SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS and CLINICAL ACTIVITY of KT-333, A TARGETED PROTEIN DEGRADER of STAT3, in PATIENTS with RELAPSED or REFRACTORY HEMATOLOGIC and SOLID TUMOR CANCERS

Document Type

Conference Proceeding

Publication Date

6-1-2024

Publication Title

HemaSphere

Keywords

biological marker, gamma interferon, lirodegimod, messenger RNA, STAT3 protein, adult, arthralgia, B cell lymphoma, blood sampling, cancer inhibition, clinical article, conference abstract, constipation, controlled study, cutaneous T cell lymphoma, down regulation, drug combination, drug concentration, drug therapy, fatigue, Hodgkin disease, human, human tissue, large granular lymphocyte leukemia, male, nausea, peripheral blood mononuclear cell, peripheral T cell lymphoma, pharmacodynamics, pharmacokinetics, phase 1 clinical trial, protein expression, RNA sequencing, side effect, solid tumor, stomatitis, T cell lymphoma, T cell prolymphocytic leukemia, therapy, tumor biopsy, tumor microenvironment, tumor regression

Abstract

Background: KT-333 is a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of the signal transducer and activator of transcription 3 (STAT3) protein. Aberrant activation of STAT3 resulting from activating mutations or deregulated cytokine signaling underlies various malignancies including peripheral T-cell lymphomas (PTCL), cutaneous Tcell lymphoma (CTCL), and large granular lymphocytic leukemia (LGL-L). In non-clinical studies, treatment with KT-333 resulted in durable tumor regressions with weekly (QW) or Q2W administration in STAT3-dependent T cell lymphomas. STAT3 degradation also sensitized immunocompetent mouse models of solid and liquid cancers to anti-PD1(ASH 2021, SITC 2021). Aims: The ongoing open-label, Phase 1a/1b study is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333. Methods: KT-33 is administered intravenously (IV) QW on Days 1, 8, 15 and 22 (28-day cycle) in patients (pts) with B-and T-cell lymphomas, Hodgkin's lymphoma (cHL) and advanced solid tumors (ST) relapsed/refractory (R/R) to at least two prior therapies and LGL-L/T-cell prolymphocytic leukemia (T-PLL) R/R to at least one prior therapy. Blood samples are collected for KT-333 plasma concentrations and to measure changes in STAT3 protein expression in peripheral blood mononuclear cells (PBMCs). Whole blood RNA sequencing measures mRNA levels of STAT3 regulated targets. STAT3 degradation and other related biomarker changes in tumor are assessed in pts with accessible tumors who consent to biopsies. Results: As of 06 February 2024, 39 pts were treated across six dose levels (DL) in Phase 1a with a mean number of 8.7 doses. Pts included B-cell non-Hodgkin's lymphoma (n=1: DL5), cHL (n=3: DL4, 6), CTCL (n=9: DL1, 2, 4, 5, 6), PTCL (n=2: DL2, 4), LGL-L (n=3: DL3, 5), T-PLL (n=1, DL3) and ST (n=20: DL1-5) with median age of 66 years (range 24,81) and ECOG performance status of 0 (n=14), 1 (n=24) or 2 (n=1). The most common AEs were stomatitis, nausea, ALT increase, constipation and fatigue. Two DLTs were observed at DL5: Grade (G) 3 stomatitis and G3 arthralgia in two separate LGL-L pts. The G3 stomatitis was also the only KT-333 related SAE. Best responses in evaluable patients at data cut-off included two complete responses (CRs) in cHL pts in DL4; three partial responses (PRs) in CTCL pts at DL2, 4, 5; and stable disease in four ST pts at DL3, 4. Pharmacodynamic evaluation of KT-333 showed mean maximum degradation of STAT3 in PBMCs increasing from 70% to 87% between DL1 and 5 in Cycle 1, with up to 97.5% maximum degradation. Downregulation of STAT3 canonical target SOCS3 in whole blood and STAT3-regulated inflammatory biomarkers in plasma demonstrated JAK/STAT pathway inhibition. Notably, KT-333 resulted in robust reduction of STAT3 (69%), pSTAT3 (87%) and SOCS3 expression in a CTCL tumor biopsy in DL4. Moreover, induction of an IFNγ stimulated gene signature predictive of sensitivity to anti-PD1 was seen in both peripheral blood and tumor, suggestive of favorable immunomodulatory response in the tumor microenvironment following KT-333 treatment. Dose dependent increases in KT-333 plasma exposure were observed with levels approaching those predicted to be efficacious. Summary/Conclusion: KT-333 is a potent and selective STAT3 degrader that has demonstrated clinically significant responses including CRs and PRs in heavily pretreated cHL and CTCL patients at tolerated doses achieving substantial target knockdown and pathway modulation, highlighting the potential of heterobifunctional degraders for targeting previously undruggable transcription factors implicated in diseases. Accrual is ongoing, and further analyses will be presented at the meeting.

Volume

8

First Page

3850

Last Page

3851

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