A Phase 2 Open-Label Safety and Tolerability Study of Single Intravenous (IV) Escalating Doses of ⁹⁰ Yttrium-Labeled Antiferritin Antibodies (⁹⁰ Y-Antiferritin) in Patients with Relapsed or Refractory Hodgkin Lymphoma

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.