Clinical trial NCT02578316: 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.
Official title: An Open-Label, Non-Randomized, Single-Center 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Lymphomas
Keywords: Advanced Solid Tumors
Lymphomas
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2015-10-16
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib
timeFrame: 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: Time of Maximum Plasma Concentration (Tmax) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib
timeFrame: 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: Terminal Phase Rate Constant (λz) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma
timeFrame: 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: Terminal Exponential Half-life (t1/2) of Radiolabeled 14^C-Lenvatinib and Non-Radiolabeled Lenvatinib in Plasma
timeFrame: 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: Area Under the Plasma Concentration-Time Curve From Time Zero to Time t (AUC(0-t))
timeFrame: 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: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC(0-inf))
timeFrame: 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: Percentage of Area Under the Plasma Concentration Curve Extrapolated to Infinity (%AUC(Extra))
timeFrame: 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: Apparent Clearance (CL/F) of Lenvatinib From Plasma
timeFrame: 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: Apparent Terminal Volume of Distribution in the Terminal Phase of Lenvatinib (Vz/F)
timeFrame: 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: Renal Clearance of Lenvatinib (CLr)
timeFrame: 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
measure: Percentage Recovery of 14^C- Lenvatinib Related Material in the Urine
timeFrame: 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
measure: Percentage Recovery of 14^C- Lenvatinib Related Material in the Feces
timeFrame: Day 1 to Day 8
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Date of first dose of study treatment till 30 days after the last dose, assessed up to 1 year
measure: Objective Tumor Response
timeFrame: Baseline to first date of documented CR, PR, SD, or PD, assessed up to 1 year
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
Study officials:
References:
citation: Dubbelman AC, Rosing H, Mejui-Roelvink M, Gupta A, Verbel D, Sellecchia R, et al. A mass balance study of 14C-lenvatinib (E7080) in patients with advanced solid tumours or lymphomas. Presented at the Scientific Meeting of the Dutch Society for Clinical Pharmacology and Biopharmacy (NVKFB); 2012 Mar 30; Utrecht (The Netherlands). 2012. Dubbelman AC, Rosing H, Thijssen B, Gebretensae A, Lucas L, Chen H, et al. Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices. J Chromatogr B, 2012; 887-888:25-34.