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.
Public Health Relevance Statement: NARRATIVE Since there are limited treatment options for patients who have relapsed and who are intolerant to or, have a suboptimal response to ibrutinib or other BTK inhibitors, there is a clear unmet need for novel therapeutics with unique mechanisms of action that can provide an enhanced safety profile, optimal responses and durable effects in patients with relapsed WM, regardless of the genetic landscape of the disease.
Project Terms: inhibitor/antagonist; inhibitor; Award; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Bone marrow biopsy; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cause of Death; Cell Survival; Cell Viability; Clinical Trials; Diagnosis; Disease; Disorder; intravenous administration; Drug Utilization; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Half-Life; Immunoglobulin M; 19S Gamma Globulin; IgM; Liver; hepatic body system; hepatic organ system; lymph nodes; Lymph Node Reticuloendothelial System; Lymph node proper; Lymphatic nodes; lymph gland; lymphnodes; Lymphoma; Germinoblastic Sarcoma; Germinoblastoma; Malignant Lymphoma; Reticulolymphosarcoma; Waldenstrom Macroglobulinemia; Lymphoplasmacytic Lymphoma; Lymphoplasmacytic Lymphoma/Waldenstrom's Macroglobulinemia; Lymphoplasmacytic Type Immunocytoma; Lymphoplasmacytoid Lymphoma; Macroglobulinemia; Waldenstrom's macroglobulinaemia; Waldenström's hyperglobulinaemia; Waldenström's hyperglobulinemia; Waldenström's macroglobulinaemia; Waldenström's macroglobulinemia; Patient Outcomes Assessments; Patient Reported Measures; Patient Reported Outcomes; Patients; Phospholipid Ethers; Ether Phosphatidates; Glycerol Phosphate Ethers; Glycerophosphate Ethers; Plasma Cells; Blood Plasma Cell; Plasmacytes; plasmocyte; Reaction Time; Response RT; Response Time; psychomotor reaction time; Recommendation; Relapse; Research Design; Study Type; study design; Safety; Signal Pathway; Spleen; Spleen Reticuloendothelial System; Time; single photon emission computed tomography; SPECT; SPECT imaging; Single-Photon Emission-Computed Radionuclide Tomography; Measures; Outcome Measure; base; gammopathy; Organ; improved; Surface; Chronic; Clinical; Refractory; Phase; Medical; Series; Targeted Radiotherapy; Agammaglobulinaemia tyrosine kinase; B cell progenitor kinase; Bruton's tyrosine kinase; bpk protein; btk protein; Serum; Blood Serum; Disease Progression; Progression-Free Survivals; analog; uptake; Multicenter Studies; Multi-center studies; Therapeutic; 131 Iodine; I-131; Iodine I 131; I131 isotope; Genetic; Exposure to; Normal Tissue; Normal tissue morphology; Plasmacytoid Lymphocyte; Lymphoplasmacytoid Cell; Malignant Cell; cancer cell; Life; C2B8 Monoclonal Antibody; MabThera; Rituxan; rituximab; Treatment Period; treatment days; treatment duration; Tumor Volume; Visit; meetings; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; Cell Proliferation; Tumor Cell; neoplastic cell; tumor growth; cohort; complete response; In complete remission; Prevention; MoAb CD20; Monoclonal Antibody CD20; Property; response; Cell Membrane Lipid Rafts; Sphingolipid Microdomains; Sphingolipid-Cholesterol Rafts; lipid raft; Membrane Microdomains; Normal Cell; PTK Inhibitors; Protein Tyrosine Kinase Inhibitors; TK Inhibitors; Tyrosine Kinase Inhibitor; Radio; Proteasome Inhibitor; Dose; Tumor Load; Tumor Burden; Symptoms; Clinical Trial Protocol; Clinical trial protocol document; Data; Molecular Marker of Prognosis; Prognosis Marker; prognostic biomarker; prognostic indicator; Prognostic Marker; Radioactive; Bone Marrow Involvement; Longterm Follow-up; Long-term Follow-up; long-term followup; longterm followup; Rodent Model; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; partial response; Modification; Radiolabeled; safety study; open label; open label study; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; B lymphoid malignancy; B cell malignancy; targeted delivery; site targeted delivery; cancer type; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; tumor; B-Cell NonHodgkins Lymphoma; B-Cell NHL; B-Cell Non-Hodgkin's Lymphoma; FDA approved; patient population; standard of care; standard care; standard treatment; screening; targeted agent; Treatment-related toxicity; therapeutic toxicity; therapy toxicity; treatment toxicity; symptom treatment; symptomatic treatment; treat symptom; Radiation exposure; efficacy study; clinical development; Immuno-Chemotherapy; Immunochemotherapy; chemo-immuno therapy; chemoimmunotherapy; anti-CD20; secondary endpoint; secondary end point; primary endpoint; primary end point; radiation delivery; targeted radiotherapeutic
