of 14^C- lenvatinib related material in the urine was summarized as the Geometric Mean (CV%) percent cumulative for all participants and expressed as percent of 14^C- lenvatinib. | Pre-dose, post-dose at 0-6, 6-12, 12-18, 18-24, 24-30, 30-36, 36-42, 42-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours |
| Percentage Recovery of 14^C- Lenvatinib Related Material in the Feces | Fecal samples were collected at specific time points, then analyzed for the amount of 14^C- lenvatinib related material. The percentage of the 14^C- lenvatinib dose excreted in feces (Aefeces%) was calculated from time of dosing to the last quantifiable measurement. If radioactivity levels were still present at the end of the Study Phase, sampling continued until each sample contained less than 1% of the total radioactive dose. Percentage recovery of 14^C- lenvatinib related material in the feces was summarized as the Geometric Mean (CV%) percent cumulative for all participants and expressed as percent of 14^C- lenvatinib. | Day 1 to Day 8 |
| Date of first dose of study treatment till 30 days after the last dose, assessed up to 1 year |
| Objective Tumor Response | A response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) was assigned by the investigator as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. CR was defined as disappearance of all target lesions. Any pathological lymph node had to be reduced in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. PD was defined as a 20% or greater increase in the sum of the longest diameter of measured lesions, taking as reference the smallest sum longest diameter recorded since treatment start or the appearance of one or more new lesions. CR or PR was confirmed no less than 4 weeks after first observation of the response. For SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. SD is defined as lasting at least 5 weeks. | Baseline to first date of documented CR, PR, SD, or PD, assessed up to 1 year |
| COMPLETED |
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| NOT COMPLETED |
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| Extension Phase |
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Safety analysis set included all participants who received at least a partial dose of study drug and had at least one postdose safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for pharmacokinetic (PK) analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
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| Primary | Maximum Plasma Concentration (Cmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Individual blood/plasma concentration-time data were analyzed using 'non-compartmental' analysis. Cmax was determined from visual inspection of the individual blood/plasma concentration-time profile and was summarized as the Geometric Mean and percent coefficient of variation for the Geometric Mean (CV%) for all participants and expressed as nanograms/milliliter (ng/mL). | The Pharmacokinetic (PK) Analysis Set is the group of participants who received the Study Phase dose of 14^C-lenvatinib and have any evaluable post 14^C- lenvatinib dose plasma and/or blood concentration data. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Time of Maximum Plasma Concentration (Tmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Individual blood/plasma concentration-time data were analyzed using 'non-compartmental' analysis. Tmax was determined from visual inspection of the individual blood/plasma concentration-time profile and was summarized as the Geometric Mean (CV%) for all participants and expressed as hours. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Terminal Phase Rate Constant (λz) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The terminal phase rate constant represents the rate at which study drug was eliminated from the body and was determined by log-linear regression of the plasma concentrations against time in the terminal phase and was summarized as the Geometric Mean (CV%) for all participants and expressed as 1/hours. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/hour | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Terminal Exponential Half-life (t1/2) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The terminal phase t1/2 is the time required to divide the plasma concentration of study drug by two after reaching pseudo-equilibrium, and not the time required to eliminate half of the administered dose of study drug. The t1/2 during the apparent terminal disposition phase was calculated at 0.693/λz and was summarized as the Geometric Mean (CV%) for all participants and expressed as hours. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Area Under the Plasma Concentration-Time Curve From Time Zero to Time t (AUC(0-t)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The AUC(0-t) was calculated by the combination of linear/log (from Tmax) trapezoidal rule where 't' is the time of last quantifiable plasma concentration following dosing. AUC(0-t) was summarized as the Geometric Mean (CV%) for all participants and expressed in nanograms·hour/milliliter (ng·hr/mL). | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng·hr/mL | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC(0-inf)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The AUC(0-inf) was calculated as AUC(0-t) + Ct/λz where Ct is the last measurable concentration and was summarized as the Geometric Mean (CV%) for all participants and expressed in ng·hr/mL. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng·hr/mL | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Percentage of Area Under the Plasma Concentration Curve Extrapolated to Infinity (%AUC(Extra)) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. %AUC(extra) was calculated as [(AUC(0-inf) - AUC(0-t)/AUC(0-inf) ]*100 and was summarized as the Geometric Mean (CV%) for all participants and expressed in (ng·hr/mL). | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | Percent lenvatinib | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Apparent Clearance (CL/F) of Lenvatinib From Plasma | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. The CL/F for parent lenvatinib only was calculated as Dose/[AUC(0-inf)] and was summarized as the Geometric Mean (CV%) for all participants and expressed in L/hr. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | L/hour | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Apparent Terminal Volume of Distribution in the Terminal Phase of Lenvatinib (Vz/F) | Blood samples were drawn at specific time points then analyzed for the amount of 14^C-lenvatinib and non-radiolabeled lenvatinib in the plasma. Vz/F for lenvatinib only was calculated as Dose/[(λz)·(AUC(0-inf))] and was summarized as the Geometric Mean (CV%) for all participants and expressed in liters (L). | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | L | Day 1 (pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, 8 and 12 hours), Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours), Day 5 (96 hours), Day 6 (120 hours), Day 7 (144 hours) and Day 8 (168 hours) |
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| Primary | Renal Clearance of Lenvatinib (CLr) | CLr was determined based on the interval amount and cumulative amount of the analyte excreted in the urine divided by its corresponding AUC over the same collection interval. Aeurine(0-t)/AUC(0-t), where t is the last measurable concentration, was calculated for lenvatinib only and was summarized as the Geometric Mean (CV%) for all participants and expressed in L/hr. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | L/hour | Pre-dose, post-dose at 0-6, 6-12, 12-18, 18-24, 24-30, 30-36, 36-42, 42-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours |
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| Primary | Percentage Recovery of 14^C- Lenvatinib Related Material in the Urine | Urine samples were collected at specific time points, then analyzed for the amount of 14^C- lenvatinib related material. The total radioactive dose of 14^C-lenvatinib excreted in urine (Aeurine%) was calculated from the time of dosing to the last quantifiable measurement. If radioactivity levels were still present at the end of the Study Phase, sampling continued until each sample contained less than 1% of the total radioactive dose. Percentage recovery of 14^C- lenvatinib related material in the urine was summarized as the Geometric Mean (CV%) percent cumulative for all participants and expressed as percent of 14^C- lenvatinib. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | Percentage of 14^C-lenvatinib | Pre-dose, post-dose at 0-6, 6-12, 12-18, 18-24, 24-30, 30-36, 36-42, 42-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours |
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| Primary | Percentage Recovery of 14^C- Lenvatinib Related Material in the Feces | Fecal samples were collected at specific time points, then analyzed for the amount of 14^C- lenvatinib related material. The percentage of the 14^C- lenvatinib dose excreted in feces (Aefeces%) was calculated from time of dosing to the last quantifiable measurement. If radioactivity levels were still present at the end of the Study Phase, sampling continued until each sample contained less than 1% of the total radioactive dose. Percentage recovery of 14^C- lenvatinib related material in the feces was summarized as the Geometric Mean (CV%) percent cumulative for all participants and expressed as percent of 14^C- lenvatinib. | PK Analysis Set | Posted | Geometric Mean | Geometric Coefficient of Variation | Percentage of 14^C-lenvatinib | Day 1 to Day 8 |
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| Secondary | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades (for both increasing and decreasing severity) and SAEs; regular monitoring of hematology, blood chemistry, and urine values; results of physical examinations, regular measurement of vital sign measurements, and 12-lead electrocardiogram (ECG), as detailed in the Schedule of Visits and Procedures. The relationship of AEs to treatment was based on investigator judgment. Details of AEs and SAEs are provided in the reported adverse event section. | The Safety Analysis Set was the group of participants who received at least one partial dose of study drug and had at least one postdose safety assessment. | Posted | Number | Percentage of participants | Date of first dose of study treatment till 30 days after the last dose, assessed up to 1 year |
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| Secondary | Objective Tumor Response | A response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) was assigned by the investigator as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. CR was defined as disappearance of all target lesions. Any pathological lymph node had to be reduced in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. PD was defined as a 20% or greater increase in the sum of the longest diameter of measured lesions, taking as reference the smallest sum longest diameter recorded since treatment start or the appearance of one or more new lesions. CR or PR was confirmed no less than 4 weeks after first observation of the response. For SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. SD is defined as lasting at least 5 weeks. | The Response Evaluable Population is the group of participants who received at least a partial dose of study treatment who had measureable disease per RECIST at baseline. | Posted | Number | Percentage of participants | Baseline to first date of documented CR, PR, SD, or PD, assessed up to 1 year |
|
Approximately 17 months.
Treatment-emergent adverse events (TEAEs) were defined as any event with start date/time beyond or equal to the day of initial dosing, and/or any adverse event (AE) for which an increase in severity occurs during the trial. All AEs were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for pharmacokinetic (PK) analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity | 3 | 6 | 6 | 6 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ileus | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Disease progression | General disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Glossodynia | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Ileus | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Oral pain | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Proctalgia | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Rectal haemorrhage | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Disease progression | General disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Feeling cold | General disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Hepatic function abnormal | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Cystitis | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
| |
| Oral candidiasis | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
| |
| Blood pressure increased | Investigations | MedDRA 13.0 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 13.0 | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Proteinuria | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Blister | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eisai Medical Services | Eisai Inc. | 888- |
| ID | Term |
|---|---|
| D008223 | Lymphoma |
| ID | Term |
|---|---|
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C531958 | lenvatinib |
Not provided
Not provided
Not provided
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
|
|
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
|
|
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
|
|
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
|
|
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
|
|
| OG001 | Lenvatinib | Study Phase: Participants received a single dose of an oral dosing solution of 14^C-labeled lenvatinib (approximately 100 μCi or 3.7 MBq) and approximately 24 mg non-radiolabeled lenvatinib on Day 1. From Days 1 to 8, participants remained in the research unit so blood, urine, and fecal samples could be collected for PK analysis and determination of 14^C-lenvatinib concentrations prior to, and for 7 days following, drug administration. Participants were discharged after the checkout procedures were completed on Day 8, or when the level of radiation in urine and fecal samples was less than 1% of the total radioactive dose. Extension Phase: Participants received 24 mg oral lenvatinib once daily at home or at the clinic on Visit Days 1, 8, 15, and 22 of each treatment cycle (1 treatment cycle = 28 days) until discontinuation from the study. The dose of lenvatinib could be reduced or discontinued during any cycle because of toxicity. |
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