Trial Outcomes & Findings for Phase 1 Study to Determine the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam in Subjects With Advanced Solid Tumors (NCT NCT02686164)
NCT ID: NCT02686164
Last Updated: 2019-08-28
Results Overview
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
51 participants
Primary outcome timeframe
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)
Results posted on
2019-08-28
Participant Flow
Participants took part in the study at 4 investigative sites in the United States from 18 Apr 2016 to 16 Aug 2018.
A total of 51 participants were screened and enrolled, of which 21 were screen failures and 30 participants received the study treatment.
Participant milestones
| Measure |
Midazolam + Lenvatinib
Participants received midazolam 4 milligram (mg) (2 milliliter \[mL\]) syrup, orally, once daily (QD), after an overnight fast on Day -3, Day 1 and Day 14 of Cycle 1 and lenvatinib 24 mg capsules, orally, QD, on each morning, continuously for 28 days of Cycle 1, starting on Day 1 of Cycle 1. Participants continued to fast for 2 hours postdose of midazolam. Duration of each cycle equal to (=) 28 days.
|
|---|---|
|
Overall Study
STARTED
|
30
|
|
Overall Study
COMPLETED
|
27
|
|
Overall Study
NOT COMPLETED
|
3
|
Reasons for withdrawal
| Measure |
Midazolam + Lenvatinib
Participants received midazolam 4 milligram (mg) (2 milliliter \[mL\]) syrup, orally, once daily (QD), after an overnight fast on Day -3, Day 1 and Day 14 of Cycle 1 and lenvatinib 24 mg capsules, orally, QD, on each morning, continuously for 28 days of Cycle 1, starting on Day 1 of Cycle 1. Participants continued to fast for 2 hours postdose of midazolam. Duration of each cycle equal to (=) 28 days.
|
|---|---|
|
Overall Study
Adverse Event
|
1
|
|
Overall Study
Withdrawal of consent
|
1
|
|
Overall Study
Clinical progression
|
1
|
Baseline Characteristics
Phase 1 Study to Determine the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam in Subjects With Advanced Solid Tumors
Baseline characteristics by cohort
| Measure |
Midazolam + Lenvatinib
n=30 Participants
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day -3, Day 1 and Day 14 of Cycle 1 and lenvatinib 24 mg capsules, orally, QD, on each morning, continuously for 28 days of Cycle 1, starting on Day 1 of Cycle 1. Participants continued to fast for 2 hours postdose of midazolam. Duration of each cycle = 28 days.
|
|---|---|
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Age, Continuous
|
59.4 years
STANDARD_DEVIATION 12.66 • n=5 Participants
|
|
Sex: Female, Male
Female
|
15 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
15 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
6 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
24 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
5 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
19 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
5 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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)Population: Pharmacokinetic (PK) analysis set included participants who had sufficient PK data to derive at least 1 PK parameter. Here number analyzed "n" are the participants who were evaluable for this outcome measure for given categories.
Outcome measures
| Measure |
Cycle 1 Day -3: Midazolam
n=29 Participants
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day-3 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 1: Lenvatinib + Midazolam
n=29 Participants
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 1 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 14: Lenvatinib + Midazolam
n=29 Participants
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 14 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
|---|---|---|---|
|
AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam
Midazolam
|
92.5 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 34.5
|
89.7 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 42.0
|
117 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 61.1
|
|
AUC(0-24): Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose for Midazolam and 1'-Hydroxymidazolam
1'-hydroxymidazolam
|
38.5 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 26.5
|
48.6 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 47.8
|
41.3 hour*nanograms per milliliter (h*ng/mL)
Standard Deviation 34.3
|
PRIMARY outcome
Timeframe: 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)Population: PK analysis set included participants who had sufficient PK data to derive at least 1 PK parameter. Here number analyzed "n" are the participants who were evaluable for this outcome measure for given categories.
Outcome measures
| Measure |
Cycle 1 Day -3: Midazolam
n=29 Participants
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day-3 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 1: Lenvatinib + Midazolam
n=29 Participants
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 1 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 14: Lenvatinib + Midazolam
n=29 Participants
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 14 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
|---|---|---|---|
|
Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'-Hydroxymidazolam
Midazolam
|
26.5 nanogram per milliliter (ng/mL)
Standard Deviation 10.7
|
24.8 nanogram per milliliter (ng/mL)
Standard Deviation 17.4
|
28.3 nanogram per milliliter (ng/mL)
Standard Deviation 13.9
|
|
Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'-Hydroxymidazolam
1'-hydroxy midazolam
|
11.0 nanogram per milliliter (ng/mL)
Standard Deviation 8.64
|
12.7 nanogram per milliliter (ng/mL)
Standard Deviation 11.6
|
10.7 nanogram per milliliter (ng/mL)
Standard Deviation 11.6
|
SECONDARY outcome
Timeframe: 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)Population: Safety analysis set included participants who received at least 1 dose of midazolam or lenvatinib and had at least 1 postdose safety assessment.
Outcome measures
| Measure |
Cycle 1 Day -3: Midazolam
n=30 Participants
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day-3 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 1: Lenvatinib + Midazolam
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 1 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
Cycle 1 Day 14: Lenvatinib + Midazolam
Participants received lenvatinib 24 mg capsules, orally, QD, in the morning and midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day 14 of Cycle 1. Participants continued to fast for 2 hours post dose of midazolam.
|
|---|---|---|---|
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Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAEs
|
30 participants
|
—
|
—
|
|
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
SAEs
|
10 participants
|
—
|
—
|
Adverse Events
Midazolam + Lenvatinib
Serious events: 10 serious events
Other events: 28 other events
Deaths: 1 deaths
Serious adverse events
| Measure |
Midazolam + Lenvatinib
n=30 participants at risk
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day -3, Day 1 and Day 14 of Cycle 1 and lenvatinib 24 mg capsules, orally, QD, on each morning, continuously for 28 days of Cycle 1, starting on Day 1 of Cycle 1. Participants continued to fast for 2 hours postdose of midazolam. Duration of each cycle = 28 days.
|
|---|---|
|
Cardiac disorders
Bradycardia
|
3.3%
1/30 • 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)
|
|
Cardiac disorders
Stress cardiomyopathy
|
3.3%
1/30 • 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)
|
|
Gastrointestinal disorders
Abdominal pain
|
6.7%
2/30 • 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)
|
|
Gastrointestinal disorders
Abdominal pain upper
|
3.3%
1/30 • 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)
|
|
Gastrointestinal disorders
Intestinal obstruction
|
3.3%
1/30 • 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)
|
|
Gastrointestinal disorders
Rectal haemorrhage
|
3.3%
1/30 • 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)
|
|
General disorders
Asthenia
|
3.3%
1/30 • 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)
|
|
General disorders
Pyrexia
|
3.3%
1/30 • 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)
|
|
Nervous system disorders
Cerebral haemorrhage
|
3.3%
1/30 • 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)
|
|
Reproductive system and breast disorders
Breast discharge
|
3.3%
1/30 • 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)
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
3.3%
1/30 • 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)
|
|
Vascular disorders
Hypertension
|
10.0%
3/30 • 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)
|
Other adverse events
| Measure |
Midazolam + Lenvatinib
n=30 participants at risk
Participants received midazolam 4 mg (2 mL) syrup, orally, QD, after an overnight fast on Day -3, Day 1 and Day 14 of Cycle 1 and lenvatinib 24 mg capsules, orally, QD, on each morning, continuously for 28 days of Cycle 1, starting on Day 1 of Cycle 1. Participants continued to fast for 2 hours postdose of midazolam. Duration of each cycle = 28 days.
|
|---|---|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
13.3%
4/30 • 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)
|
|
Endocrine disorders
Hypothyroidism
|
30.0%
9/30 • 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)
|
|
Gastrointestinal disorders
Abdominal pain
|
13.3%
4/30 • 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)
|
|
Gastrointestinal disorders
Constipation
|
16.7%
5/30 • 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)
|
|
Gastrointestinal disorders
Diarrhoea
|
33.3%
10/30 • 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)
|
|
Gastrointestinal disorders
Dyspepsia
|
6.7%
2/30 • 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)
|
|
Gastrointestinal disorders
Nausea
|
33.3%
10/30 • 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)
|
|
Gastrointestinal disorders
Stomatitis
|
10.0%
3/30 • 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)
|
|
Gastrointestinal disorders
Vomiting
|
23.3%
7/30 • 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)
|
|
General disorders
Asthenia
|
16.7%
5/30 • 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)
|
|
General disorders
Chills
|
10.0%
3/30 • 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)
|
|
General disorders
Fatigue
|
43.3%
13/30 • 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)
|
|
General disorders
Oedema peripheral
|
13.3%
4/30 • 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)
|
|
Infections and infestations
Urinary tract infection
|
6.7%
2/30 • 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)
|
|
Investigations
Blood creatinine increased
|
10.0%
3/30 • 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)
|
|
Investigations
Weight decreased
|
13.3%
4/30 • 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)
|
|
Metabolism and nutrition disorders
Decreased appetite
|
23.3%
7/30 • 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)
|
|
Metabolism and nutrition disorders
Hyperglycaemia
|
6.7%
2/30 • 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)
|
|
Metabolism and nutrition disorders
Hypertriglyceridaemia
|
6.7%
2/30 • 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)
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
13.3%
4/30 • 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)
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
6.7%
2/30 • 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)
|
|
Musculoskeletal and connective tissue disorders
Muscular weakness
|
10.0%
3/30 • 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)
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place