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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Verdinexor
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From start of study drug administration up to Day 33 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 
| 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. | 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 | 
| Maximum Observed Concentration (Cmax) of Verdinexor | Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data. | 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 | 
| 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. | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose | 
| 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. | 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 (Kel) of Verdinexor | Elimination rate constant was calculated using linear regression on the terminal portion of the log-linear concentration versus time curve. | 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 Half-life (t1/2) of Verdinexor | t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel. | 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 (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]). | 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 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). | 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 (AR) of Cmax | An AR was defined as a ratio of mean of Cmax Day 3/ Cmax Day 1 for plasma 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 | 
| 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. | Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose | 
| 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. | 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 (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. | 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 | 
| 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. | From start of study drug administration up to Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KPT-335, Verdinexor, Karyopharm, First-in-Human, Adult Subjects