FDA Grants Fast Track Designation to STAT3 Degrader in R/R T-Cell Lymphomas

Investigators are assessing the anti-tumor activity, safety, tolerability, and pharmacokinetics of KT-333 in patients with solid tumors, PTCL, and CTCL as part of a phase 1 clinical trial (NCT05225584).

The FDA has granted fast track designation to KT-333, an investigational STAT3 degrader, as a treatment for patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), according to a press release from Kymera Therapeutics, Inc.¹

Investigators are assessing the anti-tumor activity, safety, tolerability, and pharmacokinetics of KT-333 in patients with solid tumors, PTCL, and CTCL as part of a phase 1 clinical trial (NCT05225584). According to data presented at the 2023 International Conference on Malignant Lymphoma (ICML), plasma exposure was found to increase across 3 dosing levels of KT-333. Additionally, the investigational agent exhibited dose-dependent STAT3 degradation, including up to a mean maximum reduction of 88% in peripheral blood mononuclear cells at dose level 3.

In an abstract presented at ICML, investigators highlighted that plasma pharmacokinetic results were consistent with modeled predictions in 7 patients receiving the first 2 dose levels of KT-333.² The agent also yielded a mean maximum decrease in peripheral blood monocular cells of 66% at dose level 1 and 70% in dose level 2. Additionally, the most common adverse effects (AEs) were grade 1 or 2 events of constipation, fatigue, abdominal pain, dizziness, and nausea. Investigators reported no dose-limiting toxicities and that no patients discontinued study treatment following an AE.

“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 at Kymera Therapeutics, said in the press 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 anti-tumor 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.”

Investigators are currently evaluating KT-333 as part of the phase 1a dose escalation portion of the study. In the dose escalation portion, investigators will supply 10 mg/mL of KT-333 as a frozen concentration, which will then be administered to patients intravenously across various dosing levels and schedules.

The study’s primary end points include AEs and laboratory abnormalities, as well as determining the maximum tolerated dose and dose limiting toxicities. Secondary end points include the maximum plasma concentration, clinical activity, and duration of response.

Patients 18 years and older with cytologically or pathologically confirmed lymphomas, T-cell prolymphocytic leukemia, and solid tumors excluding chronic lymphocytic leukemia are eligible for enrollment on the phase 1a portion of the trial. Additional eligibility criteria include having measurable disease in the PTCL and solid tumors cohorts, an ECOG performance status of 0 to 2, and adequate bone marrow function.

Those with uncontrolled or symptomatic central nervous system metastases, carcinomatous meningitis, or leptomeningeal disease are unable to enroll on the trial. Patients are also unable to enroll if they have unresolved clinically significant AEs from previous treatments, ongoing unstable cardiovascular function, autologous hematopoietic stem cell transplant at fewer than 3 months before starting study treatment, or prior allogenic hematopoietic or bone marrow transplant.

References

1. Kymera Therapeutics receives U.S. 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 19, 2023. https://shorturl.at/jwzP2
2. Kymera Therapeutics announces updated clinical data from the phase 1 trials of STAT3 degrader KT-333 and IRAKIMiD degrader KT-413. News release. Kymera Therapeutics. June 9, 2023. Accessed September 19, 2023. https://shorturl.at/cpuvz