Phase 1 Study to Determine the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam in Subjects With Advanced Solid Tumors

NCT02686164 | Completed Phase 1 Results FDA Drug

• 1 other identifier: E7080-A001-109
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 4

Brief Summary

This is a multicenter, open-label, non-randomized Phase 1 study in participants with advanced solid tumors, excluding hepatocellular carcinoma (HCC), that have progressed after treatment with approved therapies, or for which there are no standard therapies available. The study will also include participants with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Its primary intent is to determine the effect of lenvatinib on CYP3A4 activity as well as to assess the safety and activity of lenvatinib in these participants. The study will be conducted in the following 3 phases: Pretreatment Phase, Treatment Phase, and Extension Phase.

Conditions

Tumors

Keywords

Lenvatinib; Lenvima; E7080; Phase 1; Solid tumors; Midazolam; CYP3A4

Outcome Measures

Primary Outcomes (2)

• AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam

  Cycle 1 Day-3: 0-24 hours; Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 14: 0-24 hours (Duration of each cycle=28 days)

• Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'-Hydroxymidazolam

  Cycle 1 Day-3: 0-24 hours; Cycle 1 Day 1: 0-24 hours; Cycle 1 Day 14: 0-24 hours (Duration of each cycle=28 days)

Secondary Outcomes (1)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  First dose of study drug (Baseline) up to 28 days after last dose of study drug or until resolution, whichever came first (up to approximately 2.5 years)

Study Arms (1)

Lenvatinib + midazolam

EXPERIMENTAL

Participants with histologically confirmed unresectable or refractory solid tumors.

Drug: Lenvatinib; Drug: Midazolam

Interventions

Lenvatinib DRUG

Lenvatinib 24 mg (as one 4 mg and two 10 mg capsules) will be administered orally once daily with 240 mL (8 fluid oz) of water each morning, starting on Cycle 1 Day 1, in 28-day cycles.

Also known as: Lenvima, E7080

Lenvatinib + midazolam

Midazolam DRUG

Midazolam syrup 4 mg will be administered orally after an overnight fast on Cycle 1 Day -3 and concurrently with lenvatinib on Day 1 and Day 14 of Cycle 1. Participants will have to remain fasting for 2 hours after each dose of midazolam.

Lenvatinib + midazolam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to 18 years at the time of informed consent.
• Histologically or cytologically confirmed advanced solid tumors (excluding HCC) that have progressed following standard therapy, or for which no standard therapy exists (including surgery or radiation therapy) or participants with RR-DTC.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Life expectancy greater than or equal to 3 months.
• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Cycle 1 Day 1.
• Adequate renal function defined as calculated creatinine clearance greater than or equal to 30 mL/min per the Cockcroft and Gault formula.
• Adequate bone marrow function:
• Absolute neutrophil count (ANC) greater than or equal to 750/mm3 (greater than or equal to 0.75 X 10\^9/L)
• Platelets greater than or equal to 75,000/mm3 (greater than or equal to 75 X 10\^9/L)
• Hemoglobin greater than or equal to 9.0 g/dL
• Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to 1.5.
• Adequate liver function:
• Total bilirubin less than or equal to 1.5 X the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 X ULN (less than or equal to 5 X ULN if participant has liver metastases). If ALP is greater than 3 X ULN (in the absence of liver metastases) or greater than 5 X ULN (in the presence of liver metastases) AND the participant also is known to have bone metastases, the liver-specific ALP must be separated from the total and used to assess the liver function instead of total ALP.
• All prior therapy related toxicities must have resolved to Grade less than 2 severity per Common Terminology Criteria for Adverse Events (CTCAE version 4.03), except alopecia and infertility.

You may not qualify if:

• Participants with diagnosis of HCC.
• Participants with anaplastic thyroid carcinoma with major blood vessel invasion or infiltration.
• Participants having greater than (\>) 1 plus (+) proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein greater than or equal to (\>=1) gram per 24 hours will be ineligible.
• Participants with known leptomeningeal metastases or untreated brain metastases. Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off steroids for at least 28 days.
• Participants taking medications that are known potent CYP3A4 inducers/inhibitors or substrates with narrow therapeutic indices or St. John's Wort.
• Participants unwilling to exclude grapefruit juice and grapefruit from their diet.
• Participants who have received any anticancer treatment within 3 weeks or any investigational agent within 30 days before the first dose of study drug or who have not recovered from any acute toxicity greater than Grade 0 or 1 related to previous anticancer treatment.
• Major surgery within 4 weeks before the first dose of study drug.
• Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of lenvatinib or midazolam.
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation).
• A clinically significant electrocardiogram (ECG) abnormality (ie, corrected QT interval \[QTc\] interval greater than 480 msec when electrolyte balance is normal), or a history of risk factors for torsade de pointes, hypokalemia, long QT syndrome, or the use of concomitant medications resulting in a prolongation of QTc interval.
• Active hemoptysis (bright red blood of at least 2.5 mL ie, half teaspoon) within 3 weeks prior to the first dose of study drug.
• Active infection (any infection requiring treatment).
• Known hypersensitivity to any component of lenvatinib or midazolam.
• Prior treatment with lenvatinib.

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (4)

Facility # 1

Detroit, Michigan, United States

Location

Facility # 1

The Bronx, New York, United States

Location

Facility # 1

Philadelphia, Pennsylvania, United States

Location

Facility # 1

San Antonio, Texas, United States

Location

Related Publications (1)

• Shumaker R, Ren M, Aluri J, Dutcus CE, Rance C, He C. An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors. Eur J Drug Metab Pharmacokinet. 2020 Jun;45(3):373-383. doi: 10.1007/s13318-020-00607-7.

  PMID: 32067158 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

lenvatinib; Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2016
• First Posted: February 19, 2016
• Study Start: April 18, 2016
• Primary Completion: January 4, 2017
• Study Completion: August 16, 2018
• Last Updated: August 28, 2019
• Results First Posted: August 28, 2019

Record last verified: 2018-01

Locations

US (4)