A Phase II Trial of Darinaparsin in Advanced Lymphomas: Report on Safety and Activity.

Darinaparsin (ZIO-101) is a novel organic arsenic molecule that has a mechanism of action mediated by targeted disruption of mitochondrial function, modified signal transduction, and antiangiogenesis. It is active against diverse cancers in vitro. This Phase II multi-center trial is being conducted in patients diagnosed with advanced lymphomas that have received at least 1 prior therapy and require additional treatment. Patients receive 300 mg/m² of darinaparsin intravenously for 5 consecutive days every 28 days (1 cycle) and are then evaluated for efficacy and safety by standard criteria. Treatment continues until toxicity or progression. To date the study has accrued 22 patients (15 non-Hodgkin’s [NHL], 7 Hodgkin’s); 12 are male and 10 are female. Median age at baseline was 60.5 years (range: 28–80), ECOG performance status was ≤2, and median number of prior therapies was 4 (range 2–6). Thirteen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 (diagnosed with PTCL) has achieved a complete response (CR) and 3 (diagnosed with marginal zone transformed to diffuse large B-cell, marginal zone, and Hodgkin’s nodular sclerosis, respectively) have achieved partial responses (PRs). These patients had been heavily pretreated (PTCL: CHOP, ICE, and EPOCH; marginal zone transformed to diffuse B-cell: RCHOP, RICE, RT and autologous bone marrow transplantation; marginal zone: rituximab, RCVP, and gemcitabine; and Hodgkin’s: ICE, CBV, gemcitabine+ MDX-060, and stem cell transplant). In the patient with transformed diffuse large B-cell lymphoma who achieved PR, no evidence for macroscopic disease was present, but microscopic low-grade marginal zone lymphoma was detectable in random biopsies from normal-appearing gastric mucosa. In addition, 2 patients (diagnosed with PTCL and Hodgkin’s, respectively) have achieved stable disease (SD). The only Grade 3 adverse event (AE) considered drug-related was wheezing. A total of 12 subjects have reported 37 serious adverse events (SAEs) while on study. Of these, only 2 had SAEs that were considered drug-related (neutropenic fever, fall). In conclusion, darinaparsin has been very well tolerated and has demonstrated promising activity in heavily pretreated patients diagnosed with advanced lymphoma. Initial responses (1 CR, 3 PRs, 2 SDs) have been observed among 13 evaluable patients. Accrual continues; additional safety and efficacy data will be reported.