Evaluate Severe Hepatic Impairment on Dacomitinib PK

A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL-GROUP STUDY TO EVALUATE THE PLASMA PHARMACOKINETICS AND SAFETY OF DACOMITINIB IN PARTICIPANTS WITH SEVERELY IMPAIRED HEPATIC FUNCTION RELATIVE TO PARTICIPANTS WITH NORMAL HEPATIC FUNCTION

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03865446

Enrollment

Registered

2019-03-06

Start date

2019-04-05

Completion date

2019-10-24

Last updated

2020-11-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Severe Hepatic Impairment

Keywords

Pharmacokinetics, Dacomitinib, Hepatic Impairment

Brief summary

This is a post approval requirement to study the effect of severe hepatic impairment on the pharmacokinetics of dacomitinib.

Detailed description

This is a Phase 1, open label, parallel group study to investigate the effect of severe hepatic impairment on the plasma PK, safety and tolerability after a single oral 30 mg dose of dacomitinib under fasted conditions. Approximately 18 participants will be enrolled into the study to ensure at least 6 PK evaluable (having data for estimating primary PK parameters for dacomitinib) participants in each cohort.

Interventions

DRUGDacomitinib

anti-cancer agent

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Yes

Inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply: 1. Male and/or female participants of non childbearing potential must be 18 to 75 years of age, inclusive, at the time of signing the informed consent document (ICD). 2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. Weight: 3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight \>50 kg (110 lb). 4. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Exclusion criteria

Participants are excluded from the study if any of the following criteria apply: 1. Any condition possibly affecting drug absorption (eg, gastrectomy). 2. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. 3. History of or current positive results for human immunodeficiency virus (HIV). 4. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of IP used in this study (whichever is longer). 5. Hypersensitivity to dacomitinib or its excipients. 6. A positive urine drug test. Participants with severe hepatic impairment (Cohort 1) will be eligible to participate if their urine drug test is positive with a drug for a prescribed condition that is not expected to interfere with the PK of dacomitinib. 7. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. 8. History of sensitivity to heparin or heparin induced thrombocytopenia. 9. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol. 10. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Sponsor employees, including their family members, directly involved in the conduct of the study.

Design outcomes

Primary

Measure	Time frame	Description
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of Dacomitinib	Pre-dose and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1	AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Maximum Observed Plasma Concentration (Cmax) of Dacomitinib	Pre-dose and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1	Cmax of Dacomitinib was analyzed.

Secondary

Measure	Time frame	Description
Number of Participants With Laboratory Abnormalities	Baseline up to Day 7	Laboratory abnormalities included hematology- Erythrocyte mean corpuscular hemoglobin: less than (\<) 0.9 \lower limit of normal (LLN), platelets: \< 0.5\ LLN, leukocytes: \< 0.6\* LLN, lymphocytes: \< 0.8\* LLN, eosinophils: greater than (\>) 1.2\* lower limit of normal (ULN), partial thromboplastin time (PTT): \> 1.1\* ULN, prothrombin time: \> 1.1\* ULN, Prothrombin Intl. normalized ratio: \> 1.1\* ULN, clinical chemistry- bilirubin: \> 1.5\* ULN, protein: \< 0.8\* LLN, albumin: \< 0.8\* LLN, urinalysis- urine protein: greater than or equal to (\>=) 1, urine hemoglobin: \>= 1, urobilinogen: \>= 1, urine erythrocytes: \>= 20.
Number of Participants With Vital Sign Parameters Meeting Criteria of Potential Clinical Concern	Baseline up to Day 7	Systolic blood pressure, diastolic blood pressure and pulse rate were evaluated for examination of vital signs. Criteria for potential concern in absolute values of vital sign: pulse rate: \<40 beats per minute (bpm), \>120 beats per minute; supine diastolic blood pressure: \<50 millimeter of mercury (mm Hg); supine systolic blood pressure: \<90 mm Hg. Criteria for potential concern in change from baseline in vital sign values: supine diastolic blood pressure: greater than or equal to \>= 30 mm Hg increase or decrease from baseline; supine diastolic blood pressure: \>=20 mm Hg increase or decrease from baseline. Only participants with vital sign parameters meeting criteria of potential clinical concern are reported.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to Day 35	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. A treatment emergent AE was defined as an event that emerged during the treatment period (Up to Day 35) that was absent before treatment, or worsened during the treatment period relative to the pretreatment state.
Number of Participants With ECG Parameters Meeting Criteria of Potential Clinical Concern	Baseline up to Day 7	ECG parameters RR interval, PR interval, QRS interval, QT interval, QTC interval, QTCB, QTCF and heart rate were measured. Criteria of potential concern for absolute values: PR interval: \>=300 milliseconds; QRS interval \>=140 milliseconds; QT interval: \>=500 milliseconds; QTCF (Fridericia's correction formula) : \>= 450 to \< 480 milliseconds, \>=480 to \<500 milliseconds, \>=500 milliseconds. Criteria of potential concern for change from baseline values: PR interval: when baseline is \>200 millisecond- change \>=25%, when baseline \<200 milliseconds- change \>=50%; QRS interval: change \>= 50%; QTCF: change \>=30 to \<60, change \>=60. In this outcome measure, participants meeting the criteria of potential concern for any of the ECG parameters are reported.
Number of Participants With Physical Examination Abnormalities	Baseline up to Day 7	Height and weight were measured to calculate body mass index abnormality.

Other

Measure	Time frame	Description
Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs)	Baseline up to Day 35	Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after first dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Dacomitinib was assessed by the investigator.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Severe Hepatic Impairment Participants with severe hepatic impairment received a single oral dose of dacomitinib 30 mg tablet on Day 1 and were followed up to a maximum of 35 days for safety.	8
Normal Hepatic Function Participants with normal hepatic function received a single oral dose of dacomitinib 30 mg tablet on Day 1 and were followed up to a maximum of 35 days for safety.	8
Total	16

Baseline characteristics

Characteristic	Normal Hepatic Function	Total	Severe Hepatic Impairment
Age, Continuous	59.0 years STANDARD_DEVIATION 5.37	59.5 years STANDARD_DEVIATION 5.96	60.0 years STANDARD_DEVIATION 6.82
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants	10 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	6 Participants	3 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	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	8 Participants	15 Participants	7 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	8 Participants	16 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8
other Total, other adverse events	0 / 8	0 / 8
serious Total, serious adverse events	0 / 8	0 / 8

Outcome results

Primary

Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of Dacomitinib

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

Time frame: Pre-dose and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1

Population: PK population included all participants who took one dose of dacomitinib and had at least one dacomitinib plasma PK parameters of primary interest. Here, 'Overall Number of Participants Analyzed' = participants evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Severe Hepatic Impairment	Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of Dacomitinib	735.0 nanogram*hour per milliliter	Geometric Coefficient of Variation 37
Normal Hepatic Function	Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of Dacomitinib	703.9 nanogram*hour per milliliter	Geometric Coefficient of Variation 48

90% CI: [72.12, 151.16]

Primary

Maximum Observed Plasma Concentration (Cmax) of Dacomitinib

Cmax of Dacomitinib was analyzed.

Time frame: Pre-dose and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 264 hours post dose on Day 1

Population: Pharmacokinetic (PK) population included all participants who took one dose of dacomitinib and had at least one dacomitinib plasma PK parameters of primary interest.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Severe Hepatic Impairment	Maximum Observed Plasma Concentration (Cmax) of Dacomitinib	9.673 nanogram per milliliter	Geometric Coefficient of Variation 35
Normal Hepatic Function	Maximum Observed Plasma Concentration (Cmax) of Dacomitinib	7.389 nanogram per milliliter	Geometric Coefficient of Variation 63

90% CI: [86.03, 199.22]

Secondary

Number of Participants With ECG Parameters Meeting Criteria of Potential Clinical Concern

ECG parameters RR interval, PR interval, QRS interval, QT interval, QTC interval, QTCB, QTCF and heart rate were measured. Criteria of potential concern for absolute values: PR interval: \>=300 milliseconds; QRS interval \>=140 milliseconds; QT interval: \>=500 milliseconds; QTCF (Fridericia's correction formula) : \>= 450 to \< 480 milliseconds, \>=480 to \<500 milliseconds, \>=500 milliseconds. Criteria of potential concern for change from baseline values: PR interval: when baseline is \>200 millisecond- change \>=25%, when baseline \<200 milliseconds- change \>=50%; QRS interval: change \>= 50%; QTCF: change \>=30 to \<60, change \>=60. In this outcome measure, participants meeting the criteria of potential concern for any of the ECG parameters are reported.

Time frame: Baseline up to Day 7