A Study to Investigate the Relative Bioavailability of Entrectinib Capsule Formulations F1 and F06 Under Fed Conditions in Healthy Participants

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03796260
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Days): 26
• Patients Per Site Per Month: 16.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Entrectinib Test Formulation (F1); Drug: Entrectinib Reference Formulation (F06)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Two-Treatment, Two-Period, Two-Way Crossover Study to Investigate the Relative Bioavailability of Entrectinib Capsule Formulations F1 and F06 Under Fed Conditions in Healthy Subjects
• Actual Study Start Date: Jan 9, 2019
• Actual Primary Completion Date: Feb 4, 2019
• Actual Study Completion Date: Feb 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: F1 to F06 Crossover Participants first randomized to this arm will receive a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 after a standardized meal. This dose will be followed by a minimum 14-day washout period, after which participants will receive a single oral dose of entrectinib F06 (reference formulation) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days).	Drug: Entrectinib Test Formulation (F1); Participants will receive a single oral dose of entrectinib F1 after completion of a standardized meal.; Drug: Entrectinib Reference Formulation (F06); Participants will receive a single oral dose of entrectinib F06 after completion of a standardized meal.
Experimental: F06 to F1 Crossover Participants first randomized to this arm will receive a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 after a standardized meal. This dose will be followed by a minimum 14-day washout period, after which participants will receive a single oral dose of entrectinib F1 (test formulation) under fasted conditions on Day 1 of Period 2 (Periods 1 and 2 = 6 days).	Drug: Entrectinib Test Formulation (F1); Participants will receive a single oral dose of entrectinib F1 after completion of a standardized meal.; Drug: Entrectinib Reference Formulation (F06); Participants will receive a single oral dose of entrectinib F06 after completion of a standardized meal.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance Research Unit - Daytona	Daytona Beach	Florida	United States	32117

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Nov 2, 2018
• Statistical Analysis Plan - Jan 28, 2019

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT03796260
• Other Study ID Numbers: GP41048
• First Posted: Jan 8, 2019
• Last Update Posted: Feb 26, 2020
• Last Verified: Feb 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Malnutrition; Entrectinib

Study Results

Participant Flow

Arm/Group Title	F1 to F06 Crossover	F06 to F1 Crossover
Arm/Group Description	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).	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).
Period Title: Period 1
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	F1 to F06 Crossover	F06 to F1 Crossover	Total
Arm/Group Description	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).	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).	Total of all reporting groups
Overall Participants	7	7	14
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37.3 (11.7)	33.3 (10.5)	36 (11.6)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	3 42.9%	7 50%
Male	3 42.9%	4 57.1%	7 50%
Race/Ethnicity, Customized (Count of Participants)
White	5 71.4%	7 100%	12 85.7%
Black or African American	1 14.3%	0 0%	1 7.1%
Multiple	1 14.3%	0 0%	1 7.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	4 57.1%	6 85.7%	10 71.4%
Not Hispanic or Latino	3 42.9%	1 14.3%	4 28.6%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Entrectinib and M5 Metabolite
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	F1 Test Formulation	F06 Reference Formulation
Arm/Group Description	Participants who received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).	Participants who received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).
Measure Participants	14	14
Entrectinib	44000 (52.0)	44900 (50.1)
M5 Metabolite	14400 (51.09)	15000 (50.8)

2. Primary Outcome

Title	Area Under the Concentration-Time Curve (AUC0-t) of Entrectinib and M5 Metabolite
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	F1 Test Formulation	F06 Reference Formulation
Arm/Group Description	Participants who received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).	Participants who received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).
Measure Participants	14	14
Entrectinib	41200 (50.9)	42100 (48.5)
M5 Metabolite	11600 (49.4)	12600 (48.2)

3. Primary Outcome

Title	Maximum Observed Concentration (Cmax) of Entrectinib and M5 Metabolite
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	F1 Test Formulation	F06 Reference Formulation
Arm/Group Description	Participants who received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).	Participants who received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).
Measure Participants	14	14
Entrectinib	1870 (49.4)	2000 (37.6)
M5 Metabolite	427 (60.8)	487 (50.6)

4. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	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])

Outcome Measure Data

Analysis Population Description

The Safety Population included all participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.

Arm/Group Title	F1 Test Formulation	F06 Reference Formulation
Arm/Group Description	Participants who received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).	Participants who received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).
Measure Participants	14	14
Number [Percentage of Participants]	28.6 408.6%	21.4 305.7%

Adverse Events

Time Frame	Baseline through the end of study (up to clinical cut-off date 04 Feb 2019 [27 days])
Adverse Event Reporting Description	The Safety Population included all participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.
Arm/Group Title	F1 Test Formulation		F06 Reference Formulation
Arm/Group Description	Participants who received a single oral dose of entrectinib F1 (test formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).		Participants who received a single oral dose of entrectinib F06 (reference formulation) on Day 1 of Period 1 and Day 1 of Period 2 after a standardized meal (Periods 1 and 2 = 6 days).
All Cause Mortality
	F1 Test Formulation		F06 Reference Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Serious Adverse Events
	F1 Test Formulation		F06 Reference Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	F1 Test Formulation		F06 Reference Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		3/14 (21.4%)
Gastrointestinal disorders
Paraesthesia oral	2/14 (14.3%)		0/14 (0%)
Dyspepsia	0/14 (0%)		1/14 (7.1%)
Nausea	1/14 (7.1%)		0/14 (0%)
General disorders
Fatigue	1/14 (7.1%)		0/14 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/14 (7.1%)		0/14 (0%)
Nervous system disorders
Headache	1/14 (7.1%)		1/14 (7.1%)
Paraesthesia	1/14 (7.1%)		1/14 (7.1%)
Cognitive disorder	0/14 (0%)		1/14 (7.1%)
Parosmia	1/14 (7.1%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.