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TumorsPhase 1NCT02686164

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

A Phase 1 study testing Lenvatinib and Midazolam in people with Tumors, run by Eisai Inc. at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tumors
What is being tested?
Lenvatinib and Midazolam
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
51 participants
Where
4 sitesUnited States
Study dates
18 Apr 2016to 16 Aug 2018
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • Participants with Hepatitis B or C are eligible on the condition that they have adequate liver function as defined by Inclusion Criterion 9.
  • 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.
  • Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gated acquisition (MUGA) scan.
  • Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of B-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
  • Participant must voluntarily agree to provide written informed consent.
  • Participant must be willing and able to comply with all aspects of the protocol.

Who cannot join

  • 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.
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  • 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.
  • Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks before study drug administration.
  • Immunocompromised participants, including participants known to be infected with human immunodeficiency virus (HIV).
  • Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the participant's participation in this study.
  • Participants who meet any of the following criteria will be excluded from this study:
  • Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 international units per liter (IU/L) or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
  • OR Females of childbearing potential who do not agree to use a highly effective method of contraception for the entire study period and for 28 days after study drug discontinuation i.e. i) total abstinence (if it is their preferred and usual lifestyle) ii) an intrauterine device (IUD) or hormone releasing system (IUS) iii) a contraceptive implant iv. an oral contraceptive (with additional barrier method) OR who do not have a vasectomized partner with confirmed azoospermia. For sites outside of the European Union (EU), it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, i.e. double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. 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]

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Facility # 1

    Detroit, Michigan

  • Facility # 1

    Philadelphia, Pennsylvania

  • Facility # 1

    San Antonio, Texas

  • Facility # 1

    The Bronx, New York

Other trials in United States

About this study

Official title: An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Subjects With Advanced Solid Tumors

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
Being tested
Lenvatinib, Midazolam
Keywords
Lenvatinib, Lenvima, E7080, Phase 1, Solid tumors, Midazolam, CYP3A4
Medical subject headings
Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LenvatinibDrug

    Also called Lenvima, E7080

    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.

  • MidazolamDrug

    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.

Study groups in NCT02686164
Study groupRoleWhat they receive
Lenvatinib + midazolamExperimentalParticipants with histologically confirmed unresectable or refractory solid tumors.
Receives: Drug: Lenvatinib; Drug: Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 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)

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

    Measured: 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)

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

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Feb 2016 (estimated)
  2. Study start18 Apr 2016
  3. Primary completion4 Jan 2017
  4. Study completion16 Aug 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
51 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02686164
Sponsor's protocol ID
E7080-A001-109
Status last verified
Jan 2018
First submitted
12 Feb 2016
Last updated
28 Aug 2019
FDA-regulated drug
Yes

Publications

  • 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.

    PubMed 32067158

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Lenvatinib and Midazolam in people with Tumors, run by Eisai Inc. at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam (time frame: 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02686164, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2019.

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