Tomblyn, Michael

Aim/Objectives/Background: The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or significant prolongation of disease-specific survival, and effective reduction and/or prevention of adverse disease-related symptoms or untoward events while minimizing treatment-associated side effects and complications. Radium-223 dichloride (radium-223) is an alpha particle–emitting isotope used for targeted bone therapy. This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with radium-223. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this parameter should help to maximize the efficacious use of radium-223, maintain safe conditions, and ensure compliance with applicable regulations. Methods: This practice parameter was developed according to the process described on the American College of Radiology (ACR) website (“The Process for Developing ACR Practice Parameters and Technical Standards,” www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the American College of Nuclear Medicine (ACNM), the American Society for Radiation Oncology (ASTRO), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). All these societies contributed to the development of the practice parameter and approved the final document. Results: This practice parameter addresses the many factors which contribute to appropriate, safe, and effective clinical use of radium-223. Topics addressed include qualifications and responsibilities of personnel, specifications of patient examination and treatment; documentation, radiation safety, quality control/improvement, infection control, and patient education. Conclusions: This practice parameter is intended as a tool to guide clinical use of radium-223 with the goal of facilitating safe and effective medical care based on current knowledge, available resources and patient needs. The sole purpose of this document is to assist practitioners in achieving this objective.

Abstract Abstract 3680 Background: 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. Methods: 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). Results: 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). Conclusions: 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. Disclosures: Sharkey: Immunomedics: Employment. Rojo:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.