Phase 1-2 multi-center study of intravenous Bcx-1777 in patients with refractory cutaneous T-cell lymphoma.

6733 Background: Cutaneous T-cell lymphomas (CTCL) including the leukemic variant, Sezary Syndrome (SS) are incurable extra-nodal non-Hodgkin's lymphomas caused by accumulation of skin homing T-cells. Bcx-1777 is a small molecular weight inhibitor of purine nucleoside phosphorylase (PNP). PNP deficiency results in an accumulation and preferential phosphorylation of deoxyguanosine (dGuo) leading to T cell apoptosis and decreased response to mitogens. Thus, PNP inhibition may be expected to be therapeutic. METHODS: A multi-center, open-label dose escalation phase 1-2 study was conducted in patients with refractory CTCL who had failed four prior therapies (stage IB-IIA) or one systemic therapy (stage IIB-IVB). Bcx-1777 was administered by 30 min IV infusion q. 12 hrs.x 9 doses and courses were repeated every 16 days x 3. Pharmacokinetic sampling was performed. Clinical response was determined each course using a weighted composite of disease assessment from baseline. Safety visits were conducted weekly. RESULTS: Ten CTCL patients have received at least one course of therapy at dose levels of 40 mg/m2 (n=4), 60 or 90 mg/m2 (n=3 each). One CR occurred at the first dose level, but the patient developed lethal catheter related sepsis. Minor responses were seen in four SS pts. who experienced improved erythroderma, pruritus, adnenopathy, and decreased numbers of atypical cells by flow cytometry. Side effects were minimal and included headache following the infusion (5 pts), pedal edema (4 pts), and vertigo, myalgia, or herpes zoster (1 pt, each). Hyperuricemia was seen in a SS pt. but no other dose limiting toxicities were experienced. Plasma deoxyguanosine (dGuo) levels were increased during therapy. CONCLUSIONS: This preliminary dose escalation study supports further investigation and formulation of the PNP inhibitor Bcx 1777 for treatment of CTCL patients. [Table: see text].

Duke Scholars

Author Elise Arline Olsen Dermatology