A Study to Determine the Metabolism and Elimination of 14C-E7080 in Patients With Advanced Solid Tumors or Lymphomas, Who Are Unsuitable For, or Have Failed, Existing Therapies.

Eisai Inc.6 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Solid Tumors Lymphomas

Interventions

LenvatinibDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

INCLUSION CRITERIA 1. Participants with histologically and/or cytologically confirmed solid tumor or lymphoma who were resistant/ refractory to approved therapies or for whom no appropriate therapies were available. Participants with measurable tumors according to RECIST were desirable but not essential for inclusion. 2. All previous treatment (including surgery and radiotherapy) must have been completed at least four weeks prior to study entry and any acute toxicity must have resolved 3. Aged greater than or equal to 18 years 4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 5. Could take oral study medication 6. Gave written informed consent to participate in the study 7. Willing and complied with the study protocol for the duration of the study. EXCLUSION CRITERIA 1. 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. 2. Participants with meningeal carcinomatosis 3. Any of the following values for laboratory parameters: 1. hemoglobin less than 9 g/dL (5.6 mmol/L); 2. neutrophils less than 1.5 x 10\^9/L; 3. platelets less than 100 x 10\^9/L; 4. Prothrombin time (PT) \[or International Normalized Ratio (INR)\] and Patial thromboplastin time (PTT) \> 1.5 x the upper limit of normal (ULN) 5. serum bilirubin greater than 1.5 x ULN 6. other liver parameters greater than 3 x ULN 7. creatinine clearance less than 60 mL/min per the Cockcroft and Gault formula 4. Uncontrolled infections 5. 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) 6. 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 7. Any treatment with an investigational drug within the last 30 days 8. 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. 9. Proteinuria greater than 1+ on bedside testing 10. History of gastrointestinal malabsorption 11. Surgery within four weeks of start of study treatment 12. 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. 13. 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 14. Previous lenvatinib therapy 15. History of alcoholism, drug addiction, psychiatric or psychological condition, or social situation which, in the opinion of the investigator, would impair study compliance 16. History of allergic reactions attributed to compounds of similar chemical or biological composition to lenvatinib 17. Other significant disease or disorder that, in the Investigator's opinion, would exclude the participant from the study 18. Legal incapacity

Locations (1)

Unnamed facility

Amsterdam, Netherlands

Outcomes

Primary Outcomes

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).

Time frame: 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.

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: Baseline to first date of documented CR, PR, SD, or PD, assessed up to 1 year