FDA Grants Fast Track Designation to KT-333 in R/R CTCL and PTCL

FDA

The FDA has granted fast track designation to KT-333 for the treatment of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) and relapsed/refractory peripheral T-cell lymphoma (PTCL).¹

KT-333 is a first-in-class, potent, highly selective STAT3 degrader.2 STAT3 promotes the expression of genes associated with the survival, proliferation, stemness, and metastasis of tumor cells. Additionally, STAT3 promotes the differentiation and activity of immunosuppressive cells in the tumor microenvironment.

“The KT-333 fast track designation highlights the promise of degrading STAT3, a protein that has historically been undruggable, for the treatment of patients with CTCL and PTCL,” Jared Gollob, MD, chief medical officer of Kymera Therapeutics, stated in a news release.1 “We look forward to providing an update on the KT-333 phase 1 clinical trial later this year, including initial evaluation of its antitumor activity in the target patient populations, and to working with the lymphoma community to rapidly advance this first-in-class heterobifunctional degrader in CTCL and PTCL in addition to exploring its potential in other cancers.”

A phase 1 trial (NCT05225584) is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT-333 dosed weekly in adult patients with relapsed/refractory lymphomas, leukemias, and solid tumors. Dose-escalation findings presented at the 17th Annual International Conference on Malignant Lymphoma showed that in 13 evaluable patients, KT-333 achieved up to 88% mean STAT3 degradation in peripheral blood mononuclear cells, and showcased evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers in the peripheral blood.²

In the phase 1a portion of the study, patients were required to have Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, or a solid tumor that was relapsed/refractory to at least 2 prior treatments or had no available standard therapy. Patients with relapsed/refractory large granular lymphocytic leukemia (LGL-L) were permitted to enroll if they received 1 prior systemic treatment. Patients also had to have an ECOG performance status of 0 to 2, and acceptable liver, kidney, and bone marrow function, except for those with LGL-L.

Key exclusion criteria included receipt of radiation, anticancer therapy, or major surgery within 4 weeks of enrollment; an autologous stem cell transplant within 3 months of the first dose of study treatment; or any prior allogeneic stem cell transplant or bone marrow transplant.

Of the 13 patients, 10 had solid tumors, 2 had CTCL, and 1 had PTCL. They received KT-333 at 1 of 4 dose levels: 0.05 mg/kg (dose level 1; n = 4), 0.1 mg/kg (dose level 2; n = 4), 0.2 mg/kg (dose level 3; n = 3), and 0.4 mg/kg (dose level 4; n = 2).

Safety, tolerability, and determining the maximum tolerated dose and recommended phase 2 dose of KT-333 are the primary end points of the study. Secondary end points include pharmacokinetics and preliminary efficacy. Exploratory end points included STAT3 mutational status, STAT3 pathway gene expression at baseline, and immune tumor microenvironment profiling and correlations with antitumor activity.

At the data cutoff date of May 1, 2023, patients had received a mean of 5 doses across the 4 dose levels. Five patients were ongoing treatment, and the other 8 patients discontinued treatment between day 1 or cycle 1 and day 22 of cycle 3.

Reasons for discontinuation included disease progression (n = 3), patient withdrawal (n = 2), investigator decision (n = 2), and adverse effect (AE; n = 1). Notably, the patient who discontinued due to an AE had CTCL. This patient experienced grade 2 squamous cell carcinoma of the skin, which was possibly related to KT-333 per investigator assessment. The patient had a prior history of ultraviolet type B treatment and recurrent squamous cell carcinoma of the skin.

Regarding safety, no dose-limiting toxicities or serious AEs that were determined to be related to KT-333 were reported. The most common any-grade AEs reported in at least 2 patients included fatigue (30.8%), anemia (23.1%), constipation (23.1%), nausea (23.1%), dehydration (15.4%), dizziness (15.4%), and skin infection (15.4%).

References

1. Kymera Therapeutics receives US FDA fast track designation for KT-333, a first-in-class, investigational STAT3 degrader for the treatment of relapsed/refractory cutaneous T-cell lymphoma and relapsed/refractory peripheral T-cell lymphoma. News release. Kymera Therapeutics. September 18, 2023. Accessed September 18, 2023. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-receives-us-fda-fast-track-designation-kt
2. Smith SD, Olszewski A, Starodub AN, et al. Phase 1 trial of KT-333, a STAT3 degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia and solid tumors. Hematol Oncol. 2023;41(suppl 2):567-568. doi:10.1002/hon.3164_424