Trial of Safety and Tolerability of Oral Verdinexor (KPT-335) in Healthy Adults

• Sponsor: Karyopharm Therapeutics Inc (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02431364
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 5
• Actual Duration (Months): 4.2
• Patients Per Site Per Month: 7.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Verdinexor; Other: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential, Dose-Escalating Trial to Evaluate the Safety and Tolerability of Oral Verdinexor (KPT-335) in Healthy Adult Subjects
• Actual Study Start Date: May 26, 2015
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.	Other: Placebo; Participants received placebo matched to verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Experimental: Verdinexor 5 mg Participants received verdinexor 5 milligrams (mg) (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Drug: Verdinexor; Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral; Other Names: KPT-335
Experimental: Verdinexor 10 mg Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Drug: Verdinexor; Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral; Other Names: KPT-335
Experimental: Verdinexor 20 mg Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Drug: Verdinexor; Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral; Other Names: KPT-335
Experimental: Verdinexor 40 mg Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.	Drug: Verdinexor; Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral; Other Names: KPT-335

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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]).

9. 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).

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nucleus Network	Melbourne	Victoria	Australia

Sponsors and Collaborators

• Karyopharm Therapeutics Inc

Investigators

• Principal Investigator: Michael Kauffman, MD, PhD, Karyopharm Therapeutics Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Karyopharm Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT02431364
• Other Study ID Numbers: KCP-335-701
• First Posted: May 1, 2015
• Last Update Posted: Apr 13, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Karyopharm Therapeutics Inc: KPT-335; Verdinexor; Karyopharm; First-in-Human; Adult Subjects

Study Results

Participant Flow

Recruitment Details	This study was conducted at single site in Australia from 26 May 2015 to 1 October 2015.
Pre-assignment Detail	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.

Arm/Group Title	Placebo	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.	Participants received verdinexor 5 milligrams (mg) (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Period Title: Overall Study
STARTED	8	6	6	7	6
Treated	8	6	6	6	6
COMPLETED	8	5	6	6	6
NOT COMPLETED	0	1	0	1	0

Baseline Characteristics

Arm/Group Title	Placebo	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg	Total
Arm/Group Description	Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.	Total of all reporting groups
Overall Participants	8	6	6	6	6	32
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	27.0 (3.93)	24.0 (3.35)	26.5 (1.64)	26.3 (6.09)	27.8 (4.07)	26.4 (4.00)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	3 50%	4 66.7%	5 83.3%	5 83.3%	22 68.8%
Male	3 37.5%	3 50%	2 33.3%	1 16.7%	1 16.7%	10 31.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 33.3%	0 0%	0 0%	0 0%	2 6.3%
Not Hispanic or Latino	8 100%	4 66.7%	6 100%	6 100%	6 100%	30 93.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	7 87.5%	5 83.3%	5 83.3%	3 50%	6 100%	26 81.3%
Asian	0 0%	0 0%	1 16.7%	2 33.3%	0 0%	3 9.4%
Other	1 12.5%	1 16.7%	0 0%	1 16.7%	0 0%	3 9.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Description	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

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of verdinexor or placebo.

Arm/Group Title	Placebo	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	8	6	6	6	6
Participants with TEAEs	5 62.5%	6 100%	3 50%	4 66.7%	5 83.3%
Participants with TESAEs	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	215 (34.2)	445 (69.9)	862 (129.6)	1,856 (343.9)
Day 3	196 (34.3)	440 (103.4)	991 (218.1)	2,072 (521.6)

3. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	235 (34.3)	499 (75.1)	991 (145.0)	2,137 (371.0)
Day 3	218 (31.6)	491 (104.8)	1,052 (217.6)	2,141 (539.4)

4. Secondary Outcome

Title	Maximum Observed Concentration (Cmax) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	27.8 (7.48)	65.0 (12.13)	122 (26.3)	212 (81.6)
Day 3	24.8 (5.42)	56.2 (12.94)	116 (36.9)	252 (74.6)

5. Secondary Outcome

Title	Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	8.35 (1.835)	19.6 (2.71)	42.3 (9.97)	72.4 (25.63)
Day 3	8.73 (3.281)	17.3 (4.91)	44.4 (9.05)	86.7 (29.56)

6. Secondary Outcome

Title	Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	3.0	4.0	3.0	4.0
Day 3	3.0	3.0	3.0	3.0

7. Secondary Outcome

Title	Elimination Rate Constant (Kel) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	0.113 (0.0314)	0.091 (0.0227)	0.082 (0.0177)	0.097 (0.0306)
Day 3	0.103 (0.0282)	0.087 (0.0218)	0.090 (0.0381)	0.093 (0.0215)

8. Secondary Outcome

Title	Elimination Half-life (t1/2) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	6.6 (1.97)	8.0 (1.99)	9.0 (2.68)	7.8 (2.54)
Day 3	7.3 (2.85)	8.3 (1.91)	8.7 (2.97)	7.7 (1.76)

9. Secondary Outcome

Title	Apparent Total Body Clearance (Cl/F) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	0.32 (0.075)	0.30 (0.023)	0.31 (0.057)	0.32 (0.040)
Day 3	0.35 (0.068)	0.30 (0.039)	0.30 (0.059)	0.33 (0.102)

10. Secondary Outcome

Title	Apparent Volume of Distribution (Vd/F) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	6	6	6	6
Day 1	3.0 (0.96)	3.4 (0.89)	3.9 (0.52)	3.5 (1.01)
Day 3	3.6 (1.13)	3.6 (0.46)	3.6 (0.90)	3.7 (1.72)

11. Secondary Outcome

Title	Accumulation Factor (AR) of Cmax
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	5	6	6	6
Number [Ratio]	0.9	0.9	0.9	1.2

12. Secondary Outcome

Title	Accumulation Factor (AR) of Cavg0-24Hour
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	5	6	6	6
Number [Ratio]	1.0	0.9	1.1	1.2

13. Secondary Outcome

Title	Accumulation Factor (AR) of AUC0-t
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	5	6	6	6
Number [Ratio]	0.9	1.0	1.1	1.1

14. Secondary Outcome

Title	Accumulation Factor (AR) of AUC0-inf
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	5	6	6	6
Number [Ratio]	0.9	1.0	1.1	1.0

15. Secondary Outcome

Title	Maximum Tolerated Dose (MTD) of Verdinexor
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Verdinexor 5 mg	Verdinexor 10 mg	Verdinexor 20 mg	Verdinexor 40 mg
Arm/Group Description	Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.	Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.	Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.	Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Measure Participants	0	0	0	0	0

Adverse Events

Time Frame	From start of study drug administration up to Day 33
Adverse Event Reporting Description	Safety population included all participants who received at least 1 dose of verdinexor or placebo.
Arm/Group Title	Placebo		Verdinexor 5 mg		Verdinexor 10 mg		Verdinexor 20 mg		Verdinexor 40 mg
Arm/Group Description	Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.		Participants received verdinexor 5 mg (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.		Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.		Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.		Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
All Cause Mortality
	Placebo		Verdinexor 5 mg		Verdinexor 10 mg		Verdinexor 20 mg		Verdinexor 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Placebo		Verdinexor 5 mg		Verdinexor 10 mg		Verdinexor 20 mg		Verdinexor 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Verdinexor 5 mg		Verdinexor 10 mg		Verdinexor 20 mg		Verdinexor 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)		6/6 (100%)		3/6 (50%)		4/6 (66.7%)		5/6 (83.3%)
Cardiac disorders
Palpitations	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Abdominal pain	0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Diarrhoea	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		2/6 (33.3%)
Nausea	1/8 (12.5%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		4/6 (66.7%)
Toothache	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)
Vomiting	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
General disorders
Chills	0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Infections and infestations
Nasopharyngitis	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)
Upper respiratory tract infection	0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Investigations
Spermatozoa morphology abnormal	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)
Spermatozoa progressive motility decreased	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Metabolism and nutrition disorders
Decreased appetite	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Neck pain	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)
Pain in extremity	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Nervous system disorders
Dizziness	2/8 (25%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)
Dizziness postural	0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Headache	1/8 (12.5%)		2/6 (33.3%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)
Lethargy	0/8 (0%)		3/6 (50%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Somnolence	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Syncope	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Psychiatric disorders
Insomnia	0/8 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)
Dry skin	0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Vascular disorders
Phlebitis	0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)

Limitations/Caveats

This study was terminated due to administrative reasons.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.