Forodesine, a Purine Nucleoside Phosphorylase (PNP) Inhibitor, Shows Clinical Activity In a Phase 2 Trial In Patients with Previously Treated Chronic Lymphocytic Leukemia (CLL) – Interim Analysis

• Published in: Blood 2010-11, Vol.116 (21), p.1397-1397
• Main Authors: Sher, Taimur, Azar, Jose, Spurgeon, Stephen, Catalano, John, Furman, Richard R., Prince, Miles, Bartlett, Nancy L., Durrant, Simon, Boccia, Ralph, Masood, Aisha, Lyman, Scott, Cantey-Kiser, Jean, Sheridan, William P, Chanan-Khan, Asher
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.1397.1397

Abstract 1397 Forodesine is a potent, specific transition-state inhibitor of the purine salvage pathway enzyme PNP. It induces apoptosis in primary CLL cells through accumulation of deoxyguanosine triphosphate. Unlike other nucleoside analogues, forodesine is not phosphorylated, is not incorporated into DNA and is not cytotoxic. Previous phase 1 and 2 studies showed clinical activity in T-cell acute lymphoblastic leukemia (i.v. forodesine) and cutaneous T-cell lymphoma (i.v. and oral). In a single institute exploratory study 5 of 13 (38%) CLL patients demonstrated anti-leukemic effects (decrease in peripheral blood malignant lymphocyte counts) with oral forodesine (200mg QD). However none of the patients achieved remission. Forodesine is absorbed via a saturable mechanism, and in a clinical pharmacology study in normal subjects, 200mg twice-daily (BID) dosing was found to partially overcome the exposure limits from once daily dosing; the 200mg BID regimen was used in the current study. This is a multicenter phase II open label study. Eligible CLL patients had either failed at least 1 prior therapy (progressive disease [PD] or refractory) or were treatment-naïve provided age was >65 or ECOG 2 or 3, or unable to tolerate standard therapy. Among the 26 patients enrolled 1 was deemed ineligible (Waldenstrom's). The median age was 70 (48-92) years, 65% male and 77% had Rai Stage III/IV disease. The median duration from time to CLL diagnosis was 92.7 (8.4-243.5) months. Features of high-risk disease were del (17p) (n=6), ZAP70+ (n=13), and CD38+ (n=15). All patients had relapsed or refractory CLL with a median of 2 (1-21) prior therapies including fludarabine (76%), alkylating agents (72%), anti-CD20 monoclonal antibodies (72%) and experimental agents (36%). Interim analysis was conducted when 13 patients had been observed for ≥ 6 months: maximum duration of continuous BID forodesine therapy was 364 days. At the date of data cut-off, 20 were evaluable for response (5 were not evaluable because they had received < 8 weeks of therapy), and 12 were still on study. The revised NCI-WG (1996) criteria were used for response assessment. Partial remission was noted in 3 (15%) patients. Additionally 12 (48%) patients demonstrated stabilization of disease. PR onset was noted at 2, 6 and 6 months of therapy. Three patients discontinued due to adverse events (AEs). Serious AEs were reported in 18 patients. Individual SAEs reports included 7 cases of febrile neutropenia, 7 c