Results of A Phase I Study of Milatuzumab, a Humanized Anti-CD74 Antibody, and Veltuzumab, a Humanized Anti-CD20 Antibody, In Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma,

Preclinical studies conducted at our institution (Alinari et al. Blood. 2011;117:4530–41) demonstrated superior efficacy of milatuzumab (Immunomedics, Inc.), a humanized anti-CD74 antibody, in combination with rituximab in vitro and in an in vivo preclinical model of mantle cell lymphoma (MCL), compared to either agent alone. Veltuzumab (Immunomedics, Inc.), a humanized anti-CD20 antibody, has been reported to have several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. As a result of the anti-tumor activity observed in vitro with combined veltuzumab and milatuzumab, we initiated a phase I/II trial in pts with relapsed or refractory B-cell NHL after at least 1 prior therapy to determine the safety, tolerability, and overall response rate with this combination.

Pts received veltuzumab 200 at mg/m² weekly combined with escalating doses of milatuzumab at 8, 16, and 20 mg/kg twice per wk of wks 1–4, 12, 20, 28, and 36. All pts received premedication with acetaminophen, diphenhydramine, hydrocortisone 50 mg, and famotidine prior to veltuzumab and milatuzumb doses. Dose limiting toxicity (DLT) was defined during weeks 1–4. Although not defined as DLT, 3 of the first 6 pts enrolled at dose levels 1–2, had significant grade 3 infusion reactions with milatuzumab. The study was amended to separate veltuzumab and milatuzumab dosing days and add 20 mg dexamethasone immediately prior to and 10 mg post-milatuzumab. Enrollment resumed with 3 additional pts at dose levels 1 and 2 in order to determine if tolerability was improved.

The phase I study has completed enrollment with 18 pts (follicular NHL grade 1–2 n=5; grade 3 n=5; transformed follicular n=1; diffuse large B-cell lymphoma (DLBCL) n=4; marginal zone lymphoma (MZL) n=1; MCL n=1; and lymphoplasmacytic lymphoma n=1) that have completed at least 4 weeks of combination therapy. Median age was 65 years (range 44–81), and pts received a median of 3 prior therapies (range 1 – 9), including 3 pts who had undergone prior autologous stem cell transplant. Ten of 18 (56%) pts were refractory to rituximab defined as having less than a partial response to the last rituximab-containing regimen. No DLTs were observed, and no pts experienced grade 3 infusion reactions after the protocol was modified. Other grade 3–4 toxicities at least possibly related to protocol therapy consisted of lymphopenia (n=8, 44%), fatigue (n=2, 11%), neutropenia (n=1, 6%), hyperglycemia (n=1, 6%), and anemia (n=1, 6%). Grade 1–2 infections (n=5, 27%) included thrush, sinusitis, and pneumonia with no pts requiring dose delays or hospitalization. Other frequently observed grade 1–2 toxicities were transient hyperglycemia (n=12, 66%), thrombocytopenia (n=11, 61%), reversible infusion reactions (n=9, 50%), fatigue (n=8, 44%), leukopenia (n=8, 44%), and anemia (n=7, 39%). Human anti-veltuzumab and anti-milatuzumab antibodies, collected pretreatment and day 1 of weeks 4, 12, and 36, have not been detected in any pt. Pharmacokinetic data available from 16 pts through week 10 indicated mean plasma veltuzumab and milatuzumab concentrations immediately post-infusion were 108 ± 7 and 296 ± 22 μg/mL, and mean trough levels were 47 ± 7 and 3 ± 0.3 μg/mL, respectively. All 18 pts were assessable for response at wk 5 with 5 pts currently remaining on active therapy and 4 pts completing treatment through wk 36. To date, complete response was observed in 1 pt with grade 1–2 follicular NHL (3 prior therapies) who was rituximab-refractory and ultimately underwent allogeneic transplant. Partial responses were observed in 3 pts; 2 with grade 3 follicular NHL refractory to rituximab (3 prior therapies including autologous transplant and 5 prior therapies, respectively) and 1 with MZL (1 prior therapy). All responding pts achieved response following induction therapy. Stable disease was observed in 10 pts; of these pts, 6 pts had SD of a median duration of 6 months (range 2.5–10 months) and 4 remain on active therapy.

Combination therapy with veltuzumab and milatuzumab was well-tolerated in a population of heavily pre-treated pts with relapsed or refractory NHL. 14/18 pts had evidence of antitumor activity with 22% having an objective overall response, including rituximab-refractory pts.

Christian:Immunomedics, Inc.: Research Funding. Off Label Use: Veltuzumab and milatuzumab in non-Hodgkin's lymphoma is off-label drug use. Wegener:Immunomedics, Inc.: Employment, Management and Stock / Stock-options. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.