Relative Bioavailability of Two Different Capsule Formulations of Sitravatinib in Healthy Adults

• Sponsor: BeiGene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04472650
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Actual Duration (Months): 3.6
• Patients Per Site Per Month: 7.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tumor	Drug: Sitravatinib; Drug: Sitravatinib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Single-dose, Randomized Crossover Study to Evaluate the Relative Bioavailability of Two Different Capsule Formulations of Sitravatinib in Healthy Subjects
• Actual Study Start Date: Jul 23, 2020
• Actual Primary Completion Date: Nov 9, 2020
• Actual Study Completion Date: Nov 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dosing Sequence 1: Sitravatinib Free Base then Malate Salt Sitravatinib free base capsule 120 mg on Day 1 in Period 1 then sitravatinib malate salt capsule 100 mg on Day 1 in Period 2, with a minimum washout period between dose administrations of 14 days	Drug: Sitravatinib; Administered orally as a free base capsule; Drug: Sitravatinib; Administered orally as a malate salt capsule
Experimental: Dosing Sequence 2: Sitravatinib Malate Salt then Free Base Sitravatinib malate salt capsule 100 mg on Day 1 in Period 1 then sitravatinib free base capsule 120 mg on Day 1 in Period 2, with a minimum washout period between dose administrations of 14 days	Drug: Sitravatinib; Administered orally as a free base capsule; Drug: Sitravatinib; Administered orally as a malate salt capsule

Outcome Measures

Primary Outcome Measures

1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

Secondary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Linear Clinical Research Pty Lt(LCR)	Nedlands	Western Australia	Australia	6009

Sponsors and Collaborators

• BeiGene

Investigators

• Principal Investigator: Study Director, BeiGene

Study Documents (Full-Text)

• Study Protocol - Jul 12, 2020
• Statistical Analysis Plan - Sep 9, 2020

More Information

Publications

None provided.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT04472650
• Other Study ID Numbers: BGB-Sitravatinib-101
• First Posted: Jul 15, 2020
• Last Update Posted: Dec 27, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Study Results

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.

Arm/Group Title	Dosing Sequence 1: Sitravatinib Free Base Capsule Then Malate Salt Capsule	Dosing Sequence 2: Sitravatinib Malate Salt Capsule Then Free Base Capsule
Arm/Group Description	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	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
Period Title: Period 1 (Up to 15 Days)
STARTED	13	13
COMPLETED	13	13
NOT COMPLETED	0	0
Period Title: Period 1 (Up to 15 Days)
STARTED	13	13
COMPLETED	12	13
NOT COMPLETED	1	0
Period Title: Period 1 (Up to 15 Days)
STARTED	12	13
COMPLETED	12	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Dosing Sequence 1: Sitravatinib Free Base Capsule Then Malate Salt Capsule	Dosing Sequence 2: Sitravatinib Malate Salt Capsule Then Free Base Capsule	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	13	13	26
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	27.1 (4.23)	28.2 (10.19)	27.7 (7.67)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	13 100%	13 100%	26 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	13 100%	13 100%	26 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	8 61.5%	9 69.2%	17 65.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 7.7%	1 3.8%
Black or African American	2 15.4%	0 0%	2 7.7%
White	3 23.1%	3 23.1%	6 23.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	2524.7 (28.8)	2892.6 (34.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitravatinib Malate Salt Capsule, Sitravatinib Free Base Capsule
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Least Squares Means
	Estimated Value	87.63
	Confidence Interval	(2-Sided) 90%; 78.273 to 98.111
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	2458.4 (28.2)	2821.8 (34.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitravatinib Malate Salt Capsule, Sitravatinib Free Base Capsule
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Least Squares Means
	Estimated Value	87.50
	Confidence Interval	(2-Sided) 90%; 78.12 to 98.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	54.96 (32.9)	62.40 (37.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitravatinib Malate Salt Capsule, Sitravatinib Free Base Capsule
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Least Squares Means
	Estimated Value	88.80
	Confidence Interval	(2-Sided) 90%; 77.41 to 101.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Median (Full Range) [Hours]	8.000	8.000

5. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Median (Full Range) [Hours]	30.850	28.490

6. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Liters/hour]	39.61 (28.8)	41.48 (34.5)

7. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg (test) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg (reference) on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Liters]	1733.8 (28.7)	1780.6 (35.3)

8. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included participants who received at least 1 dose of sitravatinib

Arm/Group Title	Sitravatinib Malate Salt Capsule	Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days	Sitravatinib free base capsule 120 mg on Day 1 of Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
Measure Participants	25	26
At least 1 treatment-emergent adverse event (TEAE)	10 76.9%	8 61.5%
Grade 3 or 4 TEAEs	0 0%	0 0%
Serious adverse events	0 0%	0 0%
TEAE leading to permanent discontinuation of study treatment	0 0%	1 7.7%
TEAE leading to death	0 0%	0 0%

Adverse Events

Time Frame	Up to Week 8
Adverse Event Reporting Description	Safety Analysis Set included participants who received at least 1 dose of sitravatinib
Arm/Group Title	Sitravatinib Malate Salt Capsule		Sitravatinib Free Base Capsule
Arm/Group Description	Sitravatinib malate salt capsule 100 mg on Day 1 in Periods 1 and 2, with a minimum washout period between dose administrations of 14 days		Sitravatinib free base capsule 120 mg (reference) on Day 1 in Periods 1 and 2, with a minimum washout period between dose administrations of 14 days
All Cause Mortality
	Sitravatinib Malate Salt Capsule		Sitravatinib Free Base Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/26 (0%)
Serious Adverse Events
	Sitravatinib Malate Salt Capsule		Sitravatinib Free Base Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Sitravatinib Malate Salt Capsule		Sitravatinib Free Base Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/25 (40%)		8/26 (30.8%)
Blood and lymphatic system disorders
Anaemia	0/25 (0%)	0	1/26 (3.8%)	1
Neutropenia	1/25 (4%)	1	1/26 (3.8%)	1
Gastrointestinal disorders
Abdominal discomfort	0/25 (0%)	0	1/26 (3.8%)	1
Diarrhoea	1/25 (4%)	1	0/26 (0%)	0
Nausea	1/25 (4%)	1	0/26 (0%)	0
Palatal ulcer	0/25 (0%)	0	1/26 (3.8%)	1
General disorders
Catheter site bruise	1/25 (4%)	1	0/26 (0%)	0
Catheter site pain	1/25 (4%)	1	1/26 (3.8%)	1
Catheter site related reaction	0/25 (0%)	0	1/26 (3.8%)	1
Vessel puncture site bruise	3/25 (12%)	4	0/26 (0%)	0
Vessel puncture site pain	2/25 (8%)	2	0/26 (0%)	0
Investigations
Alanine aminotransferase increased	2/25 (8%)	2	0/26 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/25 (0%)	0	1/26 (3.8%)	1
Muscle spasms	0/25 (0%)	0	1/26 (3.8%)	1
Nervous system disorders
Dizziness	1/25 (4%)	1	0/26 (0%)	0
Headache	1/25 (4%)	1	1/26 (3.8%)	1
Hypoaesthesia	0/25 (0%)	0	1/26 (3.8%)	1
Lethargy	0/25 (0%)	0	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Dermatitis contact	1/25 (4%)	1	2/26 (7.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

BeiGene has 18 months from the end of the study at all sites to publish overall study results. After the 1st multi-site publication or the expiration of publication period, Investigators are free to publish/present the results of the study. Investigators must submit all draft publications/presentations to us for review 60 days prior to the planned publication/presentation date. BeiGene may request deletion of its confidential information and may request a further delay to protect its IP rights.