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Theseus Begins First-in-Human Trial of KIT Inhibitor in Gastrointestinal Stromal Tumor Patients

NEW YORK – Theseus Pharmaceuticals on Monday said the first patient with advanced gastrointestinal stromal tumors has received its investigational drug THE-630 within a Phase I/II trial.

THE-630 is a KIT inhibitor designed to treat GIST that has stopped responding to therapy through the acquisition of multiple KIT mutations, a common resistance mechanism. In preclinical studies, THE-630 was active against all major classes of KIT activating and resistance mutations in GIST and showed promising anti-tumor activity.

"Patients with unresectable or metastatic GIST who have exhausted standard therapies have limited treatment options and poor clinical outcomes," Suzanne George, who is working with Theseus on the THE-630 trial and is also clinical director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute, said in a statement. "GIST disease progression remains largely KIT-dependent even after multiple lines of therapy, and a significant unmet need remains for these patients."

In the recently initiated, first-in-human Phase I/II trial, Theseus will explore the safety, pharmacokinetics, and anti-tumor activity of THE-630. The Phase I, dose-escalation portion of the trial will involve patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (Novartis' Gleevec), which is a standard treatment for KIT-mutated GIST, or have received sunitinib (Pfizer's Sutent), regorafenib (Bayer's Stivarga), ripretinib (Deciphera's Qinlock), or avapritinib (Blueprint Medicines' Ayvakit).

In this first part of the study, initial data from which is expected in the first half of 2023, researchers will assess the safety profile of THE-630 and establish the maximum tolerated dose as well as the recommended Phase II dose. The Phase II expansion portion of the study will enroll patients with unresectable or metastatic GIST into different cohorts based on prior lines of treatment. In this second part of the trial, researchers will track THE-630's anti-tumor activity.

Theseus expects that data from this Phase I/II trial will inform the design of a registration trial in fifth-line GIST, where patients lack treatment options. The Cambridge, Massachusetts-based company is also planning to study the drug in second-line GIST, where a pan-KIT inhibitor that targets all resistance mutations could improve upon the standard of care.