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

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

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.

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Other: Placebo; Drug: Verdinexor

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 Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Nucleus Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): May 26, 2015
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: April 22, 2015
• First Submitted That Met QC Criteria: April 27, 2015
• First Posted (Estimate): May 1, 2015

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: January 19, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: First-in-Human; Karyopharm; KPT-335; Verdinexor; Adult Subjects
• Other Study ID Numbers: KCP-335-701

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No