Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma

Abstract

CD20 antibody with structural and functional differences from rituximab. 29,30 In NHL clinical trials, veltuzumab demonstrated single-agent activity comparable to rituximab even at low doses. 31,32 Preclinical studies showed that 90 Y-epratuzumab tetraxetan with veltuzumab substantially improved therapeutic responses compared to either agent alone. 33 As such, we hypothesized that both agents could be combined clinically for maximum therapeutic benefit without interfering with tumor targeting or increasing toxicity over that reported previously when the agents were given separately. Patients with aggressive NHL in whom frontline therapy has failed and who are not eligible for or refuse stem cell transplantation remain those most in need of effective therapies. This multicenter, open-label, phase I study was undertaken to determine an acceptable dose of 90 Y-epratuzumab tetraxetan in this population for use in combination with 200 mg/m 2 doses of veltuzumab, which in our prior studies had good therapeutic activity and achieved B-cell depletion. 31 MethodsAdults with aggressive B-cell NHL in whom one or more standard chemotherapy regimen had failed were eligible if they had at least one lesion ≥1.5 cm (but none >10 cm) detectable by computed tomography (CT), Eastern Cooperative Oncology Group score/L, serum creatinine and bilirubin levels ≤1.5 x institutional upper limits of normal (IULN), and aspartate and alanine transaminases ≤2.5 x IULN. Patients who had undergone a prior stem cell transplant, received NHL therapy within the preceding 4 weeks, taken corticosteroids within the preceding 2 weeks, had an infection requiring antibiotics within the preceding 5 days, had central nervous system or ≥25% lymphomatous bone marrow involvement or pleural effusion, had ≥25% irradiation of red marrow, prior radioimmunotherapy, or prior radiation >3000 cGy to the liver or >2000 cGy to lungs or kidneys were excluded.Patients In) and administered on day 8. Veltuzumab was infused over approximately 1 hour. Radiolabeled epratuzumab tetraxetan was then infused over several minutes. Premedication included antihistamines and antipyretics; corticosteroids were not administered routinely. Adverse events and laboratory abnormalities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 3.1, with dose-limiting toxicity (DLT) defined as grade 2 immediate-type allergic/hypersensitivity reaction; non-hematologic grade 3 or 4 toxicity of any duration; anemia, neutropenia, or thrombocytopenia either grade 4 for more than 7 days or not recovered to grade 1 by 12 weeks after treatment. Baseline assessments included lymphoma classification 34 and International Prognostic Index (IPI) scores. 35 CT images, with FDG-positron emission tomography (PET) or PET/CT optional, at baseline, 4 and 12 weeks after treatment, then every 3 months until progression, were evaluated by local radiologists and classified according to 2007 revised treatment response criteria 36 as showing a complete response, pa...

Radioimmunotherapy of human tumours

“…An alternative approach is to combine RIT targeting one antigen with unlabeled monoclonal antibodies targeting a different antigen, as has been done with 90 Y-epratuzumab tetraxetan (anti-CD22) combined with veltuzumab (anti-CD20). 59 …”

Tumour targeting and radiation dose of radioimmunotherapy with 90Y-rituximab in CD20+ B-cell lymphoma as predicted by 89Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab

“…New treatment approaches, such as fractionated RIT [ 29 , 31 ] or dual-targeted antibody/radioantibody therapy [ 32 ], have the potential to further improve the clinical efficacy of RIT. A recent phase I study [ 33 ] has shown encouraging results in patients with relapsed/refractory aggressive lymphoma using a fractionated dosing schedule along with the dual-targeting approach with the intention of improving the delivery and retention of the radioconjugate at the tumour sites. In that study, unlabelled anti-CD20 veltuzumab was administered to deplete the circulating B cells, enhancing biodistribution of the anti-CD22 radioconjugate 90 Y-epratuzumab tetraxetan without interfering with tumour targeting.…”

Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges

“…A feasible prevention strategy for oncology may be targeted B-cell inhibition with anti-CD20 agents, such as rituximab, veltuzumab, or obinutuzumab, which inhibit de novo humoral antibody responses. Several trials have been done with B-cell-inhibiting agents, but these did not detect effects on ADA formation [61,69,72,87,101,102]. Hassan et al showed that rituximab was able to induce full depletion of CD20-positive B cells, but this did not prevent ADAs targeted toward the therapeutic drug [103].…”