Healthy
Conditions
Keywords
KPT-335, Verdinexor, Karyopharm, First-in-Human, Adult Subjects
Brief summary
This is a randomized, double-blind, sequential, dose-escalation, Phase 1 trial to evaluate the safety and tolerability of verdinexor. Verdinexor or placebo will be given on Days 1 and 3 to healthy adult participants.
Detailed description
This is a randomized, double-blind, sequential, dose-escalation, Phase 1 trial to evaluate the safety and tolerability of verdinexor. Verdinexor or placebo will be given on Days 1 and 3 to healthy adult participants. Cohorts of 8 participants each (6 active, 2 placebo) will be sequentially administered verdinexor or placebo (one dose on Day 1 and one dose on Day 3) using a dose-escalation scheme. A conservative, sequential, dose-escalation strategy employing decreasing escalation increments will be used.
Interventions
DRUGVerdinexor
Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
OTHERPlacebo
Participants received placebo matched to verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants must be in good health as determined by the investigator, based on the medical history, ECG, physical examination, and safety laboratory tests at screening. * Participants must be identified as a non-smoker at the screening visit (a non-smoker is defined as an individual who has abstained from smoking for at least 1 year prior to the screening visit and who has a ≤ 15 pack year history of lifetime cigarette use). A urine cotinine test will be performed at screening and at the time of clinic check-in prior to study drug treatment.
Exclusion criteria
* The participant has any surgical or medical condition that potentially may alter the absorption, metabolism, or excretion of the study drug such as gastrectomy, Crohn's disease, or liver disease. * The participant has a history of clinically significant allergies. Hay fever is allowed unless it is active or has required treatment within the previous 2 months. * Presence of a chronic condition(s) with clinical or historical evidence of recent exacerbation, or other information to suggest non-control of such condition(s). * History of alcohol abuse or drug addiction within 12 months of the screening visit. * Any participant with active cataracts or medical history of cataracts.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From start of study drug administration up to Day 33 | An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occur after participant's signed informed consent obtained. A serious adverse event (SAE) was defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) that and regardless of causality that: results in death, was life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 30 days following last dose or any event considered drug-related by the investigator through the end of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated). It was calculated as AUC0-t + Ct/kel, where: Ct = the last observed non-zero concentration, kel = elimination rate constant. |
| Maximum Observed Concentration (Cmax) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data. |
| Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose | Cavg0-24h was defined as average plasma concentration from time zero to 24 hours post-dose. |
| Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data. |
| Elimination Rate Constant (Kel) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Elimination rate constant was calculated using linear regression on the terminal portion of the log-linear concentration versus time curve. |
| Elimination Half-life (t1/2) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel. |
| Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration |
| Apparent Volume of Distribution (Vd/F) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Vd/F was calculated as Dose/ (kel \*AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kg). |
| Accumulation Factor (AR) of Cmax | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | An AR was defined as a ratio of mean of Cmax Day 3/ Cmax Day 1 for plasma verdinexor. |
| Accumulation Factor (AR) of Cavg0-24Hour | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose | An AR was defined as a ratio of mean of Cavg0-24hour Day 3/ Cavg0-24hour Day 1 for plasma verdinexor. |
| Accumulation Factor (AR) of AUC0-t | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | An AR factor was defined as a ratio of mean of AUC0-t Day 3/ AUC0-t Day 1 for plasma verdinexor. |
| Accumulation Factor (AR) of AUC0-inf | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Accumulation factor was defined as a ratio of mean of AUC0-inf Day 3/ AUC0-inf Day 1 for plasma verdinexor. |
| Maximum Tolerated Dose (MTD) of Verdinexor | From start of study drug administration up to Day 8 | MTD was defined as the dose level tested in the cohort immediately preceding a cohort where one or more dose limiting toxicities (DLTs) were observed. A DLT was defined as any AE or abnormal laboratory value that the Investigator suspected was probably related to verdinexor that was severe in intensity or serious or Indicative of an unacceptable risk to additional participants in the study in the opinion of the Investigator or Sponsor. |
| Apparent Total Body Clearance (Cl/F) of Verdinexor | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose | Apparent total body clearance was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram \[kg\]). |
Countries
Australia
Participant flow
Recruitment details
This study was conducted at single site in Australia from 26 May 2015 to 1 October 2015.
Pre-assignment details
A total of 33 participants were enrolled and randomized, of which 1 participant randomized to verdinexor 20 milligrams (mg) arm discontinued the study before the start of the treatment (due to Adverse event \[AE\] prior to the pre-dose assessment). Total 32 participants started the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3. | 8 |
| Verdinexor 5 mg Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3. | 6 |
| Verdinexor 10 mg Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3. | 6 |
| Verdinexor 20 mg Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3. | 6 |
| Verdinexor 40 mg Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3. | 6 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Randomized but never treated | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Verdinexor 40 mg | Verdinexor 20 mg | Verdinexor 10 mg | Verdinexor 5 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 27.0 Years STANDARD_DEVIATION 3.93 | 26.4 Years STANDARD_DEVIATION 4 | 27.8 Years STANDARD_DEVIATION 4.07 | 26.3 Years STANDARD_DEVIATION 6.09 | 26.5 Years STANDARD_DEVIATION 1.64 | 24.0 Years STANDARD_DEVIATION 3.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 30 Participants | 6 Participants | 6 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 7 Participants | 26 Participants | 6 Participants | 3 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 22 Participants | 5 Participants | 5 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 10 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 8 | 6 / 6 | 3 / 6 | 4 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occur after participant's signed informed consent obtained. A serious adverse event (SAE) was defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) that and regardless of causality that: results in death, was life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 30 days following last dose or any event considered drug-related by the investigator through the end of the study.
Time frame: From start of study drug administration up to Day 33
Population: Safety population included all participants who received at least 1 dose of verdinexor or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 5 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 0 Participants |
| Verdinexor 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 6 Participants |
| Verdinexor 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 0 Participants |
| Verdinexor 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 3 Participants |
| Verdinexor 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 0 Participants |
| Verdinexor 20 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 0 Participants |
| Verdinexor 20 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 4 Participants |
| Verdinexor 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 5 Participants |
| Verdinexor 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 0 Participants |
Secondary
Accumulation Factor (AR) of AUC0-inf
Accumulation factor was defined as a ratio of mean of AUC0-inf Day 3/ AUC0-inf Day 1 for plasma verdinexor.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Accumulation Factor (AR) of AUC0-inf | 0.9 Ratio |
| Verdinexor 5 mg | Accumulation Factor (AR) of AUC0-inf | 1.0 Ratio |
| Verdinexor 10 mg | Accumulation Factor (AR) of AUC0-inf | 1.1 Ratio |
| Verdinexor 20 mg | Accumulation Factor (AR) of AUC0-inf | 1.0 Ratio |
Secondary
Accumulation Factor (AR) of AUC0-t
An AR factor was defined as a ratio of mean of AUC0-t Day 3/ AUC0-t Day 1 for plasma verdinexor.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Accumulation Factor (AR) of AUC0-t | 0.9 Ratio |
| Verdinexor 5 mg | Accumulation Factor (AR) of AUC0-t | 1.0 Ratio |
| Verdinexor 10 mg | Accumulation Factor (AR) of AUC0-t | 1.1 Ratio |
| Verdinexor 20 mg | Accumulation Factor (AR) of AUC0-t | 1.1 Ratio |
Secondary
Accumulation Factor (AR) of Cavg0-24Hour
An AR was defined as a ratio of mean of Cavg0-24hour Day 3/ Cavg0-24hour Day 1 for plasma verdinexor.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Accumulation Factor (AR) of Cavg0-24Hour | 1.0 Ratio |
| Verdinexor 5 mg | Accumulation Factor (AR) of Cavg0-24Hour | 0.9 Ratio |
| Verdinexor 10 mg | Accumulation Factor (AR) of Cavg0-24Hour | 1.1 Ratio |
| Verdinexor 20 mg | Accumulation Factor (AR) of Cavg0-24Hour | 1.2 Ratio |
Secondary
Accumulation Factor (AR) of Cmax
An AR was defined as a ratio of mean of Cmax Day 3/ Cmax Day 1 for plasma verdinexor.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Accumulation Factor (AR) of Cmax | 0.9 Ratio |
| Verdinexor 5 mg | Accumulation Factor (AR) of Cmax | 0.9 Ratio |
| Verdinexor 10 mg | Accumulation Factor (AR) of Cmax | 0.9 Ratio |
| Verdinexor 20 mg | Accumulation Factor (AR) of Cmax | 1.2 Ratio |
Secondary
Apparent Total Body Clearance (Cl/F) of Verdinexor
Apparent total body clearance was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram \[kg\]).
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 1 | 0.32 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.075 |
| Placebo | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 3 | 0.35 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.068 |
| Verdinexor 5 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 3 | 0.30 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.039 |
| Verdinexor 5 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 1 | 0.30 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.023 |
| Verdinexor 10 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 1 | 0.31 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.057 |
| Verdinexor 10 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 3 | 0.30 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.059 |
| Verdinexor 20 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 1 | 0.32 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.04 |
| Verdinexor 20 mg | Apparent Total Body Clearance (Cl/F) of Verdinexor | Day 3 | 0.33 liter per hour per kilogram (L/h/kg) | Standard Deviation 0.102 |
Secondary
Apparent Volume of Distribution (Vd/F) of Verdinexor
Vd/F was calculated as Dose/ (kel \*AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kg).
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 1 | 3.0 liter per kilogram (L/kg) | Standard Deviation 0.96 |
| Placebo | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 3 | 3.6 liter per kilogram (L/kg) | Standard Deviation 1.13 |
| Verdinexor 5 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 3 | 3.6 liter per kilogram (L/kg) | Standard Deviation 0.46 |
| Verdinexor 5 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 1 | 3.4 liter per kilogram (L/kg) | Standard Deviation 0.89 |
| Verdinexor 10 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 1 | 3.9 liter per kilogram (L/kg) | Standard Deviation 0.52 |
| Verdinexor 10 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 3 | 3.6 liter per kilogram (L/kg) | Standard Deviation 0.9 |
| Verdinexor 20 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 1 | 3.5 liter per kilogram (L/kg) | Standard Deviation 1.01 |
| Verdinexor 20 mg | Apparent Volume of Distribution (Vd/F) of Verdinexor | Day 3 | 3.7 liter per kilogram (L/kg) | Standard Deviation 1.72 |
Secondary
Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor
AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated). It was calculated as AUC0-t + Ct/kel, where: Ct = the last observed non-zero concentration, kel = elimination rate constant.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 1 | 235 ng*h/mL | Standard Deviation 34.3 |
| Placebo | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 3 | 218 ng*h/mL | Standard Deviation 31.6 |
| Verdinexor 5 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 3 | 491 ng*h/mL | Standard Deviation 104.8 |
| Verdinexor 5 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 1 | 499 ng*h/mL | Standard Deviation 75.1 |
| Verdinexor 10 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 1 | 991 ng*h/mL | Standard Deviation 145 |
| Verdinexor 10 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 3 | 1,052 ng*h/mL | Standard Deviation 217.6 |
| Verdinexor 20 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 1 | 2,137 ng*h/mL | Standard Deviation 371 |
| Verdinexor 20 mg | Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor | Day 3 | 2,141 ng*h/mL | Standard Deviation 539.4 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor
AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the limit of quantification \[LOQ\]) post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 1 | 215 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 34.2 |
| Placebo | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 3 | 196 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 34.3 |
| Verdinexor 5 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 3 | 440 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 103.4 |
| Verdinexor 5 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 1 | 445 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 69.9 |
| Verdinexor 10 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 1 | 862 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 129.6 |
| Verdinexor 10 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 3 | 991 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 218.1 |
| Verdinexor 20 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 1 | 1,856 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 343.9 |
| Verdinexor 20 mg | Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor | Day 3 | 2,072 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 521.6 |
Secondary
Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor
Cavg0-24h was defined as average plasma concentration from time zero to 24 hours post-dose.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 1 | 8.35 ng/mL | Standard Deviation 1.835 |
| Placebo | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 3 | 8.73 ng/mL | Standard Deviation 3.281 |
| Verdinexor 5 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 3 | 17.3 ng/mL | Standard Deviation 4.91 |
| Verdinexor 5 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 1 | 19.6 ng/mL | Standard Deviation 2.71 |
| Verdinexor 10 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 1 | 42.3 ng/mL | Standard Deviation 9.97 |
| Verdinexor 10 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 3 | 44.4 ng/mL | Standard Deviation 9.05 |
| Verdinexor 20 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 1 | 72.4 ng/mL | Standard Deviation 25.63 |
| Verdinexor 20 mg | Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor | Day 3 | 86.7 ng/mL | Standard Deviation 29.56 |
Secondary
Elimination Half-life (t1/2) of Verdinexor
t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Elimination Half-life (t1/2) of Verdinexor | Day 1 | 6.6 hours | Standard Deviation 1.97 |
| Placebo | Elimination Half-life (t1/2) of Verdinexor | Day 3 | 7.3 hours | Standard Deviation 2.85 |
| Verdinexor 5 mg | Elimination Half-life (t1/2) of Verdinexor | Day 3 | 8.3 hours | Standard Deviation 1.91 |
| Verdinexor 5 mg | Elimination Half-life (t1/2) of Verdinexor | Day 1 | 8.0 hours | Standard Deviation 1.99 |
| Verdinexor 10 mg | Elimination Half-life (t1/2) of Verdinexor | Day 1 | 9.0 hours | Standard Deviation 2.68 |
| Verdinexor 10 mg | Elimination Half-life (t1/2) of Verdinexor | Day 3 | 8.7 hours | Standard Deviation 2.97 |
| Verdinexor 20 mg | Elimination Half-life (t1/2) of Verdinexor | Day 1 | 7.8 hours | Standard Deviation 2.54 |
| Verdinexor 20 mg | Elimination Half-life (t1/2) of Verdinexor | Day 3 | 7.7 hours | Standard Deviation 1.76 |
Secondary
Elimination Rate Constant (Kel) of Verdinexor
Elimination rate constant was calculated using linear regression on the terminal portion of the log-linear concentration versus time curve.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ) post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Elimination Rate Constant (Kel) of Verdinexor | Day 1 | 0.113 per hour (1/h) | Standard Deviation 0.0314 |
| Placebo | Elimination Rate Constant (Kel) of Verdinexor | Day 3 | 0.103 per hour (1/h) | Standard Deviation 0.0282 |
| Verdinexor 5 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 3 | 0.087 per hour (1/h) | Standard Deviation 0.0218 |
| Verdinexor 5 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 1 | 0.091 per hour (1/h) | Standard Deviation 0.0227 |
| Verdinexor 10 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 1 | 0.082 per hour (1/h) | Standard Deviation 0.0177 |
| Verdinexor 10 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 3 | 0.090 per hour (1/h) | Standard Deviation 0.0381 |
| Verdinexor 20 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 1 | 0.097 per hour (1/h) | Standard Deviation 0.0306 |
| Verdinexor 20 mg | Elimination Rate Constant (Kel) of Verdinexor | Day 3 | 0.093 per hour (1/h) | Standard Deviation 0.0215 |
Secondary
Maximum Observed Concentration (Cmax) of Verdinexor
Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Concentration (Cmax) of Verdinexor | Day 3 | 24.8 nanogram per milliliter (ng/mL) | Standard Deviation 5.42 |
| Placebo | Maximum Observed Concentration (Cmax) of Verdinexor | Day 1 | 27.8 nanogram per milliliter (ng/mL) | Standard Deviation 7.48 |
| Verdinexor 5 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 1 | 65.0 nanogram per milliliter (ng/mL) | Standard Deviation 12.13 |
| Verdinexor 5 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 3 | 56.2 nanogram per milliliter (ng/mL) | Standard Deviation 12.94 |
| Verdinexor 10 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 1 | 122 nanogram per milliliter (ng/mL) | Standard Deviation 26.3 |
| Verdinexor 10 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 3 | 116 nanogram per milliliter (ng/mL) | Standard Deviation 36.9 |
| Verdinexor 20 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 3 | 252 nanogram per milliliter (ng/mL) | Standard Deviation 74.6 |
| Verdinexor 20 mg | Maximum Observed Concentration (Cmax) of Verdinexor | Day 1 | 212 nanogram per milliliter (ng/mL) | Standard Deviation 81.6 |
Secondary
Maximum Tolerated Dose (MTD) of Verdinexor
MTD was defined as the dose level tested in the cohort immediately preceding a cohort where one or more dose limiting toxicities (DLTs) were observed. A DLT was defined as any AE or abnormal laboratory value that the Investigator suspected was probably related to verdinexor that was severe in intensity or serious or Indicative of an unacceptable risk to additional participants in the study in the opinion of the Investigator or Sponsor.
Time frame: From start of study drug administration up to Day 8
Population: MTD was not achieved at study completion due to early termination of study prior to observing protocol-specified DLT criteria. Therefore, no data was reported for this outcome measure.
Secondary
Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor
Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.
Time frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose
Population: PK population included all participants who received at least 1 dose of verdinexor, had a pre-dose (baseline) blood draw, and had at least 1 qualified (above the LOQ post-dose PK sample. Here, 'number analyzed' signifies number of participants evaluable at specific time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 1 | 3.0 hours |
| Placebo | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 3 | 3.0 hours |
| Verdinexor 5 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 3 | 3.0 hours |
| Verdinexor 5 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 1 | 4.0 hours |
| Verdinexor 10 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 3 | 3.0 hours |
| Verdinexor 10 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 1 | 3.0 hours |
| Verdinexor 20 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 1 | 4.0 hours |
| Verdinexor 20 mg | Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor | Day 3 | 3.0 hours |