Phase I/Ii Study Of Subcutaneous Injections Of Low-Dose Anti-Cd20 Veltuzumab In Relapsed Immune Thrombocytopenia

Abstract Abstract 622 Background: Veltuzumab is a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, and evidence of higher potency preclinically (Goldenberg et al., Blood. 113(5):1062–70, 2008). In non-Hodgkin lymphoma (NHL), subcutaneous (SC) injections of low-dose veltuzumab were well-tolerated and demonstrated high activity (Negrea et al., Haematologica. 96:567–73, 2011), comparable to that achieved by intravenous infusions (Morschhauser et al., J Clin Oncol. 2009;27:3346–53). As such, we postulated that low-dose SC veltuzumab also may be effective and particularly convenient for treating autoimmune diseases, especially since a high-concentration formulation was developed. Hence, a multicenter, phase I/II study was undertaken to evaluate SC veltuzumab as a monotherapy administered in immune thrombocytopenia (ITP). Methods: 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 was given twice 2 weeks apart (total dose 160, 320, 640 mg, respectively). In Cohort 2, 320 mg veltuzumab was given weekly for 4 doses (total dose 1280 mg). Steroids or other premedications were not required. Best platelet response to treatment (on at least 2 occasions, one week apart) was classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL). For responders, time to relapse 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. Results: A total of 45 patients (28 female/17 male, median 54-years old, 8 post splenectomy) were enrolled in Cohorts 1 (N=34) and 2 (N=11). They were a median of 2 years from diagnosis of ITP; 12 patients had newly-diagnosed or persistent disease (ITP ≤ 1 year) treated with corticosteroids and/or immunoglobulins, and 33 patients had chronic disease (ITP > 1 year) and also had received azathioprine or danazol (N=14), thrombopoietin-receptor agonists (N=8), rituximab (n=6), platelets (N=6) 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, 6 had objective responses (OR: CR+PR+MR), including 3 CRs. Five patients were inevaluable for treatment response (3 given rescue medication for rapidly decreasing platelets at study entry, 2 still continuing treatment). Of the 40 evaluable patients, 27 (68%) had ORs, including 7(18%) CRs, 14 (35%) PRs, and 6 (15%) MRs. Follow-up data is mature for Cohort 1, with median time to relapse for 23 responders increasing by response category (MR: 2.1, PR: 5.7, CR: 14.2 months) and 8 (35%) responding > 1 year (2 ≥ 3 years). Ignoring the generally short-lived MRs, CR and CR+PR rates are tabulated below. Results for all evaluable patients (as well as only those with potentially more refractory chronic disease) show no evidence of dose-dependence, with meaningful activity (including CRs) already achieved at the lowest dose level. Conclusions: Low-dose SC veltuzumab was convenient, well-tolerated, with good B-cell depletion and promising activity in relapsed ITP. As a single agent, SC veltuzumab appears potent across a variety of dose levels and dosing schedules even in more heavily treated patients with chronic disease. These results support further studies in ITP combining SC veltuzumab with other agents or given as a maintenance regimen. Disclosures: Horne: Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.