Phase 1
Completed N=30
Phase 1 Study to Determine the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam in Subjects With Advanced Solid Tumors
Source: ClinicalTrials.gov NCT02686164 ↗Enrolled (actual)
30
Serious AEs
33.3%
Results posted
Aug 2019
Primary outcomePrimary: AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam — 92.5; 89.7; 117; 38.5 hour*nanograms per milliliter (h*ng/mL)
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam |
92.5; 89.7; 117; 38.5; 48.6; 41.3 | — |
| PRIMARY Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'-Hydroxymidazolam |
26.5; 24.8; 28.3; 11.0; 12.7; 10.7 | — |
| SECONDARY Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |
30; 10 | — |
Eligibility Criteria
Inclusion Criteria
- 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.
- 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.
Exclusion Criteria
- 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 r
Data sourced from ClinicalTrials.gov (NCT02686164). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.