Abstract

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 (FodosineTM) 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.

Clinical and Pharmacodynamic Activity of Oral Forodesine In CTCL Patients

Patient Diagnosis Dose (mg/m2Treatment Plasma dGuo (Cmax, M) μ Clinical Response 
PR = partial response; MR = minor response; SD = stable disease; PD = progressive disease; N/A = not available 
2001 Sezary syndrome (IVA) 40 Completed 0.6 PR 
3001 Mycosis fungoides (IVB) 40 Completed 1.7 PD 
3002 Mycosis fungoides (IIB) 40 Completed 1.2 MR 
3003 Mycosis fungoides (IB) 80 Completed 1.2 MR 
3004 Sezary syndrome (IVA) 80 Completed 1.0 MR 
3005 Sezary syndrome 80 Completed 1.6 PD 
2002 IIA 80 Completed 1.1 PR 
2003 III 80 Completed 1.7 N/A 
3006 Mycosis fungoides/Sezary syndrome (IVB) 160 Completed 2.8 SD 
4001 III 320 Completed 1.8 N/A 
1001 Mycosis fungoides (IB) 320 Completed 1.3 N/A 
3012 Mycosis fungoides/Sezary syndrome (IVA vs B) 320 Not Completed N/A Not evaluable 
Patient Diagnosis Dose (mg/m2Treatment Plasma dGuo (Cmax, M) μ Clinical Response 
PR = partial response; MR = minor response; SD = stable disease; PD = progressive disease; N/A = not available 
2001 Sezary syndrome (IVA) 40 Completed 0.6 PR 
3001 Mycosis fungoides (IVB) 40 Completed 1.7 PD 
3002 Mycosis fungoides (IIB) 40 Completed 1.2 MR 
3003 Mycosis fungoides (IB) 80 Completed 1.2 MR 
3004 Sezary syndrome (IVA) 80 Completed 1.0 MR 
3005 Sezary syndrome 80 Completed 1.6 PD 
2002 IIA 80 Completed 1.1 PR 
2003 III 80 Completed 1.7 N/A 
3006 Mycosis fungoides/Sezary syndrome (IVB) 160 Completed 2.8 SD 
4001 III 320 Completed 1.8 N/A 
1001 Mycosis fungoides (IB) 320 Completed 1.3 N/A 
3012 Mycosis fungoides/Sezary syndrome (IVA vs B) 320 Not Completed N/A Not evaluable 

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