Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Bioequivalence Study to Evaluate the Impact of Varying Crystalline Polymorph Forms for the Commercial Oral Capsule Formulation of 10-mg Lenvatinib in Healthy Volunteers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02723630
Recruitment Status : Completed
First Posted : March 30, 2016
Results First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
This will be a randomized, single dose, open-label, three-treatment period crossover study in healthy participants to determine whether 2 test lots of 10-mg capsules that vary by the level of lenvatinib Type-C crystal are bioequivalent to a reference lot of 10-mg capsules.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Lenvatinib 10 mg Phase 1

Detailed Description:
The study will consist of 2 phases: Prerandomization and Randomization. The Prerandomization Phase will have 2 periods: Screening and Baseline. The Randomization Phase will consist of three 6-day long Treatment Periods with each Treatment Period separated by a 1-day long Baseline. Sixty participants will be evenly randomized to 1 of 6 possible treatment sequences (A, B, C, D, E, or F). The 3 treatments vary by the level of crystalline polymorph Type-C present in the drug product batch used in each arm, respectively: Treatment 1 - low Type-C crystal level less than 12%; Treatment 2 - reference Type-C crystal level 12% to 26%; and Treatment 3 - high Type-C crystal level greater than 26%.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Three-treatment, Three-period, Six-sequence Crossover, Single-center, Bioequivalence Study to Evaluate the Impact of Varying Crystalline Polymorph Forms for the Commercial Oral Capsule Formulation of 10-mg Lenvatinib in Healthy Volunteers
Study Start Date : July 2013
Actual Primary Completion Date : August 2013
Actual Study Completion Date : August 2013

Resource links provided by the National Library of Medicine

Drug Information available for: Lenvatinib

Arm Intervention/treatment
Experimental: Sequence A:
Participants will receive one dose of Treatment 1 followed by one dose of Treatment 2, then one dose of Treatment 3
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima

Experimental: Sequence B
Participants will receive one dose of Treatment 2, followed by one dose of Treatment 3, then one dose of Treatment 1
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima

Experimental: Sequence C
Participants will receive one dose of Treatment 3, followed by one dose of Treatment 1, then one dose of Treatment 2
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima

Experimental: Sequence D
Participants will receive one dose of Treatment 3, followed by one dose of Treatment 2, then one dose of Treatment 1
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima

Experimental: Sequence E
Participants will receive one dose of Treatment 1, followed by one dose of Treatment 3, then one dose of Treatment 2
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima

Experimental: Sequence F
Participants will receive one dose of Treatment 2, followed by one dose of Treatment 1, then one dose of Treatment 3
Drug: Lenvatinib 10 mg

Treatment 1: low Type-C crystal level <12%

Treatment 2: reference* Type-C crystal level 12% to 26%

Treatment 3: high Type-C crystal level >26%

Other Name: E7080;Lenvima




Primary Outcome Measures :
  1. Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methodology using a previously validated assay. The lower limit of quantitation (LLOQ) for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. No concentration estimates were provided for missing sample values. Any sample with a missing value was treated as if the sample had not been scheduled for collection.

  2. Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. AUC(0-inf) was calculate as follows; (AUC(0-inf)) = (AUC(0-t)) + (Ct/Kel), where Ct is the last measurable drug concentration and Kel is the elimination rate constant. The apparent first-order Kel was estimated, when possible, from the slope of the regression line for the terminal ln-linear concentration-time values.

  3. Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, and 24 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.


Secondary Outcome Measures :
  1. Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

  2. Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

  3. Time to Cmax (Tmax) for Lenvatinib [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

  4. Terminal Elimination Phase Half-life (t1/2) [ Time Frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose ]
    Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

  5. Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib [ Time Frame: From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 months ]
    Safety assessments consisted of monitoring and recording all adverse events (AEs) (serious and non-serious); regular monitoring of hematology, blood chemistry and urine values; periodic measurement of vital signs and electrocardiograms, performance of physical examinations. A TEAE was defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline), or reemerges during treatment, having been present at pretreatment but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous. TEAEs considered by the investigator to be possibly or probably related to study drug, or TEAEs with missing causality, were included.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy male and female participants age greater than or equal to 18 years and less than or equal to 55 years old
  2. Nonsmokers or smokers who smoke no more than 10 cigarettes per day
  3. BMI greater than or equal to 18 and less than or equal to 32 kg/m2 at Screening
  4. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin)
  5. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
  6. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
  7. Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
  8. Provide written informed consent

Exclusion Criteria:

  1. Clinically significant illness that requires medical treatment within 8 weeks of Screening or a clinically significant infection that requires medical treatment within 4 weeks of dosing
  2. Evidence of disease that may influence the outcome of the study within 4 weeks prior to dosing, e.g., psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism
  3. Any history of GI surgery that may affect pharmacokinetic profiles of lenvatinib e.g., hepatectomy, nephrotomy, digestive organ resection known at Screening or Baseline
  4. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG findings, or laboratory test results that require medical treatment at Screening or Baseline
  5. Blood pressure measurements of greater than 150/90 mm Hg. Confirmation should be obtained by performing three measurements (at least 5 minutes apart) to yield a mean value. Participants may be enrolled if they are on a stable dose of a single antihypertensive drug at least 30 days prior to the first dose of study drug and do not intend to change the dose or drug during the study.
  6. A prolonged QTcF interval (QTcF greater than 450 ms) demonstrated on ECG at Screening or Baseline
  7. Known history of clinically significant drug allergy at Screening or Baseline
  8. Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline or with a known history of sensitivity to any of the components of the test products
  9. Known to be human immunodeficiency virus positive at Screening
  10. Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening
  11. History of drug or alcohol dependency or abuse within the 2 years prior to Screening or a positive urine drug test at Screening or Baseline
  12. Intake of grapefruit or grapefruit-containing beverages or food within 72 hours prior to dosing
  13. Intake of medications known to be strong inhibitors or inducers of CYP450 3A4 metabolizing enzymes within 2 weeks prior to dosing
  14. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent
  15. Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing
  16. Engagement in strenuous exercise within 2 weeks prior to check-in (e.g., marathon runners, weight lifters)
  17. Any condition that would make the participant, in the opinion of the investigator or sponsor unsuitable for the study or not likely to complete the study for any reason

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02723630


Locations
Layout table for location information
United States, Nevada
Las Vegas, Nevada, United States
Sponsors and Collaborators
Eisai Inc.

Layout table for additonal information
Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02723630     History of Changes
Other Study ID Numbers: E7080-A001-008
First Posted: March 30, 2016    Key Record Dates
Results First Posted: March 14, 2019
Last Update Posted: March 14, 2019
Last Verified: March 2018

Keywords provided by Eisai Inc.:
Bioequivalence
Lenvatinib
Healthy Volunteers
Lenvima
E7080

Additional relevant MeSH terms:
Layout table for MeSH terms
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action