Solid Tumor
Conditions
Brief summary
This study will evaluate the bioavailability, palatability, safety and tolerability of entrectinib in healthy volunteers. Part 1 of the study will explore the performance of entrectinib multi-particle formulation. Part 2 will evaluate the effect of drug substance particle size on entrectinib bioavailability.
Interventions
DRUGEntrectinib 200 mg (T)
Test formulation (T): entrectinib HPMC capsules
DRUGEntrectinib 600 mg (T1)
Test formulation 1 (T1): Multi-particulate formulation 1: entrectinib film-coated mini-tablets
DRUGEntrectinib 600 mg (T2)
Test formulation 2 (T2): Multi-particulate formulation 2: entrectinib film-coated mini-tablets
DRUGEntrectinib 200 mg (R)
Reference formulation (R): entrectinib hard capsules
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
* A body mass index (BMI) between 18.0 and 32.0 kilogram per square meter (kg/m2), inclusive, and weighing \>/=50 kg. * Agreement to comply with measures to prevent pregnancy and restrictions on egg and sperm donation
Exclusion criteria
* Women of childbearing potential, women who are pregnant or breastfeeding, or intending to become pregnant during the study or within 14 days after the final dose of entrectinib or have a pregnant partner * A clinical significant medical history of gastrointestinal surgery (e.g., gastric bypass) or other gastrointestinal disorder (e.g., malabsorption syndrome) 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 * Clinically significant change in health status, or any major illness, or clinically significant acute infection or febrile illness * Use of moderate or potent inhibitors or inducers of CYP P450 3A4 enzyme or P-gp transporter, or use of other prohibited medications * Participation in any other clinical study involving an investigational medicinal product (IMP) or device * A positive test result for hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV) * Current smokers and those who have smoked, or users of e-cigarettes and nicotine replacement products within the last 12 months * Known history of clinically significant hypersensitivity, or severe allergic reaction, to entrectinib or related compounds
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days) |
| AUC0-inf of Entrectinib Active Metabolite M5 | At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days) |
| Maximum Plasma Concentration (Cmax) of Entrectinib | At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days) |
| Cmax of Entrectinib Active Metabolite M5 | At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | From Day -1 to Day 5 of each periods (each period=7 days) | An adverse event (AE) 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. Treatment-emergent adverse events (TEAEs) are AEs that were not present before the first dose of study drug or that were present before the first dose of study drug but worsened in intensity during exposure to study drug. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1 T1T2R Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was administered as a single 600 milligram (mg) oral dose under fed condition in three different formulations. Test formulation 1 (T1): film-coated mini-tablet; Test formulation 2 (T2): film-coated mini-tablet; Reference formulation (R): hard capsule. The washout period between entrectinib doses was at least 14 days. | 5 |
| Part 1 T2RT1 Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was administered as a single 600 milligram (mg) oral dose under fed condition in three different formulations. Test formulation 1 (T1): film-coated mini-tablet; Test formulation 2 (T2): film-coated mini-tablet; Reference formulation (R): hard capsule. The washout period between entrectinib doses was at least 14 days. | 5 |
| Part 1 RT1T2 Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was administered as a single 600 milligram (mg) oral dose under fed condition in three different formulations. Test formulation 1 (T1): film-coated mini-tablet; Test formulation 2 (T2): film-coated mini-tablet; Reference formulation (R): hard capsule. The washout period between entrectinib doses was at least 14 days. | 5 |
| Part 2 TR Sequence Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was administered as a single 200 mg oral dose under fasted condition in two different formulations. Test formulation (T): hydroxypropyl methylcellulose (HPMC) capsule; Reference formulation (R): hard capsule. The washout period between entrectinib doses was at least 14 days. | 8 |
| Part 2 RT Sequence Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was administered as a single 200 mg oral dose under fasted condition in two different formulations. Test formulation (T): hydroxypropyl methylcellulose (HPMC) capsule; Reference formulation (R): hard capsule. The washout period between entrectinib doses was at least 14 days. | 8 |
| Total | 31 |
Baseline characteristics
| Characteristic | Part 1 T1T2R Sequence | Part 1 T2RT1 Sequence | Part 1 RT1T2 Sequence | Part 2 TR Sequence | Part 2 RT Sequence | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 38.6 Years STANDARD_DEVIATION 17.3 | 47.2 Years STANDARD_DEVIATION 15.2 | 39.8 Years STANDARD_DEVIATION 15.2 | 40.6 Years STANDARD_DEVIATION 11.5 | 46.8 Years STANDARD_DEVIATION 15.3 | 42.8 Years STANDARD_DEVIATION 14.1 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 5 Participants | 5 Participants | 8 Participants | 8 Participants | 31 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 5 Participants | 4 Participants | 6 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 4 Participants | 21 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 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 15 / 15 | 14 / 15 | 15 / 15 | 5 / 16 | 6 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib
Time frame: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 T1/F15 (Test Formulation 1) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | 41500 nmol*h/L | Geometric Coefficient of Variation 38.2 |
| Part 1 T2/F16 (Test Formulation 2) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | 46600 nmol*h/L | Geometric Coefficient of Variation 34.5 |
| Part 1 R/F06 (Reference Formulation) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | 43400 nmol*h/L | Geometric Coefficient of Variation 40.9 |
| Part 2 T/F06 Coarse (Test Formulation) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | 9860 nmol*h/L | Geometric Coefficient of Variation 64.7 |
| Part 2 R/F06 Fine (Reference Formulation) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib | 10100 nmol*h/L | Geometric Coefficient of Variation 56 |
Primary
AUC0-inf of Entrectinib Active Metabolite M5
Time frame: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 T1/F15 (Test Formulation 1) | AUC0-inf of Entrectinib Active Metabolite M5 | 12400 nmol*h/L | Geometric Coefficient of Variation 31.1 |
| Part 1 T2/F16 (Test Formulation 2) | AUC0-inf of Entrectinib Active Metabolite M5 | 12200 nmol*h/L | Geometric Coefficient of Variation 20.9 |
| Part 1 R/F06 (Reference Formulation) | AUC0-inf of Entrectinib Active Metabolite M5 | 13600 nmol*h/L | Geometric Coefficient of Variation 31.7 |
| Part 2 T/F06 Coarse (Test Formulation) | AUC0-inf of Entrectinib Active Metabolite M5 | 3900 nmol*h/L | Geometric Coefficient of Variation 42.8 |
| Part 2 R/F06 Fine (Reference Formulation) | AUC0-inf of Entrectinib Active Metabolite M5 | 3780 nmol*h/L | Geometric Coefficient of Variation 28.1 |
Primary
Cmax of Entrectinib Active Metabolite M5
Time frame: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 T1/F15 (Test Formulation 1) | Cmax of Entrectinib Active Metabolite M5 | 398 nmol/L | Geometric Coefficient of Variation 32.2 |
| Part 1 T2/F16 (Test Formulation 2) | Cmax of Entrectinib Active Metabolite M5 | 325 nmol/L | Geometric Coefficient of Variation 32.3 |
| Part 1 R/F06 (Reference Formulation) | Cmax of Entrectinib Active Metabolite M5 | 360 nmol/L | Geometric Coefficient of Variation 30.1 |
| Part 2 T/F06 Coarse (Test Formulation) | Cmax of Entrectinib Active Metabolite M5 | 100 nmol/L | Geometric Coefficient of Variation 63.2 |
| Part 2 R/F06 Fine (Reference Formulation) | Cmax of Entrectinib Active Metabolite M5 | 113 nmol/L | Geometric Coefficient of Variation 42.4 |
Primary
Maximum Plasma Concentration (Cmax) of Entrectinib
Time frame: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 T1/F15 (Test Formulation 1) | Maximum Plasma Concentration (Cmax) of Entrectinib | 1930 nmol/L | Geometric Coefficient of Variation 24.9 |
| Part 1 T2/F16 (Test Formulation 2) | Maximum Plasma Concentration (Cmax) of Entrectinib | 1940 nmol/L | Geometric Coefficient of Variation 21.3 |
| Part 1 R/F06 (Reference Formulation) | Maximum Plasma Concentration (Cmax) of Entrectinib | 1880 nmol/L | Geometric Coefficient of Variation 26.1 |
| Part 2 T/F06 Coarse (Test Formulation) | Maximum Plasma Concentration (Cmax) of Entrectinib | 494 nmol/L | Geometric Coefficient of Variation 54.7 |
| Part 2 R/F06 Fine (Reference Formulation) | Maximum Plasma Concentration (Cmax) of Entrectinib | 522 nmol/L | Geometric Coefficient of Variation 33.8 |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) 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. Treatment-emergent adverse events (TEAEs) are AEs that were not present before the first dose of study drug or that were present before the first dose of study drug but worsened in intensity during exposure to study drug.
Time frame: From Day -1 to Day 5 of each periods (each period=7 days)
Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 T1/F15 (Test Formulation 1) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 100 Percentage of Participants |
| Part 1 T2/F16 (Test Formulation 2) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 93.3 Percentage of Participants |
| Part 1 R/F06 (Reference Formulation) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 100 Percentage of Participants |
| Part 2 T/F06 Coarse (Test Formulation) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 31.3 Percentage of Participants |
| Part 2 R/F06 Fine (Reference Formulation) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 37.5 Percentage of Participants |