Neoplasm Metastasis
Conditions
Brief summary
This study is known as a drug interaction study and is being done to see how abemaciclib may affect the blood levels of a drug mixture of commonly used drugs (caffeine, warfarin, dextromethorphan, and midazolam) when taken in combination with abemaciclib. Each participant will complete screening and four study periods in a fixed sequence, with the option to continue to receive abemaciclib in a safety extension phase. All participants will complete a safety follow-up.
Interventions
DRUGDrug Cocktail
Administered orally
DRUGAbemaciclib
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic * Have adequate organ function * Have a performance status of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale * Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug and have recovered from the acute effects of therapy(treatment related toxicity resolved to baseline), except for residual alopecia
Exclusion criteria
* Require treatment with inducers or inhibitors of cytochrome P450 (CYP)1A2, CYP2C9, CYP2D6, and CYP3A within 14 days before the first dose of study drug through the end of Period 2 * History or presence of significant bleeding disorders * Have known active uncontrolled or symptomatic CNS metastases * Have a primary liver tumor * Have lymphoma or leukemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Midazolam | Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hr Postdose | PK: AUC (zero to infinity) of midazolam after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Maximum Concentration (Cmax) of Midazolam | Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hr Postdose | Maximum concentration of midazolam after single dose of drug cocktail on Day 1 of Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Caffeine | Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hr Postdose | PK: AUC zero to infinity of caffeine after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of S-Warfarin | Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hr Postdose | AUC (zero to infinity) of S-warfarin after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Dextromethorphan | Days 1 and 8: 1, 2, 4, 6, 8, 10, 24, 48, 72 hr Postdose | PK: AUC (zero to infinity) of dextromethorphan after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Maximum Concentration (Cmax) of Caffeine | Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours (hr) Postdose | Maximum concentration of caffeine after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Maximum Concentration (Cmax) S-Warfarin | Days 1 and 8: Predose, 0.5 1, 2, 3, 4, 6, 8, 12, 48, 72, 96 hr Postdose | Maximum concentration of S-warfarin after single dose of drug cocktail on Day 1 in Period 1and in combination with Abemaciclib on Day 8 in Period 2. |
| Pharmacokinetics: Maximum Concentration (Cmax) of Dextromethorphan | Days 1 and 8: Predose, 1, 2, 4, 6, 8, 10, 24, 48, 72 hr postdose | Maximum concentration of dextromethorphan after single dose of drug cocktail on Day 1 of Period 1 and in combination with Abemaciclib on Day 8 in Period 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline at 24 Hours in Pulse Rate in Period 1 | Day 8: Baseline, 24 h postdose | Mean change from baseline in pulse rate over 24 hours (h) postdose following single dose drug cocktail in Period 1. |
| Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2 | Day 1: Baseline, 24 h postdose | Mean change from baseline in systolic and diastolic blood pressure (BP) over 24 hours (h) postdose following single dose of abemaciclib in Period 2, Day 1. |
| Mean Change From Baseline at 24 Hours in Pulse Rate in Period 2 | Day 1: Baseline, 24 h postdose | Mean change from baseline in pulse rate over 24 hours (h) postdose following single dose drug cocktail in Period 2, Day 1. |
| Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 1 | Day 8: Baseline, 24 h postdose | Mean change from predose in systolic and diastolic blood pressure (BP) over 24 hours (h) postdose following single dose drug cocktail in Period 1. |
Countries
United States
Participant flow
Recruitment details
Abemaciclib dose adjustments were allowed due to drug-related toxicity. Before the start of each cycle, drug-related toxicities must have resolved to either baseline or at least Grade 2. Participants not recovered from toxicities within 14 days were discontinued from the study. For Period 2, if abemaciclib dose adjustments occurred, dosing with the drug cocktail was permitted to be delayed to allow for adequate exposure.
Participants by arm
| Arm | Count |
|---|---|
| Overall A single dose of drug cocktail was administered on Day 1 of Period 1. Abemaciclib 200 mg was administered Q12H starting on Day 1 of Period 2 with coadministration of drug cocktail on Day 8. Participants continued to receive 200 mg abemaciclib (or modified dose as required) Q12H up to 16 days in Period 3 and up to 28 days in Period 4. Participants could participate in a safety extension phase in which they received 200 mg abemaciclib (or modified dose as required) Q12H until discontinuation criteria are met. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Abemaciclib Days 13 to 28 - Period 3 | Physician Decision | 0 | 0 | 7 | 0 | 0 |
| Abemaciclib Days 13 to 28 - Period 3 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
| Abemaciclib Days 1 to 28 - Period 4 | Physician Decision | 0 | 0 | 0 | 7 | 0 |
| Abemaciclib Days 1 to 28 - Period 4 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
| Abemaciclib + Drug Cocktail - Period 2 | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Abemaciclib + Drug Cocktail - Period 2 | Death | 0 | 1 | 0 | 0 | 0 |
| Abemaciclib + Drug Cocktail - Period 2 | Physician Decision | 0 | 2 | 0 | 0 | 0 |
| Abemaciclib + Drug Cocktail - Period 2 | Withdrawal by Subject | 0 | 3 | 0 | 0 | 0 |
| Abemaciclib Safety Extension Period | Met Discontinuation Criteria | 0 | 0 | 0 | 0 | 18 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 44 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 44 | 0 / 42 | 0 / 35 | 0 / 28 | 0 / 18 |
| other Total, other adverse events | 22 / 44 | 33 / 42 | 26 / 35 | 25 / 28 | 16 / 18 |
| serious Total, serious adverse events | 1 / 44 | 3 / 42 | 2 / 35 | 6 / 28 | 2 / 18 |
Outcome results
Primary
Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Caffeine
PK: AUC zero to infinity of caffeine after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hr Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Caffeine | 32500 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 72 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Caffeine | 47100 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 89 |
90% CI: [1.35, 1.81]
Primary
Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Dextromethorphan
PK: AUC (zero to infinity) of dextromethorphan after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: 1, 2, 4, 6, 8, 10, 24, 48, 72 hr Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Dextromethorphan | 32.6 ng*h/mL | Geometric Coefficient of Variation 316 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Dextromethorphan | 32.1 ng*h/mL | Geometric Coefficient of Variation 238 |
90% CI: [0.805, 1.18]
Primary
Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Midazolam
PK: AUC (zero to infinity) of midazolam after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hr Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Midazolam | 7.34 ng*h/mL | Geometric Coefficient of Variation 74 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of Midazolam | 6.03 ng*h/mL | Geometric Coefficient of Variation 63 |
90% CI: [0.775, 0.972]
Primary
Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of S-Warfarin
AUC (zero to infinity) of S-warfarin after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hr Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of S-Warfarin | 21400 ng*h/mL | Geometric Coefficient of Variation 43 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Area Under the Concentration Versus Time Curve [AUC(0-infinity)] of S-Warfarin | 20600 ng*h/mL | Geometric Coefficient of Variation 40 |
90% CI: [0.956, 1.13]
Primary
Pharmacokinetics: Maximum Concentration (Cmax) of Caffeine
Maximum concentration of caffeine after single dose of drug cocktail on Day 1 in Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours (hr) Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Caffeine | 2890 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Caffeine | 2950 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33 |
90% CI: [0.965, 1.06]
Primary
Pharmacokinetics: Maximum Concentration (Cmax) of Dextromethorphan
Maximum concentration of dextromethorphan after single dose of drug cocktail on Day 1 of Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 1, 2, 4, 6, 8, 10, 24, 48, 72 hr postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Dextromethorphan | 3.18 ng/mL | Geometric Coefficient of Variation 182 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Dextromethorphan | 3.30 ng/mL | Geometric Coefficient of Variation 164 |
90% CI: [0.898, 1.22]
Primary
Pharmacokinetics: Maximum Concentration (Cmax) of Midazolam
Maximum concentration of midazolam after single dose of drug cocktail on Day 1 of Period 1 and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hr Postdose
Population: All subjects who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Midazolam | 2.12 ng/mL | Geometric Coefficient of Variation 54 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) of Midazolam | 1.75 ng/mL | Geometric Coefficient of Variation 48 |
90% CI: [0.76, 0.94]
Primary
Pharmacokinetics: Maximum Concentration (Cmax) S-Warfarin
Maximum concentration of S-warfarin after single dose of drug cocktail on Day 1 in Period 1and in combination with Abemaciclib on Day 8 in Period 2.
Time frame: Days 1 and 8: Predose, 0.5 1, 2, 3, 4, 6, 8, 12, 48, 72, 96 hr Postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) S-Warfarin | 561 ng/mL | Geometric Coefficient of Variation 35 |
| Abemaciclib + 100 mg Caffeine | Pharmacokinetics: Maximum Concentration (Cmax) S-Warfarin | 526 ng/mL | Geometric Coefficient of Variation 35 |
90% CI: [0.871, 1]
Secondary
Mean Change From Baseline at 24 Hours in Pulse Rate in Period 1
Mean change from baseline in pulse rate over 24 hours (h) postdose following single dose drug cocktail in Period 1.
Time frame: Day 8: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Pulse Rate in Period 1 | -1.3 Beats per minute (bpm) | Standard Deviation 11.1 |
Secondary
Mean Change From Baseline at 24 Hours in Pulse Rate in Period 2
Mean change from baseline in pulse rate at 24 h postdose following 200 mg abemaciclib and drug cocktail.
Time frame: Day 8: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Pulse Rate in Period 2 | 4.1 bpm | Standard Deviation 14.9 |
Secondary
Mean Change From Baseline at 24 Hours in Pulse Rate in Period 2
Mean change from baseline in pulse rate over 24 hours (h) postdose following single dose drug cocktail in Period 2, Day 1.
Time frame: Day 1: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Pulse Rate in Period 2 | -0.2 bpm | Standard Deviation 12.5 |
Secondary
Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 1
Mean change from predose in systolic and diastolic blood pressure (BP) over 24 hours (h) postdose following single dose drug cocktail in Period 1.
Time frame: Day 8: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 1 | Systolic BP | -2.5 millimeter of mercury (mmHg) | Standard Deviation 13.9 |
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 1 | Diastolic BP | -0.7 millimeter of mercury (mmHg) | Standard Deviation 10.1 |
Secondary
Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2
Mean change from baseline in systolic and diastolic blood pressure (BP) at 24 h postdose following 200 mg abemaciclib and drug cocktail.
Time frame: Day 8: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2 | Systolic BP | -11.6 mmHg | Standard Deviation 16.8 |
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2 | Diastolic BP | -6.1 mmHg | Standard Deviation 10.5 |
Secondary
Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2
Mean change from baseline in systolic and diastolic blood pressure (BP) over 24 hours (h) postdose following single dose of abemaciclib in Period 2, Day 1.
Time frame: Day 1: Baseline, 24 h postdose
Population: All subjects who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2 | Systolic BP | -7.8 mmHg | Standard Deviation 15.2 |
| 100 mg Caffeine | Mean Change From Baseline at 24 Hours in Systolic and Diastolic Blood Pressure in Period 2 | Diastolic BP | -1.8 mmHg | Standard Deviation 10.4 |