An Open-Label, Multicenter, Phase 2/3 Efficacy and Safety Study of a targeted radiotherapy in Patients with Relapsed or Refractory Waldenstroms Macroglobulinemia

ABSTRACT Waldenstrom’s Macroglobulinemia (WM) is an incurable and life-threatening malignant tumor. It is a rare and chronic form of B-cell non-Hodgkin lymphoma (NHL), characterized by small B lymphocytes, plasmacytoid lymphocytes, and plasma cells typically involving the bone marrow, lymph nodes, and organs such as spleen and liver. Patients also have detectable levels of monoclonal immunoglobulin (Ig) M gammopathy with bone marrow involvement. The median survival of WM patients from the time of diagnosis is approximately 6 years, depending on prognostic indicators. The main causes of death include disease progression, transformation to high-grade lymphoma or therapeutic complications. While many drugs are utilized, there is no standard treatment in first-line WM patients. Recommendations include using chemoimmunotherapy with rituximab (anti-CD20 monoclonal antibodies) or the combination of rituximab with proteasome inhibitors as well as ibrutinib for some patients. Because all patients’ disease eventually progresses, and ibrutinib is the only approved second line therapy, there continues to be a significant unmet medical need in patients in the relapsed or refractory setting. We propose the clinical development of CLR 131 for the treatment of relapsed WM in patients who do not respond to ibrutinib (or other Bruton’s tyrosine kinase inhibitors) or are intolerant to it. CLR 131, a tumor targeted radiotherapeutic with a phospholipid ether (PLE) core, is expected to have an enhanced efficacy and safety profile and provide durable efficacy due to CLR 131 actually modifying the disease, regardless of the underlying genetic landscape of WM. CLR 131 exploits the tumor-targeting properties of PLEs to provide a targeted delivery of radiation to malignant tumor cells and minimizes radiation exposure to normal tissues. PLEs selectively insert into lipid rafts, which are enriched on the surface of tumor cells, and use them as a gateway for cellular entry. The combined nonclinical data confirm that administration with CLR 131 results in inhibition of tumour growth and increased survival. More importantly, preliminary data from 6 WM subjects participating in our Phase II open- label, multi-center, study of CLR 131 in patients with relapsed or refractory select types of B-cell malignancies, showed an overall response rate of 100%, with one patient with a complete response, four patients with a partial response, one patient with a minimal response showing a 45% reduction in IgM (50% reduction equates to a partial response). In this project. we will conduct a non-randomized open-label, multi-center, Phase II/III efficacy and safety study of intravenous administration of CLR 131 in at least 50 patients with WM who have failed standard of care first line treatment and either failed or had a suboptimal response to any BTK inhibitors (i.e., ibrutinib, zanubrutinib or acalabrutinib). This study will allow us to receive regulatory approval for CLR 131 in the examined patient population.