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.

Advanced Solid Tumors Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02578316
• Other study ID #: E7080-E044-104
• Status: Completed
• Phase: Phase 1
• First received: October 15, 2015
• Last updated: December 10, 2015
• Start date: June 2009
• Est. completion date: October 2010

Study information

• Verified date: November 2015
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: October 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Lymphoma
• Lymphomas

Intervention

Drug:
• Lenvatinib
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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum plasma concentration (Cmax) of radiolabeled 14C-lenvatinib and lenvatinib		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Time of maximum plasma concentration (tmax) of radiolabeled 14C-lenvatinib and lenvatinib		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Terminal phase rate constant of radiolabeled 14C-lenvatinib and lenvatinib in plasma		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Terminal half-life of radiolabeled 14C-lenvatinib and lenvatinib in plasma		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Area under the plasma concentration-time curve from time zero to time t (AUC 0-t)		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Area under the plasma concentration-time curve from time zero to infinity (AUC 0-inf)		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Percentage of area under the plasma concentration curve extrapolated to infinity (%AUC extra)		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Apparent clearance of lenvatinib (CL/F)		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Apparent volume of distribution in the terminal phase of lenvatinib (Vz/F)		Day 1 (pre-dose, post-dose at 15 and 30 mins, 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)	No
Primary	Renal Clearance of lenvatinib (CLR)		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 hrs	No
Primary	Percentage recovery of 14C- lenvatinib related material in the urine		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 hrs	No
Primary	Percentage recovery of 14C- lenvatinib related material in the feces		Day 1 to Day 8	No
Secondary	Number of participants with Adverse Events (AEs)/Serious Adverse Events (SAEs)		For each participant, from the first patient first dose till 30 days after the last dose up to approximately 17 months	Yes
Secondary	Objective tumor response	Tumor assessments will be performed in accordance with Response Evaluation Criteria in Solid Tumors (RECIST)	Within 21 days from baseline (enrollment), repeated between Day 21 and Day 28 and at study termination visit or up to approximately 17 months	No