Monotherapy with Subcutaneous (SC) Injections of Low Doses of Humanized Anti-CD20 Veltuzumab Is Active in Chronic Lymphocytic Leukemia (CLL)

Veltuzumab is a 2^nd generation humanized anti-CD20 monoclonal antibody with structure-function differences and improved preclinical properties compared to chimeric rituximab. In non-Hodgkin lymphoma, 4 SC injections of low-dose veltuzumab administered every other week demonstrated clinical activity (Negrea et al., Haematologica 2011;96:567–73), comparable to that demonstrated earlier with low veltuzumab doses delivered intravenously (Morschhauser et al., J Clin Oncol, 2009;27:3346–53), but avoiding the need for lengthy IV administration and dedicated infusion suites. In CLL, with high levels of circulating leukemic cells, more frequent and prolonged veltuzumab dosing may be required, which was investigated.

A multicenter, phase I/II study was undertaken to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of SC veltuzumab in patients with previously untreated or relapsed CD20+ CLL. Patients initially received the NHL dosing schedule with 4 doses administered every other week at 80, 160, or 320 mg (Cohort 1, cumulative dose range: 320 – 1280 mg). After protocol amendment, subsequent patients received 16 doses administered twice-weekly at levels of either 160 or 320 mg (Cohort 2, cumulative dose range: 2560 – 5120 mg). Evaluations included adverse events, routine safety assessments, CT scans, lymphocyte (ALC) and CD19+ B-cell blood levels, with serum veltuzumab levels and human anti-veltuzumab antibody (HAHA) titers measured by ELISA assays performed by the Sponsor. Efficacy was assessed by hematology-based NCI/IWCLL criteria 4 and 12 weeks post-treatment, with responding patients continuing follow-up until progression up to 2 years.

A total of 20 patients (10 males/10 females, 50 – 93 years old, 7.9 – 138.5 × 10⁹/μL WBC) were entered in Cohorts 1 (N=11) and 2 (N=9). Thirteen patients were treatment naïve, while 7 had received 1–6 prior treatments (including a rituximab-containing regimen in 6 patients). Most patients had Rai intermediate risk scores (N=14) and presented with one or more B symptoms (N=16). Pre-treatment with antihistamines or steroids was not required before SC veltuzumab. Veltuzumab was well tolerated with only transient Grade 1–2 injection-site reactions. One patient developed bacterial meningitis and withdrew during treatment, while another patient with a complicated medical history developed malignant hypertension, transient ischemic attack, and pneumonia 6 months after treatment; no other SAEs or Grade 3–4 events occurred. One patient previously treated with rituximab had anti-veltuzumab antibodies at study entry; HAHA response results for the other patients have all been negative. Circulating leukemic cells decreased after treatment in all patients by 7.7 to 90.8%, with 13 patients having >50% decreases from baseline, and 3 patients achieving ALC values <4000 cells/μL. Consistent with high and widely varying baseline ALC levels (5 – 116 cells x10⁹/μL), veltuzumab serum levels were often low and variable at all except the highest dose level, with mean Cmax values, respectively, of 1.8, 4.5, and 30.8 μg/mL at dose levels of 80, 160, or 320 mg in Cohort 1, and 36.2 and 199.5 μg/mL at dose levels of 160 and 320 mg in Cohort 2. By IWCLL criteria, 3 patients had partial responses (PR) (including 2 continuing relapse-free at 12 and 24 months) and 12 patients had stable disease (SD) as best response (most progressing within 12 weeks, but 4 remaining relapse-free for 6 – 12 months). Three patients progressed by first evaluation and 2 patients withdrew consent prior to any response assessment. As such, 15 (83%) of 18 evaluable patients achieved either PR or SD after treatment. Veltuzumab appeared active at all dose groups, and, despite increasing cumulative doses from 320 to 5120 mg delivered with these 5 dose groups, treatment responses and percent ALC decreases appeared similar regardless of dose level (80 vs. 160 vs. 320 mg) or dosing schedule (Cohort 1 vs. 2).

In CLL, with high levels of circulating leukemic cells, SC administration of veltuzumab is convenient, well-tolerated, and shows evidence of single-agent pharmacologic activity across a variety of dose levels and dosing schedules. These results support further studies in CLL, including combining veltuzumab with chemotherapy or given as a maintenance regimen.

Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.