Phase 1 Trial of Kt-413, a Degrader of Irak4 and Imid Substrates, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphomas

Document Type

Conference Proceeding

Publication Date

6-9-2023

Publication Title

Hematol Oncol

Keywords

interferon regulatory factor 4, interleukin 1 receptor associated kinase 4, myeloid differentiation factor 88, adult, B cell lymphoma, B lymphocyte, blood sampling, cell death, cell killing, conference abstract, diffuse large B cell lymphoma, drug therapy, fatigue, flow cytometry, follicular lymphoma, human, human cell, human tissue, immunophenotyping, marginal zone lymphoma, mass spectrometry, molecularly targeted therapy, mouse, multiple myeloma, neoplastic cell transformation, peripheral blood mononuclear cell, phase 1 clinical trial, prediction, tumor biopsy, upregulation

Abstract

Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in about 25% of diffuse large B-cell lymphoma (DLBCL), including approximately one-third of activated B-cell (ABC) nodal DLBCL and 70-80% of ABC-like primary extranodal lymphomas, and are associated with poor survival. MYD88 mutations also occur in up to 90-95% of patients with Waldenström's Macroglobulinemia (WM). These mutations result in activation of the NF-B pathway via interleukin-1 receptor associated kinase 4 (IRAK4), as well as IMiD substrate (Ikaros and Aiolos)- dependent upregulation of IRF4, which further activates NF-kB while also downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. KT-413 is a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of IRAK4, Ikaros and Aiolos. Degradation of these 3 targets has been shown to maximize NF-B inhibition and upregulate the Type I IFN response in MYD88-mutant DLBCL, leading to potent cell killing. In mouse xenograft models of MYD88-mutant DLBCL, KT-413 achieved complete tumor responses associated with >60% IRAK4 and >90% Ikaros/Aiolos degradation for at least 48 hours in tumors. Methods: Ongoing Phase 1a/1b study to evaluate the safety, identify the recommended phase 2 dose (based on dose limiting toxicity (DLT) observed in Cycle 1 (Phase 1a)), PK, PD, and preliminary clinical activity of IV infused KT-413 on Day 1 of 21-day cycles in patients with R/R B-cell NHL. Blood samples are collected in Cycles 1 and 2 to measure KT-413 plasma concentrations and target degradation in PBMC and perform immunophenotyping. Serial tumor biopsies, when available, are also evaluated for PD. Result: As of February 3, 2023, three patients have been treated in the first 3 dose levels (DLs) in Phase 1a, including transformed ABCDLBCL, follicular lymphoma and marginal zone lymphoma that were all MYD88 wild-type. No DLTs were observed and the most common adverse events across all three dose levels were Grade 1 and 2 fatigue and pyrexia. Plasma PK results were in line with the modeled predictions and dose-dependent, sustained target knockdown in PBMC was observed by flow cytometry starting at DL1, with up to 57% reduction in IRAK4 and 96-100% reduction in Ikaros and Aiolos by DL3. Degradation measured by mass spectrometry was achieved in serial tumor biopsies obtained in DL1. Conclusion: Initial clinical data with KT-413 demonstrate degradation of IRAK4 and Ikaros/Aiolos in PBMC and tumor. It is anticipated that higher doses will achieve the predicted degradation profile in tumors that may confer clinical benefit in MYD88-mutant patients. Dose escalation is ongoing, and analyses from additional patients will be presented at the meeting. The research was funded by: Kymera Therapeutics

Volume

41

First Page

808

Last Page

809

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