Combination Therapy Targeting Two Different Antigens with Anti-CD22 Radioimmunotherapy and Anti-CD20 Immunotherapy in Non-Hodgkin Lymphoma (NHL): Phase I Results

Current NHL radioimmunotherapy is administered with unlabeled antibody targeting the same B-cell antigen. This decreases sequestration of the radiolabeled antibody by normal B-lymphocytes, but potentially blocks access of the radiolabeled antibody to the tumor sites. In clinical studies, yttrium-90 radiolabeled anti-CD22 epratuzumab (⁹⁰Y-epratuzumab) has demonstrated therapeutic activity with acceptable toxicity when given weekly × 2 at doses up to 20 mCi/m² (Morschhauser et al., J Clin Oncol. 2010;28:3709–16), while separate studies showed that a 200-mg/m² dose of anti-CD20 veltuzumab given weekly × 4 readily depletes peripheral blood B-cells and is also therapeutically active (Morschhauser et al., J Clin Oncol, 2009;27:3346–53). In mice bearing human B-cell lymphoma xenografts, this non-competing combination showed improved therapeutic responses over either agent alone (Mattes et al., Clin Cancer Res. 2008;14:6154–60). As such, a multicenter, phase I/II study was undertaken to evaluate combination therapy with ⁹⁰Y-epratuzumab and veltuzumab.

Adult patients with aggressive NHL who failed ≥ 1 prior standard regimen (excluding autologous SCT) were eligible if they had measurable CT lesions, ECOG 0–1 performance status, <25% bone marrow involvement, hemoglobin ≥ 10 g/dL, ANC ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L and were >4 weeks beyond last treatment. All patients received a 4-week treatment regimen (weekly 200 mg/m² veltuzumab, 3–5 mCi ¹¹¹In-epratuzumab on week 2, ⁹⁰Y-epratuzumab on weeks 3 and 4). Using NCI CTCAE v4.0 toxicity criteria, dose-limiting toxicity (DLT) was defined as Grade 4 hemoglobin, platelet or neutrophil levels >7 days or not recovered to Grade 1 by 12 weeks, or any non-hematologic Grade 3 or 4 events. Starting at 15 mCi/m², a standard 3+3 dose escalation determined the MTD of ⁹⁰Y-epratuzumab. Treatment response utilized CT-based 2007 IWG revised criteria. Serial ¹¹¹In imaging and serum samples were used to assess biodistribution, tumor targeting and determine normal organ radiation dosimetry. ELISA-based assays were used to measure veltuzumab pharmacokinetics and any human anti-veltuzumab antibodies (HAHA).

Fifteen patients (10 male/5 female, 56 – 84 years old) with diffuse large B-cell lymphoma (DLBCL N=7), transformed follicular lymphoma (TFL, N=4) or mantle cell lymphoma (MCL, N=4) have now been enrolled. They had 3 median prior treatments (1 – 7) [RCHOP (N=15); bendamustine plus rituximab (N=5); ICE, lenalidomide, bortezomib (N=2 each); others (1 each)] and had low (N=3), low-intermediate (N=3), high-intermediate (N=7), or high (N=2) IPI risk scores. Treatment was well-tolerated with no infusion reactions. ¹¹¹In-imaging showed normal biodistribution, with acceptable normal organ dosimetry for the scheduled ⁹⁰Y dose, and tumor targeting occasionally visualized. There was no evidence of HAHA, and the serum clearance of veltuzumab and ¹¹¹In-epratzumab in combination was comparable to that reported previously for these agents alone. The ⁹⁰Y dose was repeatedly de-escalated from 15 (N=3) to 12 (N=3), 9 (N=6), and currently 6 (N=3) mCi/m² due to 7 hematologic DLTs at ≥ 9 mCi/m²in 6 patients involving Grade 3-thrombocytopenia (N=5) or neutropenia (N=2). Clinically, there were 3 SAEs (pneumonia, non-infectious pneumonitis, fracture from fall), but no other major infections or bleeding. Of 11 patients who have now had treatment response assessments, 5 (45%) had objective responses, including one DLCBL patient with a complete response (CR) continuing 12 months later and 4 patients (1 DLBCL, 3 TFL) with partial responses (PRs), with one continuing at 4 weeks and 3 relapsed at 3 – 6 months. Four other patients (1 DLBCL, 3 MCL) achieved stable disease (SD) continuing up to 6 months as best response, resulting in a disease control rate of 82% (CR+PR+SD).

Combination treatment was well-tolerated, with the PK behavior of the two agents substantially unchanged, and with initial evidence of therapeutic activity (including one durable CR) in these difficult-to-treat patients. Hematologic toxicity necessitated lowering the ⁹⁰Y dose, most likely due to the prior aggressive chemotherapies or depletion of the normal sequestering B-cell pool by veltuzumab preceding ⁹⁰Y-epratzumab. The trial is continuing to determine an acceptable ⁹⁰Y dose and define the safety and efficacy profile of this combination approach.

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