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 Overview
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Brief Summary
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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.

Detailed Description
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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%.

Official Title
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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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Lenvatinib 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female participants age greater than or equal to 18 years and less than or equal to 55 years old Nonsmokers or smokers who smoke no more than 10 cigarettes per day BMI greater than or equal to 18 and less than or equal to 32 kg/m2 at Screening Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin) 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) 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. 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. Provide written informed consent Exclusion Criteria: 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 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 Any history of GI surgery that may affect pharmacokinetic profiles of lenvatinib e.g., hepatectomy, nephrotomy, digestive organ resection known at Screening or Baseline 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 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. A prolonged QTcF interval (QTcF greater than 450 ms) demonstrated on ECG at Screening or Baseline Known history of clinically significant drug allergy at Screening or Baseline 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 Known to be human immunodeficiency virus positive at Screening Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening 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 Intake of grapefruit or grapefruit-containing beverages or food within 72 hours prior to dosing Intake of medications known to be strong inhibitors or inducers of CYP450 3A4 metabolizing enzymes within 2 weeks prior to dosing Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing Engagement in strenuous exercise within 2 weeks prior to check-in (e.g., marathon runners, weight lifters) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A:<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|
| Experimental: Sequence B<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|
| Experimental: Sequence C<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|
| Experimental: Sequence D<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|
| Experimental: Sequence E<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|
| Experimental: Sequence F<br>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<br>* 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%<br>* Other names: E7080;Lenvima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | 
| Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) | 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. | Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. | 
| Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, and 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours postdose | 
| Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | 
| Time to Cmax (Tmax) for Lenvatinib | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | 
| Terminal Elimination Phase Half-life (t1/2) | 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. | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | 
| 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 | 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. | From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lenvima, Bioequivalence, Lenvatinib, Healthy Volunteers, E7080