Tumor
Conditions
Brief summary
The primary objective of the study was to investigate the relative bioavailability and pharmacokinetics (PK) of sitravatinib free base and malate salt capsule formulations following oral administration in healthy adults.
Interventions
DRUGSitravatinib
Administered orally as a free base capsule
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: 1. Body mass index between 18.0 and 32.0 kg/m2, inclusive. 2. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at Screening and/or Check-in as assessed by the Investigator (or designee). 3. Able to swallow multiple capsules. Key
Exclusion criteria
1. History of stomach or intestinal surgery or resection 2. Have previously completed or withdrawn from this study or any other study investigating sitravatinib and have previously received the investigational product. 3. Participants who, in the opinion of the Investigator (or designee), should not participate in this study. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Apparent Volume of Distribution (Vz/F) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-∞) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-t) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Maximum Observed Plasma Concentration (Cmax) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Time of the Maximum Observed Plasma Concentration (Tmax) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Apparent Terminal Elimination Half-life (T1/2) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
| Apparent Total Plasma Clearance (CL/F) of Sitravatinib | Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to Week 8 | Adverse events (AEs) and serious adverse events are defined as an AE that starts during or after the first dose, or starts prior to the first dose and increases in severity after the first dose, including vital signs, physical examination, electrocardiogram, and laboratory parameters |
Countries
Australia
Participant flow
Recruitment details
Participants were randomized in a 1:1 ratio in two dosing sequences in a 2-period crossover design at a single site in Australia. Periods 1 and 2 were separated by a minimum of 14 days between dose administrations. Total duration of study participation was up to approximately 8 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Dosing Sequence 1: Sitravatinib Free Base Capsule Then Malate Salt Capsule Sitravatinib free base capsule 120 mg on Day 1 of Period 1 then sitravatinib malate salt capsule 100 mg on Day 1 of Period 2, with a minimum washout period between dose administrations of 14 days | 13 |
| Dosing Sequence 2: Sitravatinib Malate Salt Capsule Then Free Base Capsule Sitravatinib malate salt capsule 100 mg on Day 1 of Period 1 then sitravatinib free base capsule 120 mg on Day 1 of Period 2, with a minimum washout period between dose administrations of 14 days | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period (Minimum 14 Days) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Dosing Sequence 2: Sitravatinib Malate Salt Capsule Then Free Base Capsule | Total | Dosing Sequence 1: Sitravatinib Free Base Capsule Then Malate Salt Capsule |
|---|---|---|---|
| Age, Continuous | 28.2 Years STANDARD_DEVIATION 10.19 | 27.7 Years STANDARD_DEVIATION 7.67 | 27.1 Years STANDARD_DEVIATION 4.23 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 26 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 17 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 26 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 |
| other Total, other adverse events | 10 / 25 | 8 / 26 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 |
Outcome results
Primary
Apparent Terminal Elimination Half-life (T1/2) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitravatinib Malate Salt Capsule | Apparent Terminal Elimination Half-life (T1/2) of Sitravatinib | 30.850 Hours |
| Sitravatinib Free Base Capsule | Apparent Terminal Elimination Half-life (T1/2) of Sitravatinib | 28.490 Hours |
Primary
Apparent Total Plasma Clearance (CL/F) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Apparent Total Plasma Clearance (CL/F) of Sitravatinib | 39.61 Liters/hour | Geometric Coefficient of Variation 28.8 |
| Sitravatinib Free Base Capsule | Apparent Total Plasma Clearance (CL/F) of Sitravatinib | 41.48 Liters/hour | Geometric Coefficient of Variation 34.5 |
Primary
Apparent Volume of Distribution (Vz/F) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Apparent Volume of Distribution (Vz/F) of Sitravatinib | 1733.8 Liters | Geometric Coefficient of Variation 28.7 |
| Sitravatinib Free Base Capsule | Apparent Volume of Distribution (Vz/F) of Sitravatinib | 1780.6 Liters | Geometric Coefficient of Variation 35.3 |
Primary
Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-∞) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-∞) of Sitravatinib | 2524.7 h*ng/mL | Geometric Coefficient of Variation 28.8 |
| Sitravatinib Free Base Capsule | Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-∞) of Sitravatinib | 2892.6 h*ng/mL | Geometric Coefficient of Variation 34.5 |
Comparison: Sitravatinib Malate Salt Capsule (Test) vs. Sitravatinib Free Base Capsule (Reference). Analysis based on Relative Bioavailability Analysis Set, defined as the subset of participants in the PK Parameters Analysis Set who had at least 1 primary PK parameter (AUC0-t, AUC0-inf and Cmax of sitravatinib) in both periods.90% CI: [78.273, 98.111]
Primary
Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-t) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-t) of Sitravatinib | 2458.4 h*ng/mL | Geometric Coefficient of Variation 28.2 |
| Sitravatinib Free Base Capsule | Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-t) of Sitravatinib | 2821.8 h*ng/mL | Geometric Coefficient of Variation 34.3 |
Comparison: Sitravatinib Malate Salt Capsule (Test) vs. Sitravatinib Free Base Capsule (Reference). Analysis based on Relative Bioavailability Analysis Set, defined as the subset of participants in the PK Parameters Analysis Set who had at least 1 primary PK parameter (AUC0-t, AUC0-inf and Cmax of sitravatinib) in both periods.90% CI: [78.12, 98.01]
Primary
Maximum Observed Plasma Concentration (Cmax) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Maximum Observed Plasma Concentration (Cmax) of Sitravatinib | 54.96 ng/mL | Geometric Coefficient of Variation 32.9 |
| Sitravatinib Free Base Capsule | Maximum Observed Plasma Concentration (Cmax) of Sitravatinib | 62.40 ng/mL | Geometric Coefficient of Variation 37.7 |
Comparison: Sitravatinib Malate Salt Capsule (Test) vs. Sitravatinib Free Base Capsule (Reference). Analysis based on Relative Bioavailability Analysis Set, defined as the subset of participants in the PK Parameters Analysis Set who had at least 1 primary PK parameter (AUC0-t, AUC0-inf and Cmax of sitravatinib) in both periods.90% CI: [77.41, 101.87]
Primary
Time of the Maximum Observed Plasma Concentration (Tmax) of Sitravatinib
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours postdose in each study period
Population: Pharmacokinetic (PK) parameters analysis set included all participants who received at least 1 dose of sitravatinib and had at least 1 PK parameter of sitravatinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitravatinib Malate Salt Capsule | Time of the Maximum Observed Plasma Concentration (Tmax) of Sitravatinib | 8.000 Hours |
| Sitravatinib Free Base Capsule | Time of the Maximum Observed Plasma Concentration (Tmax) of Sitravatinib | 8.000 Hours |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) and serious adverse events are defined as an AE that starts during or after the first dose, or starts prior to the first dose and increases in severity after the first dose, including vital signs, physical examination, electrocardiogram, and laboratory parameters
Time frame: Up to Week 8
Population: Safety Analysis Set included participants who received at least 1 dose of sitravatinib
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sitravatinib Malate Salt Capsule | Number of Participants With Adverse Events | Grade 3 or 4 TEAEs | 0 Participants |
| Sitravatinib Malate Salt Capsule | Number of Participants With Adverse Events | TEAE leading to permanent discontinuation of study treatment | 0 Participants |
| Sitravatinib Malate Salt Capsule | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Sitravatinib Malate Salt Capsule | Number of Participants With Adverse Events | TEAE leading to death | 0 Participants |
| Sitravatinib Malate Salt Capsule | Number of Participants With Adverse Events | At least 1 treatment-emergent adverse event (TEAE) | 10 Participants |
| Sitravatinib Free Base Capsule | Number of Participants With Adverse Events | TEAE leading to death | 0 Participants |
| Sitravatinib Free Base Capsule | Number of Participants With Adverse Events | At least 1 treatment-emergent adverse event (TEAE) | 8 Participants |
| Sitravatinib Free Base Capsule | Number of Participants With Adverse Events | Grade 3 or 4 TEAEs | 0 Participants |
| Sitravatinib Free Base Capsule | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Sitravatinib Free Base Capsule | Number of Participants With Adverse Events | TEAE leading to permanent discontinuation of study treatment | 1 Participants |