Healthy
Conditions
Brief summary
The main purpose of this study is to assess the effect of Selpercatinib (LY3527723) on the heart rate-corrected QT (QTc) interval. The study will last up to 41 days.
Interventions
DRUGSelpercatinib
Administered orally
DRUGMoxifloxacin
Administered orally
DRUGPlacebo
Administered orally.
Sponsors
Loxo Oncology, Inc.
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, adult, non-smoking, male or female (of non childbearing potential only or undergone sterilization procedures at least 6 months prior to the Screening) with no ECG abnormalities. * Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kilograms per meter squared (kg/m²) at Screening and have a minimum weight of at least 50 kg at Screening * Female of non childbearing potential: must have undergone sterilization procedures at least 6 months prior to the Screening * Males who are capable of fathering a child must agree to use contraception from the time of the dose administration through 6 months after the last dose
Exclusion criteria
* Estimated creatinine clearance \<90 milliliter per minute (mL/min) at Screening or Check in (Day -1; rechecks will be permitted up to two times to confirm participant eligibility for study participation). * Has serum potassium levels \<3.8 milliequivalents per liter (mEq/L) at Screening or Check in (Day -1; rechecks will be permitted up to two times to confirm participant eligibility for study participation). * Has serum calcium levels \< 8.5 milligrams/deciliter (mg/dL) at Screening or Check in (Day -1; rechecks will be permitted up to two times to confirm participant eligibility for study participation). * Has serum magnesium levels \<2.0 mEq/L at Screening or Check in (Day -1; rechecks will be permitted up to two times to confirm participant eligibility for study participation)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiodynamics: Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) for Treatments A, B, and C | Pre-dose, -0.25, -0.5, -0.25, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect |
| Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to the Time of the Last Observed Non-zero Concentration (AUC0-t) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: AUC0-t of Selpercatinib is reported. |
| PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: AUC0-inf of Selpercatinib is reported. |
| PK: Percent of AUC0-inf Extrapolated (AUC%Extrap) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: AUC%extrap of Selpercatinib is reported. |
| PK: Maximum Observed Concentration (Cmax) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: Cmax of Selpercatinib is reported. |
| PK: Time to Reach Cmax (Tmax) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: Tmax of Selpercatinib is reported. |
| PK: Apparent First Order Terminal Elimination Rate Constant (Kel) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: Kel of Selpercatinib is reported. |
| PK: Apparent First-order Terminal Elimination Half-life (t½) of Selpercatinib | Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose | PK: t½ of Selpercatinib is reported. |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized to 4 treatment sequences (ABCD, BDAC, CADB, and DCBA), with each sequence having 4 periods where participants were crossed over between the periods. There was a washout period of 10 days between dosing in each period.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence 1: ABCD Period 1: 320 mg Selpercatinib and Selpercatinib matching placebo (Treatment A)
Period 2: 640 mg Selpercatinib (Treatment B)
Period 3: 400 mg moxifloxacin (Treatment C)
Period 4: Selpercatinib matching placebo (Treatment D)
Participants received their assigned treatments in each of the above treatment period on Day 1 orally. | 8 |
| Treatment Sequence 2: BDAC Period 1: 640 mg Selpercatinib (Treatment B)
Period 2: Selpercatinib matching placebo (Treatment D)
Period 3: 320 mg Selpercatinib and Selpercatinib matching placebo (Treatment A)
Period 4: 400 mg moxifloxacin (Treatment C)
Participants received their assigned treatments in each of the above treatment period on Day 1 orally. | 8 |
| Treatment Sequence 3: CADB Period 1: 400 mg moxifloxacin (Treatment C)
Period 2: Selpercatinib matching placebo (Treatment D)
Period 3: 320 mg Selpercatinib and Selpercatinib matching placebo (Treatment A)
Period 4: 640 mg Selpercatinib (Treatment B)
Participants received their assigned treatments in each of the above treatment period on Day 1 orally. | 8 |
| Treatment Sequence 4: DCBA Period 1: Selpercatinib matching placebo (Treatment D)
Period 2: 400 mg moxifloxacin (Treatment C)
Period 3: 640 mg Selpercatinib (Treatment B)
Period 4: 320 mg Selpercatinib and Selpercatinib matching placebo (Treatment A)
Participants received their assigned treatments in each of the above treatment period on Day 1 orally. | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | Treatment Sequence 1: ABCD | Total | Treatment Sequence 4: DCBA | Treatment Sequence 3: CADB | Treatment Sequence 2: BDAC |
|---|---|---|---|---|---|
| Age, Continuous | 35.0 years STANDARD_DEVIATION 11.44 | 40.5 years STANDARD_DEVIATION 10.02 | 10.18 years STANDARD_DEVIATION 10.18 | 44.0 years STANDARD_DEVIATION 8.88 | 40.3 years STANDARD_DEVIATION 8.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 14 Participants | 4 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 18 Participants | 4 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 25 Participants | 8 Participants | 6 Participants | 6 Participants |
| Region of Enrollment United States | 8 Participants | 32 Participants | 8 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Female | 7 Participants | 26 Participants | 5 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 3 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 32 | 0 / 32 | 0 / 32 |
| other Total, other adverse events | 6 / 32 | 2 / 32 | 0 / 32 | 4 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 32 | 0 / 32 | 0 / 32 |
Outcome results
Primary
Cardiodynamics: Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) for Treatments A, B, and C
The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect
Time frame: Pre-dose, -0.25, -0.5, -0.25, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, and 24 hours post-dose
Population: All randomized participants who received at least one dose of selpercatinib or moxifloxacin with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 320 mg Selpercatinib (Treatment A) | Cardiodynamics: Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) for Treatments A, B, and C | 3.4 milliseconds |
| 640 mg Selpercatnib (Treatment B) | Cardiodynamics: Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) for Treatments A, B, and C | 4.4 milliseconds |
| 400 mg Moxifloxacin (Treatment C) | Cardiodynamics: Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) for Treatments A, B, and C | 6.4 milliseconds |
Primary
Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to the Time of the Last Observed Non-zero Concentration (AUC0-t) of Selpercatinib
PK: AUC0-t of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to the Time of the Last Observed Non-zero Concentration (AUC0-t) of Selpercatinib | 33730 nanogram*hour per millilitre (ng*h/mL) | Geometric Coefficient of Variation 42.3 |
| 640 mg Selpercatnib (Treatment B) | Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 to the Time of the Last Observed Non-zero Concentration (AUC0-t) of Selpercatinib | 42670 nanogram*hour per millilitre (ng*h/mL) | Geometric Coefficient of Variation 65.8 |
Primary
PK: Apparent First-order Terminal Elimination Half-life (t½) of Selpercatinib
PK: t½ of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Apparent First-order Terminal Elimination Half-life (t½) of Selpercatinib | 31.189 hour | Standard Deviation 11.6988 |
| 640 mg Selpercatnib (Treatment B) | PK: Apparent First-order Terminal Elimination Half-life (t½) of Selpercatinib | 30.582 hour | Standard Deviation 9.2791 |
Primary
PK: Apparent First Order Terminal Elimination Rate Constant (Kel) of Selpercatinib
PK: Kel of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Apparent First Order Terminal Elimination Rate Constant (Kel) of Selpercatinib | 0.02515 1/hour | Standard Deviation 0.0087987 |
| 640 mg Selpercatnib (Treatment B) | PK: Apparent First Order Terminal Elimination Rate Constant (Kel) of Selpercatinib | 0.02459 1/hour | Standard Deviation 0.0070524 |
Primary
PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selpercatinib
PK: AUC0-inf of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selpercatinib | 33830 ng*hr/mL | Geometric Coefficient of Variation 42.3 |
| 640 mg Selpercatnib (Treatment B) | PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selpercatinib | 42830 ng*hr/mL | Geometric Coefficient of Variation 65.7 |
Primary
PK: Maximum Observed Concentration (Cmax) of Selpercatinib
PK: Cmax of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Maximum Observed Concentration (Cmax) of Selpercatinib | 2024 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 74.6 |
| 640 mg Selpercatnib (Treatment B) | PK: Maximum Observed Concentration (Cmax) of Selpercatinib | 2356 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 103 |
Primary
PK: Percent of AUC0-inf Extrapolated (AUC%Extrap) of Selpercatinib
PK: AUC%extrap of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Percent of AUC0-inf Extrapolated (AUC%Extrap) of Selpercatinib | 0.2986 percentage of AUC0-inf extrapolated | Standard Deviation 0.21464 |
| 640 mg Selpercatnib (Treatment B) | PK: Percent of AUC0-inf Extrapolated (AUC%Extrap) of Selpercatinib | 0.3734 percentage of AUC0-inf extrapolated | Standard Deviation 0.535 |
Primary
PK: Time to Reach Cmax (Tmax) of Selpercatinib
PK: Tmax of Selpercatinib is reported.
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.5, 2, 2.5, 3, 4, 7, 9, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose
Population: All randomized participants who received at least one dose of selpercatinib and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 320 mg Selpercatinib (Treatment A) | PK: Time to Reach Cmax (Tmax) of Selpercatinib | 1.557 hour |
| 640 mg Selpercatnib (Treatment B) | PK: Time to Reach Cmax (Tmax) of Selpercatinib | 2.051 hour |