Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma

Abstract

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Keywords: Forodesine; Overall response rate; Peripheral T cell lymphoma; Progression-free survival; Purine nucleoside phosphorylase inhibitor.

Fig. 1

Disposition of patients in phase 1 and phase 2

Fig. 2

Scatterplots of lymphocyte subsets at baseline and on day 15

Fig. 3

Duration of response (n = 10 responding patients) (a), progression-free survival (b), and overall survival (OS) (c) among evaluable phase 2 patients (n = 41)

Fig. 4

Progression-free survival (a) and overall survival (b) among responders and non-responders in the phase 2 populations. CI confidence interval, NE not estimable

Fig. 5

Reduction of target lesions measured by the sum of the products of the greatest diameters in the phase 2 populations: waterfall plot of maximum reduction (a) and target lesion reduction rate (b). CR complete response, PD progressive disease, PR partial response, SD stable disease

Fig. 6

Plasma forodesine and 2′-deoxyguanosine (dGuo) concentrations. Concentration-time profile of plasma forodesine on days 1 and 15 (a), trough plasma forodesine concentrations from days 1 to 57 (b), concentration-time profile of plasma dGuo on days 1 and 15 (c), and trough plasma dGuo concentrations from days 1 to 57 (d)