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

• Maximum plasma concentration (Cmax) [ Time Frame: 46 days ]
• Maximum Tolerated Dose (MTD) Determination [ Time Frame: 46 days ]
• Area under the curve from 0 to 24 hours post-dose (AUC(0-24) [ Time Frame: 24 hours ]

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 subjects.

Cohorts of 8 subjects 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.

• Drug: Verdinexor
  Other Name: KPT-335
• Other: Placebo

• Experimental: Cohort 1
  5 mg verdinexor on Days 1 and 3 or Placebo
  Interventions:

  • Drug: Verdinexor
  • Other: Placebo
• Experimental: Cohort 2
  10 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor
• Experimental: Cohort 3
  20 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor
• Experimental: Cohort 4
  40 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor
• Experimental: Cohort 5
  60 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor
• Experimental: Cohort 6
  80 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor
• Experimental: Cohort 7
  100 mg verdinexor on Days 1 and 3
  Intervention: Drug: Verdinexor

Inclusion Criteria:

• Subjects must be in good health as determined by the investigator, based on the medical history, ECG, physical examination, and safety laboratory tests at screening.
• Subjects 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 subject 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 subject 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 subject with active cataracts or medical history of cataracts.