Healthy Volunteers
Conditions
Brief summary
This study aims to demonstrate similarities between two different forms of entrectinib (A and C) when administered under fasted conditions in healthy subjects.
Interventions
DRUGEntrectinib Form A
Participants will receive a single oral dose of entrectinib form A under fasted conditions.
DRUGEntrectinib Form C
Participants will receive a single oral dose of entrectinib form C under fasted conditions.
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 |
|---|---|
| Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | At pre-defined intervals from Hour 0 through Day 5 of each study Period (Periods 1 and 2 = 6 days) |
| Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | At pre-defined intervals from Hour 0 through Day 5 of each study Period (Periods 1 and 2 = 6 days) |
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 06 Feb 2019 [28 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 |
|---|---|
| Form A to Form C Crossover Participants first randomized to this arm received a single oral dose of entrectinib form A (reference form) under fasted conditions on Day 1 of Period 1. This dose was followed by a minimum 14-day washout period, after which participants received a single oral dose of entrectinib form C (test form) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days). | 14 |
| Form C to Form A Crossover Participants first randomized to this arm received a single oral dose of entrectinib form C (test form) under fasted conditions on Day 1 of Period 1. This dose was followed by a minimum 14-day washout period, after which participants received a single oral dose of entrectinib form A (reference form) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days). | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | Form A to Form C Crossover | Form C to Form A Crossover | Total |
|---|---|---|---|
| Age, Continuous | 43.9 Years STANDARD_DEVIATION 8.4 | 44.4 Years STANDARD_DEVIATION 11.7 | 44 Years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 9 Participants | 11 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 2 / 28 | 0 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite
Time frame: At pre-defined intervals from Hour 0 through Day 5 of each study Period (Periods 1 and 2 = 6 days)
Population: The PK Population consisted of 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 |
|---|---|---|---|---|
| Form A Reference Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | Entrectinib | 18500 nmol*h/L | Geometric Coefficient of Variation 37.9 |
| Form A Reference Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | M5 metabolite | 3610 nmol*h/L | Geometric Coefficient of Variation 37 |
| Form C Test Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | Entrectinib | 16600 nmol*h/L | Geometric Coefficient of Variation 30.7 |
| Form C Test Formulation | Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite | M5 metabolite | 3070 nmol*h/L | Geometric Coefficient of Variation 36.9 |
Primary
Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite
Time frame: At pre-defined intervals from Hour 0 through Day 5 of each study Period (Periods 1 and 2 = 6 days)
Population: The PK Population consisted of 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 |
|---|---|---|---|---|
| Form A Reference Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | Entrectinib | 796 nmol/L | Geometric Coefficient of Variation 35.6 |
| Form A Reference Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | M5 metabolite | 138 nmol/L | Geometric Coefficient of Variation 47.9 |
| Form C Test Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | Entrectinib | 726 nmol/L | Geometric Coefficient of Variation 28.9 |
| Form C Test Formulation | Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite | M5 metabolite | 114 nmol/L | Geometric Coefficient of Variation 50.3 |
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 06 Feb 2019 [28 days])
Population: The Safety Population consisted of all participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Form A Reference Formulation | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 7.1 Percentage of Participants |
| Form C Test Formulation | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 0 Percentage of Participants |