Comparison Of Two Dosing Schedules For Subcutaneous Injections Of Low-Dose Anti-CD20 Veltuzumab In Relapsed Immune Thrombocytopenia: Final Results Of a Phase I Study

As a 2nd-generation humanized anti-CD20 monoclonal antibody, veltuzumab has structure-function differences from rituximab and has shown increased potency in comparative preclinical studies (Goldenberg et al., Blood. 113(5):1062-70, 2008). In non-Hodgkin lymphoma (NHL), subcutaneous (SC) injections of low-dose veltuzumab using a high-concentration formulation demonstrated activity (Negrea et al., Haematologica. 96:567-73, 2011) comparable to that achieved previously by intravenous infusions (Morschhauser et al., J Clin Oncol. 27:3346-53, 2009). The prospect of SC veltuzumab for treating autoimmune diseases is particularly attractive. We present final phase I results from a multicenter study comparing two dosing schedules of low-dose SC veltuzumab administered as a monotherapy in immune thrombocytopenia (ITP).

Adults with primary ITP who failed ≥1 standard therapy were eligible if platelets were ≤30 K/μL without major bleeding. In Cohort 1, 80, 160, or 320 mg SC veltuzumab doses were given twice, 2 weeks apart (total dose 160, 320, 640 mg, respectively). All patients in Cohort 2 received once-weekly 320 mg doses for 4 weeks (total dose 1280 mg). Steroids or other premedications were not required. An objective response (OR, ≥30 K/μL platelets twice, one week apart, and at least doubled from baseline) was classified as complete (CR) if ≥100K μL, otherwise as partial (PR). For responders, time to relapse (TTR) was measured from first injection to relapse with platelets below 30K/μL, initiation of subsequent treatment, or lost to follow-up. Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers.

A total of 50 patients (31 female/19 male, median 54-years old, 8 post splenectomy) were enrolled in Cohorts 1 (N=34) and 2 (N=18, including 2 rollovers). They were a median of 2 years from diagnosis of ITP; 14 patients had newly-diagnosed or persistent disease (ITP ≤ 1 year) treated with corticosteroids and/or immunoglobulins, and 36 patients had chronic disease (ITP > 1 year) and also had received azathioprine or danazol (N=15), thrombopoietin-receptor agonists (N=10), rituximab (n=7), platelets (N=5) or chemotherapy (N=4). SC veltuzumab was well tolerated with a limited number of AEs (all Grade 1-2 transient injection reactions) and no other safety issues. At all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with each injection, achieving mean Cmax values of 11.7, 19.3 and 40.6 µg/mL at dose levels of 80, 160, and 320 mg, respectively, in Cohort 1, and 67.0 µg/mL at 320 mg in Cohort 2. HAHA titers were positive in 7 patients; interestingly, 4 had ORs, including 3 CRs. Three patients given rescue medication for rapidly decreasing platelets at study entry were inevaluable for treatment response. Of 47 evaluable patients, 22 (47%) had ORs, including 13 (28%) CRs, which differed little with ITP duration (≤1 year: 51% OR, 29% CR; >1 year: 42% OR, 27% CR). For responders, median TTR was comparable for CRs and PRs (7.9 vs 7.6 months, respectively) but decreased with ITP duration (14.4 vs 6.9 mo. for ≤1 year vs >1 year, respectively). OR and PR rates tabulated below for each dose group show meaningful activity (including CRs) already achieved at the lowest dose level, with no evidence of dose-dependent response rates, although response duration appears increased with higher total doses delivered.

Low-dose SC veltuzumab was convenient, well-tolerated, with good B-cell depletion and therapeutic activity across all dose levels and with comparable outcome when administered as 2 doses, 2 weeks apart, or as 4 consecutive weekly doses. These results support further studies in ITP combining SC veltuzumab with other agents or given as a maintenance regimen.

Liebman:Immunomedics: Research Funding. Off Label Use: Veltuzumab is investigational agent for treatment of ITP. Bussel:Immunomedics: Research Funding. Saleh:Immunomedics: Research Funding. Horne:Immunomedics: Employment, Equity Ownership. Wegener:Immunomedics: Employment, Equity Ownership. Goldenberg:Immunomedics: Employment, Equity Ownership.