Low-Dose Humanized Anti-CD20 Monoclonal Antibody (MAb), Veltuzumab, in Adult Immune Thrombocytopenic Purpura (ITP): Initial Results of a Phase I/II Study.

BACKGROUND: Veltuzumab (hA20), a humanized MAb with significant structurefunction differences from rituximab, has shown clinical activity at low doses in non- Hodgkin’s lymphoma. Since anti-CD20 immunotherapy has demonstrated activity in ITP with standard doses of rituximab, we hypothesized that low-dose veltuzumab would be effective in this disorder, thus also justifying subcutaneous injections. The goal of this first study in ITP is to evaluate the safety and tolerability of veltuzumab administered at low doses either intravenously or by subcutaneous injection, to obtain information on efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity, and to determine feasible doses for further studies.

METHODS: A multicenter, phase I/II study was initiated in adult ITP patients with platelets <30K/μL, and a prior history of platelets <150K/μL for >6 months, who had failed ≥1 standard therapy. Patients were administered 2 doses of veltuzumab 2 weeks apart and evaluated for efficacy over 12 weeks, with responding patients continuing evaluation in long-term follow-up. Efficacy was assessed by platelet level responses with increases confirmed at least 1 week apart classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL) responses. Adverse events and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Pharmacodynamics were evaluated by B-cell levels (CD19), while pharmacokinetics and immunogenicity were evaluated by serum veltuzumab levels and human anti-veltuzumab antibody (HAHA) titers, respectively, using an ELISA assay performed by the Sponsor.

RESULTS: Seven patients (5F/2M, median age 41, 2 splenectomized) have now received intravenous veltuzumab at doses of 80 mg (N=3), 120 mg (N=3) or 200 mg (N=1). They had ITP for 0.5 – 12 years, had received prior steroids (N=7), IVIG and/or WinRho (N=6), or chemotherapy (N=3), and had 6–27 K platelets/μL and Grade 0–1 bleeding scores at study entry. One patient withdrew after receiving 100 mg and experiencing a Grade 3 infusion reaction, subsequently undergoing splenectomy. Otherwise, the treatment was well tolerated with all infusions completed within 60 – 90 minutes. Of the 6 evaluable patients, all 4 non-splenectomized patients responded to treatment with at least a doubling of their baseline platelet levels, achieving 2 CRs, 1 PR, and 1 MR. At present, both CRs are still continuing with >100 K platelets/μL at 16 and 24 weeks after treatment. The patient with a PR, who was treated at 80 mg, had platelets decreased <30K/μL at 11 weeks, but then achieved a second PR after retreatment at 120 mg, which is now ongoing 6 weeks later. The patient with MR still has platelets at least double the baseline levels at 12 weeks. Although neither of the 2 splenectomized patients responded, one had spontaneously increased platelets >30 K/μL just prior to 1^st infusion and has continued to maintain these levels now 12 weeks after treatment, while the other has since been treated with cyclosporine, also without response. Veltuzumab quickly depleted B cells after the first dose, with decreases sustained >12 weeks. Even at these low doses, veltuzumab achieved expected serum levels (mean Cmax, 20.3 and 46.0 μg/mL at 80 and 120 mg, respectively) and remained in circulation without evidence of rapid clearance or sequestration (mean post-treatment half-life ~1 week). Two patients developed low-level positive HAHA results of uncertain clinical significance after treatment.

CONCLUSIONS: These initial results indicate that doses of 80 or 120 mg veltuzumab have acceptable safety and demonstrate promising activity for ITP, including durable complete responses. Based on these findings, the study is proceeding, with patients now being recruited for therapy with low-dose veltuzumab administered by subcutaneous injection.