Response to Oral Forodesine in Refractory Cutaneous T-Cell Lymphoma: Interim Results of a Phase I/II Study.

Background: Forodesine is a rationally designed, potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of dGTP and then apoptosis. Intravenous forodesine has demonstrated activity in treatment of cutaneous T-cell lymphoma (CTCL) and served as the basis for the design of an oral forodesine Phase I/II trial Methods: An open label dose escalation study of oral forodesine (40 mg/m 2 to 320 mg/m 2 QD) for 4 weeks was performed to determine the maximum tolerated dose (MTD) and/or the optimal biologic dose (OBD) based on PK, and PNP inhibition as evidenced by elevation of plasma deoxyguanosine (dGuo) levels. Additional subjects were accrued at the optimal dose (80 mg/m 2 ) to further assess clinical safety and efficacy. Patients with previously treated, refractory CTCL with stage IB disease or higher were eligible. The primary efficacy endpoint (objective response rate [ORR]) for this analysis was defined as at least a 50% decrease in modified severity-weighted assessment tool (mSWAT) from baseline maintained for at least 28 days. Only subjects who had at least 6 months follow-up as of March 1, 2007 were included in this analysis. Results: Although an MTD was not reached, based on plateau of the AUC versus dose plot at and above 80 mg/m 2 , and the same observation for plasma dGuo versus dose, 80 mg/m 2 was judged as an OBD. The 36 subjects treated at 80 mg/m 2 are the main subject of this report. Median age was 61.6 years (range 28.4–81.1) and 67% were males and were exposed to a median of 3 prior systemic therapies (range 0, 8). The ORR using mSWAT was 39% (14/36) with a median duration of response of 127 days (25%–75%, 71 - NA). Response by stage was: IB 3/9, IIA 1/1, IIB 3/5, III 4/12, IVA 2/5, IVB 1/4. Median time to response was 42 days (25%–75%, 29–58). The median time on treatment was 131 days (range 1, 479) with 6 subjects remaining on treatment. For subjects with Sezary Syndrome (n=20, defined by ISCL B2 classification), the ORR by mSWAT was 40%, and 65% by erythroderma score. More than a 50% reduction in Sezary cells (detected by flow cytometry) was observed in 9/20 (45%) subjects with SS. For all 56 forodesine-treated subjects, the only grade 3 or higher non-laboratory adverse events (without regard to attribution and observed in at least 2 subjects) were diarrhea, acute renal failure (not related), cellulitis, and rash (2 subjects each). The only grade 3 or higher related non-laboratory AEs were vertigo, diarrhea, generalized edema, and pneumonia (1 each). For laboratory events, a single grade 3 elevation for each of the following liver-related parameters was noted: AST, ALT, bilirubin, and alkaline phosphatase. There were no grade 3 or higher elevations of creatinine. Grade 3 or higher lymphopenia and low CD4 counts were observed in 71% and 31% of subjects and these rates were similar across dose groups. Median baseline, nadir, and last visit lymphocytes counts (1000/mm 3 ) were 0.8 (95%CI: 0.0, 6.0), 0.2 (95% CI: 0.0, 0.8), and 0.6 (95% CI: 0.0, 2.9) respectively. Hematopoietic toxicity was limited to 1 episode of grade 3 neutropenia, and 1 episode of grade 3 anemia. Conclusion: Oral forodesine demonstrates clinical activity in subjects with refractory CTCL, including those with SS, with minimal toxicity to date.