Phase 1/2 Study of THE-630 Terminates Enrollment of Patients With GIST


THE-630 will no longer be developed for patients with GIST after patients treated at the 27 mg dose experienced dose-limiting toxicities.

Image credit: © Crystal light - Adobe Stock

Image credit: © Crystal light - Adobe Stock

The phase 1/2 study evaluating THE-630 in patients with gastrointestinal stromal tumors (GIST) will discontinue enrollment, and the development of THE-630 will be ended, according to ​​Theseus Pharmaceuticals, Inc.1

The termination of enrollment follows data from the third patient enrolled in cohort 7 of the trial who was treated with THE-630 at 27 mg. This patient experienced grade 3 hand-foot skin reaction (HFSR), which required an expansion of the cohort to 6 patients. One patient in the cohort 7 expansion group experienced grade 2 HFSR, which required a dose interruption of ≥7 days. Both the grade 3 and grade 2 HFSR were determined to be dose-limiting toxicities.

With 2 out of 6 patients in this cohort experiencing a DLT, the 27 mg dose exceeds the maximum tolerated dose (MTD), and the company does not believe that THE-630 has a differentiated profile at doses below 27 mg. As a result, they have come to the conclusion to end the development of THE-630 in GIST with patients currently enrolled in the trial continuing to receive THE-630 until a treatment discontinuation criterion is met.

"We are disappointed that we will not be able to achieve the target exposure for pan-variant inhibition with THE-630, as we continue to believe a therapy with potent activity against all major classes of activating and resistance mutations in KIT has the potential to confer significant clinical benefit, given the unmet need in GIST," said Tim Clackson, PhD, president and chief executive officer of Theseus, in a press release.

Initial data from the dose-escalation portion of the phase 1/2 trial were released on May 25, 2023. As of the data cutoff date of April 21, 2023, 23 patients had been dosed through cohort 6 which administered patients THE-630 at 18 mg, and 2 patients were enrolled in cohort 7.

The phase 1/2 study employed a standard 3 + 3 dose-escalation design and planned to investigate the safety, pharmacokinetics, and antitumor activity of THE-630 in patients with advanced GIST.2

With THE-630 out of development, Theseus will pursue a new clinical devAdvance KIT program for patients with GIST as KIT-mutant GIST remains an area of major unmet medical need. According to the press release, this type of GIST requires a pan-variant molecule to target all major activating and resistance mutations in KIT, with high selectivity, for use in early-line patients.

Outside of GIST, the company plans to advance THE-349 into clinical studies for the treatment of patients with EGFR mutant non–small cell lung cancer, as well as the BCR-ABL Program which aims to develop a potent and selective, next-generation, pan-variant BCR-ABL tyrosine kinase inhibitor for patients with relapsed/refractory chronic myelogenous leukemia and those with newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

“We remain committed to helping [patients with] GIST with plans to nominate a new, highly selective pan-variant KIT inhibitor candidate for GIST in the first half of 2024. Moving forward, we are excited to have THE-349 as our next near-term clinical program, with its potential best-in-class profile as a fourth generation EGFR inhibitor appropriate for both monotherapy and combination approaches," added Clackson, in the press release.

  1. ​​Theseus Pharmaceuticals to discontinue enrollment in phase 1/2 study and terminate development of THE-630 in patients with GIST. News release. ​​Theseus Pharmaceuticals, Inc. July 13, 2023. Accessed July 18, 2023.
  2. A study of THE-630 in patients with advanced gastrointestinal stromal tumors (GIST). Updated January 25, 2023. Accessed July 18, 2023.
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