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Background: Radioimmunotherapy (RIT) is an innovative, promising approach to treatment of relapsed or refractory (RR) Hodgkin lymphoma (HL). RIT confers the dual benefit of specific-antibody recognition of tumor regions coupled with selective irradiation of antigen-presenting cells and cells contiguous/proximal to tumor sites. We are developing a rabbit polyclonal IgG antibody directed against human ferritin (a tumor-associated antigen in HL) that is tightly chelated - via stable thiourea binding with bifunctional NCS-DOTA - to 90Yttrium (90Y, a pure β-emitting radioisotope) for treatment of RR-HL. An earlier study in RR HL patients of 90Y-antiferritin using a DTPA chelator at doses from 11.1-18.5 MBq/kg (0.3-0.5 mCi/kg) produced 22%-86% overall response rates (CR + PR) with median response durations of 6-8 months (Vriesendorp et al., Clinical Cancer Res, 1999; 5:3324S-3329S). Methods: This study in RR-HL patients conducted at two centers was designed to evaluate the safety and tolerability of single ascending doses of 90Y-antiferritin in MBq/kg (mCi/kg): 7.4 (0.2), 11.1 (0.3), 14.8 (0.4), then in increments of 2 MBq/kg (0.05 mCi/kg) until reaching the maximum tolerated dose (MTD) in order to select dosing for further investigations (one dose step below MTD). Patients ranging from 15 to 75 years of age who had received 2-4 courses of chemotherapy, performance status ≤2, bone marrow involvement ≤25% and no CNS HL who signed informed consent could receive a diagnostic IV injection of 2 mg antiferritin labeled with 111MBq (3 mCi) 111Indium (Day -7). Patients with positive tumor targeting by immunoscintigraphy were eligible for therapeutic dosing with 90Y-antiferritin (Day 1, Week 1). Death, prolonged grade 4 (G4) hematologic toxicity through study Week 11 or any G4 nonhematological toxicity/infection were the prespecified dose-limiting toxicities (DLTs). The MTD was reached when 2 of 2 (at the 7.4 or 11.1 MBq/kg dose levels) or 3 of 3 patients (at higher dose levels) experienced DLTs. Criteria for safety evaluation included laboratory parameters, human anti-rabbit antibodies (HARA), physical examination, chest X-ray, ECG, adverse events (AEs) and overall safety assessment at Week 11. All dose escalations required authorization by the Drug Safety Monitoring Board (DSMB) who reviewed data on an ongoing basis. Results: N=17 patients (8 M, 9 F) with RR-HL were enrolled; 4 were dismissed before treatment with 90Y-antiferritin (2 had no measurable disease [PET scan], 1 had negative tumor targeting, 1 was obese and dose could not be calculated). The mean age of 13 patients (6M, 7F) treated with 90Y-antiferritin was 37.6 years (18-64). Two patients each received single doses of 7.4 and 11.1 MBq/kg, and 3 each received 14.8 and 16.65 MBq/kg. A second block of 3 patients received 14.8 MBq/kg after the MTD (16.65 MBq/kg) was established. Most hematologic toxicities were G2 or G3. At the 16.65 MBq/kg dose level, 1 patient experienced prolonged G4 thrombocytopenia and another experienced prolonged G4 thrombocytopenia and lymphopenia. Four patients experienced serious AEs, most of which were of hematologic nature, possibly or probably-related to study drug. There were no deaths on study, and no hepatic, lung or cardiac toxicities were observed. HARA assay was positive in only one of 9 patients who were tested. Conclusions: This study established that the MTD of 90Y-antiferritin in patients with RR HL was 16.65 MBq/kg (0.45 mCi/kg). In these heavily-pretreated and immunocompromised patients with RR HL, 90Y-antiferritin was very well-tolerated at doses up to 14.8 MBq/kg (0.4 mCi/kg), which will be considered as the initial dose in a forthcoming phase 3 safety and efficacy study in this population. Disclosures Decaudin: MatBiopharma: Research Funding. Kadouche:Alissa Pharma: Employment, Equity Ownership. Allard:Alissa Pharma: Employment, Equity Ownership.

The aim of this study was to evaluate the safety and efficacy of radiolabelled DTPA-chelated rabbit polyclonal antiferritin antibody (Ab) in relapsed or refractory HL. The protocol included a first intravenous injection of 111Indium-labelled antiferritin Ab followed by immunoscintigraphy at 4, 48, and 72 hours and intravenous injection of 90Yttrium-labelled antiferritin Ab in the case of tumour targeting. Ten patients were included in the study: median number of chemotherapy regimens: 3; number of autografted pts: 8; number of previously irradiated pts: 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed tumour targeting. Nine patients were treated, as the last patient died from progressive HL before therapeutic injection. Median injected activity was 12 MBq/kg (0.32 mCi/kg). Among the ten patients who were included in the study, 1 CR and 6 PR were observed (ORR 70%) with a median duration of response of 8 months (range: 7–12 months). Toxicity was mainly haematological, with grade 1 or 2 neutropenia and anaemia, and grade 2 and 3 thrombocytopenia. The pharmacokinetic study showed that the half-lives of 111Indium and 90Yttrium were almost identical. These results confirm those previously reported in the literature and show the therapeutic potential of rabbit polyclonal antiferritin Ab in relapsed or refractory HL. On the basis of all these results, MATBioPharma proposed to test a radioimmunotherapy with polyclonal antiferritin antibodies (Abs) in patients with refractory or relapsed HL. The treatment is constituted with chelated rabbit polyclonal antiferritin Abs to be loaded with 111Indium for the diagnosis of the tumour(s) by immunoscintigraphy and with 90Yttrium for the treatment of the tumour(s). A phase I study is still ongoing at the Institut Curie / Centre René Huguenin (France) to evaluate the safety and tolerability of ascending doses of 90Yttrium antiferritin until the maximum tolerated dose (MTD) is reached and to select a dose for further investigation (one dose step below MTD). A pharmacokinetics is concomitantly performed to determine dose linearity and pharmacokinetic parameters of increasing 90Y-Ab and Ab. The second dose level will be completed in the third quarter 2007 and available data on immunoscintigraphy, safety, and efficacy of included HL patients will be provided for the 49th ASH congress.