Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases, including approximately 30% of activated B-cell DLBCL and up to 70% of primary extranodal DLBCL, and are associated with poor survival following 1^st line therapy. MYD88 mutations result in activation of the NF-κB pathway which drive a range of pro-tumor activities including upregulation of proinflammatory cytokines and genes involved in tumor cell proliferation and survival. Activation of this pathway results in upregulation of IRF4 through the transcription factors Ikaros and Aiolos, which in turn further augments NF-kB activation while simultaneously downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. Constitutive NF-kB pathway activation resulting from MYD88 mutations is dependent on the interleukin-1 receptor associated kinase 4 (IRAK4), a key component of the myddosome complex which normally stimulates NF-kB signaling following TLR or IL-1R engagement and MYD88 activation. KT-413 is a potent and selective heterobifunctional small molecule protein degrader mediating the degradation of both IRAK4 and the IMiD substrates Ikaros and Aiolos via the ubiquitin-proteasome system. The therapeutic hypothesis is that degradation of IRAK4 and IMiD substrates will maximize NF-κB inhibition while simultaneously upregulating the Type I Interferon response, thus restoring the apoptotic response and enabling oncogene-mediated cell death, resulting in robust antitumor response in MYD88-mutant DLBCL. KT-413 induced strong antitumor activity, including complete or partial regressions, in cell line- and patient-derivedxenograft models of MYD88^MT DLBCL (Mayo 2021). Methods: KT-413 is being evaluated in an open label, dose escalation (Phase 1a) study in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), followed by dose expansion (Phase 1b) in patients with R/R DLBCL with documented tumor MYD88 mutation status. All patients must be ineligible or refused auto-SCT or CAR-T therapy. The Phase 1a (n = 40) utilizes an accelerated titration followed by a 3+3 design in ascending doses of IV administered KT-413 in once every 21-day cycles to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) and preliminary pharmacodynamic effects (PD) using blood and tumor tissue. Once MTD/RP2D is determined in 3-6 patients, it will be confirmed by enrolling additional patients with B-cell NHL, for a total of nine. In Phase 1b, up to 40 R/R DLBCL patients will be enrolled into one of two cohorts (n = 20): MYD88^MT or MYD88^WT to further characterize tolerability, PK, PD and evaluate the clinical activity of KT-413. KT413-DL-101 began enrollment in February 2022. Clinical trial information: NCT05233033.