Healthy Volunteers
Conditions
Brief summary
This study aims to investigate the relative bioavailability, safety, and tolerability of entrectinib capsule formulations F1 and F06 under fed conditions in healthy adult male and female participants.
Interventions
DRUGEntrectinib Test Formulation (F1)
Participants will receive a single oral dose of entrectinib F1 after completion of a standardized meal.
DRUGEntrectinib Reference Formulation (F06)
Participants will receive a single oral dose of entrectinib F06 after completion of a standardized meal.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy in the opinion of the investigator. Healthy is defined by the absence of evidence of any active disease or clinically significant medical condition based on a detailed medical history and examination * Negative test results for Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus (HIV) * Females must not be pregnant or breastfeeding, and females of childbearing potential will agree to use highly-effective contraception. Females of childbearing potential must also agree to refrain from donating eggs during the treatment period and for 6 weeks after the final dose of study drug * Males must agree to use contraception and to refrain from sperm donation from check-in (Day -1 of Period 1) to 90 days after the final dose of study drug
Exclusion criteria
* History of gastrointestinal surgery or other gastrointestinal disorder that might affect absorption of medicines from the gastrointestinal tract * Presence of a clinically significant disease, illness, medical condition or disorder, or any other medical history determined by the investigator to be clinically significant and relevant. Ongoing chronic disorders which are not considered clinically significant are permissible providing they are stable * Clinically significant change in health status, as judged by the investigator, or any major illness within the 4 weeks before screening, or clinically significant acute infection or febrile illness within the 14 days before screening * Participation in any other clinical study involving an investigational medicinal product (IMP) or device within 30 days or 5 half-lives (if known), whichever is longer, before screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite | At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days) | The area under the concentration-time curve extrapolated to infinity is calculated using the formula: AUC0-inf = AUC0-t + (Ct/λz) where Ct is the last measurable concentration and λz is the apparent terminal elimination rate constant. The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern. |
| Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days) | The area under the concentration-time curve calculated from Hour 0 to the last measurable concentration, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern. |
| Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days) | The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline through the end of study (up to clinical cut-off date 04 Feb 2019 [27 days]) | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| F1 to F06 Crossover Participants first randomized to F1/F06 arm and received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 after a standardized meal. This dose was followed by a minimum 14-day washout period, after which participants received a single oral dose of entrectinib F06 (reference formulation) under fed conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days). | 7 |
| F06 to F1 Crossover Participants first randomized to this arm received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 after a standardized meal. This dose was followed by a minimum 14-day washout period, after which participants received a single oral dose of entrectinib F1 (test formulation) under fed conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days). | 7 |
| Total | 14 |
Baseline characteristics
| Characteristic | F1 to F06 Crossover | F06 to F1 Crossover | Total |
|---|---|---|---|
| Age, Continuous | 37.3 Years STANDARD_DEVIATION 11.7 | 33.3 Years STANDARD_DEVIATION 10.5 | 36 Years STANDARD_DEVIATION 11.6 |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 4 / 14 | 3 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite
The area under the concentration-time curve calculated from Hour 0 to the last measurable concentration, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern.
Time frame: At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days)
Population: The PK Population included all participants who received at least 1 dose of study drug and had at least 1 evaluable postdose PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| F1 Test Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | Entrectinib | 41200 nmol*h/L | Geometric Coefficient of Variation 50.9 |
| F1 Test Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | M5 Metabolite | 11600 nmol*h/L | Geometric Coefficient of Variation 49.4 |
| F06 Reference Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | Entrectinib | 42100 nmol*h/L | Geometric Coefficient of Variation 48.5 |
| F06 Reference Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | M5 Metabolite | 12600 nmol*h/L | Geometric Coefficient of Variation 48.2 |
Primary
Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite
The area under the concentration-time curve extrapolated to infinity is calculated using the formula: AUC0-inf = AUC0-t + (Ct/λz) where Ct is the last measurable concentration and λz is the apparent terminal elimination rate constant. The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern.
Time frame: At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days)
Population: The PK Population included all participants who received at least 1 dose of study drug and had at least 1 evaluable postdose pharmacokinetic (PK) sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| F1 Test Formulation | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite | Entrectinib | 44000 nmol*h/L | Geometric Coefficient of Variation 52 |
| F1 Test Formulation | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite | M5 Metabolite | 14400 nmol*h/L | Geometric Coefficient of Variation 51.09 |
| F06 Reference Formulation | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite | M5 Metabolite | 15000 nmol*h/L | Geometric Coefficient of Variation 50.8 |
| F06 Reference Formulation | Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite | Entrectinib | 44900 nmol*h/L | Geometric Coefficient of Variation 50.1 |
Primary
Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite
The presented values in the table are based on all 14 participants receiving the F1 formulation in a 2-way crossover pattern.
Time frame: At pre-defined intervals from study Day 1 through Day 5 of each Period (Periods 1 and 2 = 6 days)
Population: The PK Population included all participants who received at least 1 dose of study drug and had at least 1 evaluable postdose PK sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| F1 Test Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | Entrectinib | 1870 nmol/L | Geometric Coefficient of Variation 49.4 |
| F1 Test Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | M5 Metabolite | 427 nmol/L | Geometric Coefficient of Variation 60.8 |
| F06 Reference Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | M5 Metabolite | 487 nmol/L | Geometric Coefficient of Variation 50.6 |
| F06 Reference Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | Entrectinib | 2000 nmol/L | Geometric Coefficient of Variation 37.6 |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline through the end of study (up to clinical cut-off date 04 Feb 2019 [27 days])
Population: The Safety Population included all participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| F1 Test Formulation | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 28.6 Percentage of Participants |
| F06 Reference Formulation | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 21.4 Percentage of Participants |