Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors resulting in tumor growth and promotion and hindering antitumor immunity. Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3). Aberrant activation of STAT3 has been observed in many cancers including lymphomas and leukemias through activating mutations, hyper-signaling through upstream regulators or loss of negative feedback regulation. Additionally, STAT3-mediated cross-talk in the tumor microenvironment results in suppression of immune surveillance compromising anti-tumor immunity. Hyperactivation of STAT3 has been reported in a variety of solid tumors. In several of these cancers, the levels of pSTAT3 and/or activated STAT3 have been shown to correlate with poor clinical prognosis. As with other transcription factors, selective inhibition of STAT3 has proven to be difficult with conventional therapeutic approaches, such as small molecule inhibitors. KT-333 is a potent, highly selective, heterobifunctional small molecule degrader of STAT3. In preclinical studies, durable tumor regressions were seen with once weekly IV administration of KT-333 in STAT3-dependent T cell lymphomas, and antitumor activity was seen in solid tumors in combination with anti-PD1 (ASH 2021, SITC 2021).

Methods: KT-333 is being evaluated in an open-label, dose escalation (Phase 1a, n=40) and dose expansion (Phase 1b, n=80) study. Patients with advanced solid tumor and lymphomas, including Hodgkin's, B-cell, T cell, Small Lymphocytic or NK-cell Lymphomas, relapsed or refractory (R/R) to at least two prior systemic treatments or for whom standard therapies are unavailable, will enroll in the Phase 1a. The Phase 1b portion will enroll patients with PTCL, CTCL, LGL-L, or solid tumors that are R/R to at least 1 prior systemic treatment. Patients with chronic lymphocytic leukemia are excluded and patients with LGL-L are only eligible in the Phase 1b. Dose escalation will be conducted by accelerated titration followed by a 3+3 design in ascending doses of intravenous KT-333 administered once weekly in 28-day cycles to evaluate safety and define the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) in plasma and urine and preliminary pharmacodynamic effects (PD) of KT-333 using blood and tumor tissue. After determination of the tolerable and pharmacologically optimal dose (RP2D) in patients with advanced solid tumor and lymphoma and prior to initiation of the Phase 1b, the dose will be confirmed in at least nine patients with a minimum of 6 patients of each disease type. In the Phase 1b portion, patients with PTCL, CTCL, LGL-L (T-cell LGL-L or chronic lymphoproliferative disorder of natural killer-cells), or solid tumors R/R to at least one prior systemic standard of care treatment or for whom standard therapies are not available, will be enrolled in four separate 20 patient cohorts. The primary objective of these cohorts is to further characterize safety and tolerability, along with secondary objectives defined to evaluate PK, PD and the clinical activity of KT-333. Enrollment in an individual cohort will be discontinued if there is no evidence of clinical benefit (complete response/partial response) in at least 1 patient among the first 12 patients treated. Treatment with KT-333 will continue until disease progression, unacceptable toxicity, or patient refusal. Enrollment in the Phase 1a portion of the study is ongoing. NCT05225584

Smith:Portola Pharmaceuticals: Research Funding; Numab Therapeutics AG: Consultancy; Nanjing Pharmaceuticals Co., Ltd: Research Funding; MorphoSys: Research Funding; Merck Sharp/Dohme Corp: Research Funding; Kymera Therapeutics: Research Funding; KITE pharma: Consultancy; Karyopharm: Consultancy; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Epizyme: Consultancy; Enterome: Research Funding; De Novo Biopharma: Research Funding; Beigene: Consultancy, Research Funding; Bayer: Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Viracta Therapeutics: Research Funding. Starodub:BMS: Speakers Bureau. Shastri:Janssen: Consultancy; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; NACE: Honoraria; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Porcu:Teva: Honoraria, Research Funding; DrenBio: Consultancy; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi, Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees; Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Ono: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees. Feldman:Genomic Testing Cooperative: Other: Equity holder in privately-traded company; Takeda: Speakers Bureau; SecuraBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seagen: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC: Speakers Bureau; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Biotech, Inc.: Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sakyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Speakers Bureau; BMS: Speakers Bureau; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ewesuedo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. DeSavi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: curie.bio. Dey:KymeraTx: Current Employment. Agarwal:Kymera Therapeutics: Current Employment. Donohue:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Perea:Kymera Therapeutics: Current Employment; Agios: Ended employment in the past 24 months. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Author notes

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Asterisk with author names denotes non-ASH members.

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