Phase I/II Study of Oral Fodosine^TM, a PNP Inhibitor in Refractory Cutaneous T-Cell Lymphoma Patients.

Suppression of T-cell immunity seen in children with inherited purine nucleoside phosphorylase (PNP) deficiency supports the potential application of PNP inhibitors for the therapy of T-cell malignancies. Forodesine (Fodosine^TM) is a specific PNP inhibitor that raises plasma 2′-deoxyguanosine (dGuo) and intracellular dGTP levels, leading to T-cell apoptosis. IV administration of forodesine has shown activity in cutaneous T-cell lymphoma (CTCL) patients. To determine the safety, pharmacokinetics and pharmacodynamics of oral forodesine in patients with refractory CTCL, as well as preliminary evidence of efficacy, five cohorts of patients (≥ 3patients per cohort) were evaluated sequentially, receiving forodesine at 40, 80, 160, 320, and 480 mg/m² once per day for 28 days. At the end of the treatment cycle (Day 28), all patients with stable or improved disease could enter a long-term, follow-up period. To date, 12 patients have been treated, 11 completing the 28-day cycle. Forodesine is orally absorbed (40%–50%), mean terminal half-life of 12 to 20 h. dGuo levels were elevated in all patients (0.8–2.8 μM, predose levels ≤ 0.004 μM). Forodesine was generally safe and well tolerated in this population. Safety data is available for first 7 patients. No serious adverse events possibly related to the drug occurred. The most common adverse event possibly drug related was nausea (2 patients). Of the 11 patients completing the treatment cycle, 9 began long-term treatment. Of these 9 patients, 4 have received >3 months of treatment, while 1 patient continues to receive for >8 months. Efficacy data are available for 8 patients: 2 with partial response, 3 with minor response, 2 with progressive disease, and 1 with stable disease (Table). Forodesine showed preliminary evidence of clinical activity in refractory CTCL patients. Additional clinical and pharmacodynamic data will be presented.