Abstract: Background - Verdinexor is a selective inhibitor of nuclear export (SINE) conditionally approved by the FDA for treatment of lymphoma. SINE compounds have demonstrated encouraging results in in vitro preclinical studies when combined with cytotoxic chemotherapeutics; however, understanding the tolerability of combination strategies in tumor-bearing dogs is necessary before therapeutic activity can be assessed.
Hypothesis/Objectives - The primary objective is to define tolerability of verdinexor given concurrently with doxorubicin over a 42-day exposure period. Secondary objectives include evaluation of chronic tolerability of this combination over a 120-day period.
Animals - 20 client-owned dogs with spontaneous malignancy.
Methods - This was a single-arm, rolling six interpatient dose escalation trial. Dogs were administered doxorubicin (30mg/m2 or 1mg/kg for BW< 15kg) IV on day 0 and continued every 3 weeks. Verdinexor was started on day 7 at 1.0 mg/kg PO twice weekly, pending tolerability to doxorubicin and escalated or de-escalated at fixed dose increments according to rolling six design. Adverse events (AEs) were recorded/graded according to VCOG-CTCAE v2.0.
Results - Verdinexor dose regimens began at 1.0 mg/kg PO twice weekly, with increments of 0.25 mg/kg, to a maximum dose of 1.5 mg/kg. Dose-limiting toxicities were hematologic and gastrointestinal, with the maximal tolerated dose of verdinexor determined to be 1.25 mg/kg twice weekly when given concurrently with doxorubicin. No unexpected toxicities occurred. Incidence of AEs was not increased beyond that expected with single-agent doxorubicin.
Conclusions - Combination verdinexor and doxorubicin was well-tolerated and warrants further investigation to characterize whether efficacy is enhanced in this setting.
.jpg "Joelle M. Fenger, DVM, PhD, DACVIM (Oncology) (she/her/hers) photo")
