The main goal of this Phase I/II SBIR application is to translate rapidly preclinical findings that show the advantage of using a combination radioimmunotherapy plus immunotherapy treatment regimen that uses non-competing antibodies for the improved treatment of aggressive non-Hodgkin's lymphoma [NHL;i.e., diffuse large B-cell lymphoma (DLBCL) and mantle cell (MC)] patients prior to or in place of a high-dose chemotherapy/transplant. This treatment paradigm is intended to provide a meaningful treatment alternative for aggressive NHL Phase I/II clinical trials with 90Y-epratuzumab (humanized anti-CD22 IgG) and veltuzumab (humanized anti-CD20 IgG) have established the maximum tolerated dose (MTD) of a fractionated injection of 90Y-epratuzumab, and the optimal biological dose of veltuzumab, with both agents showing encouraging anti-tumor responses in follicular and aggressive NHL. This study first will re-evaluate the MTD for the fractionated weekly injection of 90Y-epratuzumab (previously found to be 2 x 20 mCi/m2) in a standard Phase I setting, and then proceed immediately into a Phase II trial to evaluate response and safety. The treatment regimen consists of 2 courses of veltuzumab spaced 4 weeks apart, with each course consisting of 4 weekly 120 mg/m2 of veltuzumab). 90Y-epratuzumab will be co-injected with the 3rd and 4th veltuzumab injection during the first veltuzumab course. This treatment regimen is based on preclinical data showing how a consolidation treatment with veltuzumab amplifies the treatment response of a radioconjugate treatment, but also how current anti-CD20-based radioimmunotherapy regimens may be reducing the impact of the therapeutic response by co-administered large amounts of competing anti-CD20 IgG. By substituting a 90Y-anti-CD22 radioconjugate, we can gain greater benefit from the radioconjugate and still provide the immunotherapeutic boost in response. Thus, this treatment scheme optimizes the use of both the radio- and immuno-conjugate for treating NHL. Standard pharmacokinetics and imaging studies will be performed in addition to safety and efficacy monitoring. 111In-epratuzumab imaging studies will be performed before the first veltuzumab treatment and with the first 90Y-epratuzumab injection to determine if there are any changes in biodistribution as a result of the prior veltuzumab injections. With encouraging results from this study, the company expects to initiate a registration trial.
This project will assess the safety and efficacy of a new combination radioimmunotherapy and immunotherapy treatment paradigm that will be applied to aggressive non-Hodgkin lymphoma. The treatment consists of a fractionated 90Y-DOTA-humanized anti-CD22 IgG (epratuzumab) given in combination with a humanized anti-CD20 IgG (veltuzumab), given in conjunction with the radioimmunotherapy, as well as a consolidation follow-up.