A Phase I Study of 177 lu-DOTA-HH1 (Betalutin) Radioimmunotherapy for Patients with Relapsed CD37+ Non-Hodgkin's B Cell Lymphoma
Authors: Kolstad Arne , Madsbu Ulf , Dahle Jostein , Stokke Caroline , Bach-Gansmo Tore , Muftuler Løndalen Ayca , Holtedahl Jon Erik , Revheim Mona Elisabeth , Bruland Øyvind , Bolstad Bjørg , Bolstad Nils , Tierens Anne , Larsen Roy Hartvig , Alfheim Jan Alan , Delabie Jan , Signe Spetalen , Erlanson Martin , Nygaard Rudå Stine , Holte Harald 
Published: October 2019

Abstract
Background and aim: The CD37 antigen is expressed at high levels predominantly by normal B cells and the majority of malignant B-cell lymphomas. Hence, this surface antigen represents an interesting therapeutic target for treatment of B-cell non-Hodgkin lymphomas (NHL). 177Lu-DOTA-HH1 (Betalutin™) is a novel anti-CD37 radioimmunoconjugate currently under clinical development. Betalutin™ consists of the β-emitting isotope Lutetium-177 (t/2 = 6.7 days) chelated to DOTA (a chemical linker) which is conjugated to the murine mAb HH1. Betalutin™ is delivered in a ready-to-use formulation at the study centers. Pre-clinical studies have demonstrated significant anti-tumor activity; both ex vivo and in models of human B-cell lymphomas in mice. Based on these results, a phase I study has been initiated in order to determine the maximum tolerated dose (MTD), overall safety and to explore tumor response.
Methods: Patients with relapsed incurable CD37+ NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic lymphomas with < 25% bone marrow infiltration and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study. In order to deplete normal B cells patients first received a pre-treatment consisting of single infusions of rituximab (375 mg/m2) on day 1 and day 8. On day 29 the patients received a pre-dose infusion of HH1 (50 mg, cold CD37 antibody) followed by the radioimmunoconjugate 177Lu-DOTA-HH1administered as a 10 minute iv bolus. A 3 x 3 dose escalation design was used with 10 MBq/kg as the starting level. Patients were assessed for distribution of radioactivity by gamma camera wholebody scans and SPECT/CT. Clinical response was studied by 18F-FDG PET/CT, CT and bone marrow specimens. Evaluation of response was performed according to the NCI criteria of 1999 and 2007. Adverse events were monitored and scored in agreement with the NCI Common Terminology Criteria for Adverse Events (CTCAE) for toxicity grading.
Results: A total often patients (9 follicular lymphoma,1 mantle cell lymphoma) have been treated according to protocol since the study was initiated in December 2012. The median number of prior therapies were 2 (range 1-7) and four out of ten patients had previously not responded to or progressed during treatment with rituximab as single agent. Serious adverse events were reported for four patients. Two patients developed thrombocytopenia requiring platelet transfusions and one of these patients had epistaxis. Another patient with a previous history of pulmonary embolism (PI) presented with pneumonia and PI. The fourth SAE was a transient case of atrial fibrillation, unlikely to be related to the study drug. Apart from these events, the most common toxicities were hematological, as expected with median time to nadir for platelets and neutrophils of 39 days and 48 days, respectively. Dose-limiting toxicity (DLT) was observed in all three patients treated at dose level 2 (20 MBq/kg), with grade III/IV neutropenia and/or thrombocytopenia, all reversible. However, no patients developed neutropenic fever. Based on the assumption that MTD is 15 MBq/kg, three patients are currently in follow-up after treatment at this dose level. With regard to efficacy, clinical responses have been observed at both dose level 1 (10 MBq/kg) and 2 (20 MBq/kg). At level 10 MBq/kg, two out of four patients had partial remissions, one had stable disease and one progressed. At level 20 MBq/kg two out of three patients obtained a complete remission and one had a partial remission. At dose level 15 MBq/kg efficacy results are pending. The first patient treated in this study has now been in stable remission with an observation time of 18 months.
Conclusion: 177Lu-DOTA-HH1 in a single dose ready-to-use formulation has a favorable safety profile, mostly with hematological toxicities as expected. DLT was observed at dose level 20 MBq/kg, and dose level 15 MBq/kg is currently predicted to be the MTD for the phase II part of this trial. Complete and partial responses have been observed so far, hence, 177Lu-DOTA-HH1 targeting the CD37 antigen is a promising new candidate against NHL.

Disclosures
Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dahle:Nordic Nanovector AS: Employment, Equity Ownership, Patents & Royalties. Bruland:Nordic Nanovector AS: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolstad:Nordic Nanovector AS: Employment, Equity Ownership. Larsen:Nordic Nanovector AS: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Alfheim:Nordic Nanovector as: Employment, Equity Ownership. Holte:Nordic Nanovector AS: Membership on an entity's Board of Directors or advisory committees.