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| ID | Type | Description | Link |
|---|---|---|---|
| 2021-000198-10 | EudraCT Number |
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| Name | Class |
|---|---|
| Quotient Sciences | INDUSTRY |
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Quizartinib, a selective FLT3 inhibitor, is being developed as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The absolute oral bioavailability of quizartinib has not yet been studied. This study is designed to estimate quizartinib bioavailability of quizartinib following oral and intravenous (IV) administration.
Quizartinib bioavailability based on the dose-adjusted exposure of quizartinib following oral and IV administration will be assessed in healthy male subjects. The primary objective of this study is to determine the absolute oral bioavailability of quizartinib. Secondary objectives will include characterizing the plasma PK of quizartinib, radiolabeled quizartinib, and the major circulating metabolite after a single oral dose and IV administration. Safety and tolerability of quizartinib will also be assessed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| All Participants | Experimental | Participants who will receive a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Quizartinib dihydrochloride | Drug | Single oral dose of 60 mg quizartinib (2 x 30 mg tablets) |
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| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Absolute Oral Bioavailability for Quizartinib As Assessed By Pharmacokinetic Parameters for Area Under the Plasma Concentration-Time Curve Following Intravenous and Oral Administrations of Quizartinib | The absolute bioavailability assessment for quizartinib was based on the pharmacokinetic parameters area under the curve (AUC) from the time of dosing to time Tlast (AUClast) and AUC from the time of dosing extrapolated to infinity (AUCinf) for quizartinib following intravenous and oral administrations. Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). | Relative to oral dosing: Pre-dose and at 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib | Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for Quizartinib and active metabolite AC886. | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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Inclusion Criteria:
Exclusion Criteria:
History or presence of:
History of a clinically significant illness, in the opinion of the Investigator, within 4 weeks prior to administration of quizartinib.
History, or presence in the average of triplicate ECGs at screening and admission (Day -1), of any of the following cardiac conduction abnormalities:
Laboratory results (serum chemistry, hematology, coagulation, and urinalysis) outside the normal range, if considered clinically significant by the Investigator at screening or admission (Day -1).
Estimated creatinine clearance (CrCl) <90 mL/min (calculated using Cockcroft-Gault Equation) at screening.
Use of drugs with a risk of QT interval prolongation or Torsades de Pointes (TdP) within 14 days of admission (Day -1) (or 5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days).
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| Name | Affiliation | Role |
|---|---|---|
| Global Clinical Leader | Daiichi Sankyo | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Quotient Sciences | Nottingham | NG11 6JS | United Kingdom |
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Participants underwent preliminary screening procedures up to 21 days before investigational medicinal product (IMP) administration (Day -21 to Day-2). Participants were admitted in the morning on the day prior to IMP administration (i.e., Day -1), at which time admission procedures were undertaken to confirm eligibility. Participants were dosed in the morning of Day 1 following an overnight fast of a minimum of 8 hours for the oral dose (a minimum of 12 hours for the intravenous dose).
A total of 8 participants who met all inclusion criteria and no exclusion criteria were included in this study and were enrolled at 1 clinic center in the United Kingdom.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Participants | Participants who received a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Patient demographic and baseline characteristics were reported from the Safety Population.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Participants who received a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Absolute Oral Bioavailability for Quizartinib As Assessed By Pharmacokinetic Parameters for Area Under the Plasma Concentration-Time Curve Following Intravenous and Oral Administrations of Quizartinib | The absolute bioavailability assessment for quizartinib was based on the pharmacokinetic parameters area under the curve (AUC) from the time of dosing to time Tlast (AUClast) and AUC from the time of dosing extrapolated to infinity (AUCinf) for quizartinib following intravenous and oral administrations. Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | percentage of oral bioavailability | Relative to oral dosing: Pre-dose and at 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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Treatment-emergent adverse events were collected from baseline up to 6 weeks post-dose.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Participants | Participants who will receive a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cerumen impaction | Ear and labyrinth disorders | MedDRA 24.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Contact for Clinical Trial Information | Daiichi Sankyo | 908-992-6400 | CTRinfo@dsi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 23, 2021 | Apr 15, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C544967 | quizartinib |
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| 14C-Quizartinib solution for infusion | Drug | 50 μg solution for infusion containing NMT 22.84 kBq 14C in 5 mL; administered once as a 15-minute infusion |
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| Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib | Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for 14C-Quizartinib and 14C-AC886. | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib | Time to maximum plasma concentration (Tmax) was an observed value from the study. Tmax was assessed for Quizartinib and AC886. | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Half-life (t1/2) was assessed for Quizartinib, 14C-Quizartinib, AC886, 14C-AC886. | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for Quizartinib and AC886. | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for 14C-Quizartinib and 14C-AC886. | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter for Total Body Clearance (CL) Following Single-Dose Intravenous Administration of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Total body clearance (CL) was assessed following single-dose IV administration for 14C-quizartinib. | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter for Volume of Distribution (Vz) Following Following Single-Dose Intravenous Administration of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Volume of distribution based on the terminal phase (Vz) was assessed following single-dose IV administration for 14C-quizartinib. | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). MPR was assessed for AC886 and 14C-AC886. | Relative to oral dosing: Pre-dose (AC886 only), 1 hour (AC886 only), 2 hours (AC886 only), 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
| Number of Participants With Any Treatment-emergent Adverse Event Following Intravenous and Oral Administrations of Quizartinib | Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. | Baseline up to approximately 6 weeks post-dose |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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Participants who received a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing. |
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| Secondary | Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib | Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | ng/mL | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib | Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for 14C-Quizartinib and 14C-AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | pg/mL | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib | Time to maximum plasma concentration (Tmax) was an observed value from the study. Tmax was assessed for Quizartinib and AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Median | Full Range | hours | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Half-life (t1/2) was assessed for Quizartinib, 14C-Quizartinib, AC886, 14C-AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | hours | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for Quizartinib and AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | ng*h/mL | Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for 14C-Quizartinib and 14C-AC886. | Pharmacokinetic parameters were assessed in patients with available data in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | pg*h/mL | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter for Total Body Clearance (CL) Following Single-Dose Intravenous Administration of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Total body clearance (CL) was assessed following single-dose IV administration for 14C-quizartinib. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | L/h | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter for Volume of Distribution (Vz) Following Following Single-Dose Intravenous Administration of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Volume of distribution based on the terminal phase (Vz) was assessed following single-dose IV administration for 14C-quizartinib. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | Liters | Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib | Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). MPR was assessed for AC886 and 14C-AC886. | Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population. | Posted | Mean | Standard Deviation | metabolite-to-parent ratio | Relative to oral dosing: Pre-dose (AC886 only), 1 hour (AC886 only), 2 hours (AC886 only), 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours |
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| Secondary | Number of Participants With Any Treatment-emergent Adverse Event Following Intravenous and Oral Administrations of Quizartinib | Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. | Treatment-emergent adverse events were assessed in the Safety Population. | Posted | Count of Participants | Participants | Baseline up to approximately 6 weeks post-dose |
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| 0 |
| 8 |
| 0 |
| 8 |
| 1 |
| 8 |
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| Intravenous: Quizartinib |
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| Intravenous: AC886 |
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| Intravenous: Quizartinib |
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| Intravenous: AC886 |
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| Oral (plasma): AC886, AUCinf |
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| Intravenous: 14C-AC886, AUCinf |
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| Intravenous: MPR(AUClast), 14C-AC886 |
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| Intravenous: MPR(AUCinf), 14C-AC886 |
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