Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphomas: Final Results from a Phase 1-2 Trial

Background: Clofarabine is a second-generation purine analogue FDA-approved as an intravenous formulation for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL). Clofarabine may offer pharmacologic advantages over other nucleoside analogues including being a more efficient substrate for deoxycytidine kinase, more completely inhibiting ribonucleotide reductase and DNA polymerase α, and demonstrating improved activity in cells that are non-dividing or have a low proliferation rate. This phase 1-2 trial studied an oral formulation of clofarabine in relapsed or refractory NHL.

Methods: Patients were eligible if they had relapsed or refractory NHL of any histologic subtype. All pts were required to have adequate organ function and performance status ≤2 as well as absence of CNS involvement. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1-21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design followed by a 10 patient dose expansion at the recommended phase 2 dose (RP2D). The phase 1 portion of this study has been published (Leuk Lymph 2013; 45:1915-1920). Phase 2 was designed to enroll 24 additional subjects. The primary endpoint in phase 2 was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A total of 50 patients were accrued on the phase 1-2 trial; 31 subjects were treated in phase 1 and 19 in phase 2. Phase 2 accrual was stopped prematurely due to discontinuation of the drug formulation used in the study. All patients treated at the RP2D (n=36) are included in the phase 2 efficacy analysis since there were no differences in treatment or follow-up for these patients.

Results: The median age for all patients was 69 years (range 45-92). Eighty-two percent had advanced stage at study entry. The median number of prior regimens was 2 (range 1-7) and 4 patients had prior auto stem cell transplant. Histologies included follicular lymphoma (FL, 13 pts), small lymphocytic lymphoma (SLL, 8 pts), diffuse large B-cell lymphoma (DLBCL, 6 pts), marginal zone lymphoma (MZL, 11 pts), mantle cell lymphoma (MCL, 9 pts), T-cell lymphoma (TCL, 2 pts) and lymphoplasmacytic lymphoma (LPL 1 pt). The 3mg dose was declared the RP2D, as previously reported. The most common toxicities were anemia (78%), leukopenia (66%), neutropenia (64%), thrombocytopenia (62%) and fatigue (60%). Twenty-nine patients (58%) experienced at least one grade 3-4 toxicity. The most common grade 3-4 toxicities were leukopenia and neutropenia (48%), thrombocytopenia (30%), anemia (14%) and fatigue (6%). There were 2 deaths on study, both considered unrelated to study drug (cardiac arrest, progressive disease). The median number of cycles administered was 4, and 18 patients (36%) completed all 6 cycles of therapy. The most common reasons for discontinuing therapy were progressive disease (34%) and toxicity (16%).

Of 50 patients on study, the ORR was 28% (95% CI: 16 - 42%) with complete response rate (CRR) of 10% (95% CI: 3 - 22%). An additional 36% had stable disease (SD). By histology, responses were seen in 5/11 MZL, 4/9 MCL, 3/8 SLL, 3/13 FL, and 1/1 LPL. No responses were observed in DLBCL or TCL, although an angioimmunoblastic T-cell lymphoma patient had SD with a 42% reduction in tumor volume, and a mycosis fungoides patient had significant reduction in cutaneous disease burden. Among 36 patients treated at the RP2D and included in the phase 2 analysis, the ORR was 28% (95% CI: 14 - 45%) with CRR of 8% (95% CI: 2 - 22%), and 44% of patients with SD. A higher proportion of patients treated at a non-RP2D experienced progressive disease on study (43% vs. 28% in the RP2D cohort). The median PFS was 5.5 months, and the one- and two- year PFS were 32% (95% CI: 20%, 45%) and 16% (95% CI: 7.5%, 27%), respectively. The median duration of follow-up was 3.8 years, with 26 patients alive and 22 deceased at last follow-up; two patients were lost to follow-up. The median OS was not reached, and the 3 year OS was 58% (95% CI: 43%, 71%).

Conclusion: Oral clofarabine is generally well tolerated and produces disease control in a substantial proportion of patients with relapsed/refractory NHL, particularly in indolent histologies and MCL.