Theseus Pharmaceuticals Terminates Development of THE-630 in Gastrointestinal Stromal Tumors

Theseus Pharmaceuticals has announced that the development of THE-630 as a potential therapeutic option for patients with gastrointestinal stromal tumor (GIST) has been terminated, and enrollment to the ongoing phase 1/2 trial (NCT05160168) evaluating the agent’s safety and efficacy in this population has been discontinued.¹

Initial dose-escalation data from cohort 1 through 6 (n = 23), which evaluated the agent at doses of 3 mg, 4 mg, 6 mg, 9 mg, 12 mg, and 18 mg, revealed evidence of prolonged stable disease and a toxicity profile that supported continued dose escalation.²

At that time point, 2 patients in cohort 7 had received THE-630 at a dose of 27 mg and did not experience a dose-limiting toxicity (DLT).1 Subsequently, a third patient enrolled to that cohort experienced grade 3 hand-foot skin reaction (HFSR), which mandated an expansion of the cohort to 6 patients. One of the patients in the expansion group was then found to have grade 2 HFSR. These 2 effects required dose interruptions of 7 days or more and were identified as DLTs per the study protocol, and thus, this dose level was found to exceed the maximum tolerated dose (MTD) of the agent.

“The Company does not believe that THE-630 has a differentiated profile at doses below 27 mg, which would provide exposure well below the target level of 100 nanomolar average concentration,” the clinical-stage biopharmaceutical company shared in a recently issued press release.¹ “As a result, the Company has made the decision to terminate the development of THE-630 in GIST.”

Notably, those who are already enrolled to the early-phase trial will continue to receive the investigative agent unless discontinuation criteria are met.¹

The phase 1/2 trial enrolled patients with histologically or cytologically confirmed unresectable or metastatic GIST who were at least 18 years of age, had at least 1 measurable lesion by modified RECIST (mRECIST) v1.1 criteria, and an ECOG performance status ranging from 0 to 2.3 Patients could not have known KIT and PDGFRA wild-type disease.

For the phase 1 portion of the research, patients must have progressed on or been intolerant to imatinib (Gleevec) and have also received 1 or more TKIs such as sunitinib (Sutent), regorafenib (Stivarga), ripretinib (Qinlock), or avapritinib (Ayvakit).

The phase 2 dose-expansion phase of the trial was comprised of 3 cohorts, each seeking to enroll approximately 20 patients: those in the second-line must have only received prior imatinib; those in the third- or fourth-line cohort must have previously received imatinib and sunitinib, as well as 0 to 1 additional lines of treatment; and those in the fifth- or later-line cohort must have previously received imatinib, sunitinib, regorafenib, and ripretinib.

The trial utilized a 3+3 design, and THE-630 was evaluated at once-daily escalating doses, starting at 3 mg (cohort 1, n = 3), to 4 mg (cohort 2, n = 7), 6 mg (cohort 3, n = 3), 9 mg (cohort 4, n = 3), 12 mg (cohort 5, n = 3), 18 mg (cohort 6, n = 4), and 27 mg (cohort 7). The projected target exposure was 40 mg daily (cohort 8).

The primary objective of the first phase of the research was to evaluate the toxicity profile of THE-630, specifically DLTs, and to identify the MTD as well as the recommended phase 2 dose. Secondary objectives comprised analyzing the pharmacokinetic profile of the drug and assessing antitumor activity. For the second phase, primary and secondary objectives were to assess antitumor activity in the form of objective response rate by mRECIST v1.1 criteria and further examine the safety and PK profile, respectively.

The initial dose-escalation data were shared via webcast on May 25, 2023.^2,3 At the time of data cutoff, a total of 25 patients were enrolled to cohorts 1 through 6 and 2 patients were enrolled to cohort 7. Regarding patients enrolled in cohorts 1 to 6 (n = 23), the median age was 59 years and 43.5% were female.3 In terms of ECOG performance status, 47.8% of patients had a status of 0, 47.8% had a status of 1, and 4.3% had a status of 2. All patients had stage IV disease at the time of screening.

Moreover, 13%, 17.4%, 52.2%, 8.7%, and 8.7% of patients had previously received 2, 3, 4, 5, or 6 or more unique TKIs, respectively. Prior TKIs included imatinib (100%), sunitinib (100%), regorafenib (73.9%), and ripretinib (78.3%). The median number of prior lines of therapy received was 4 (range, 2-8). Notably, 70% of patients received at least 4 prior TKIs.

Data showed that in cohort 1, 2 patients had treatment-related hypertension that was grade 2 or higher in severity. This triggered a change to dose escalations of up to 50%. This toxicity was not observed in cohorts 2 to 6. For cohort 2, 1 patient experienced grade 5 myocardial infarction which was determined to be a DLT because the relationship between the drug and the event could not be indisputably ruled out. No additional DLTs or cardiac ischemic effects were reported.

Moreover, 65.2% of the 23 patients experienced any-grade treatment-related adverse effects (TRAEs) with THE-630; these effects were grade 3 or higher in 21.7% of patients.

The most common TRAEs experienced by at least 10% of patients included fatigue (all grade, 21.7%; grade ≥3, 4.3%), dyspnea (13%; 0%), nausea (13%; 0%), diarrhea (13%; 0%), increased aspartate aminotransferase (13%; 0%), dry mouth (13%; 0%), abdominal pain (8.7%; 0%), anemia (8.7%; 4.3%), hypertension (8.7%; 4.3%), back pain (4.3%; 0%), constipation (4.3%; 0%), arthralgia (4.3%; 0%), reduced appetite (4.3%; 0%), dehydration (4.3%; 0%), peripheral edema (4.3%; 0%), extremity pain (4.3%; 0%), and vomiting (4.3%; 0%).

As of July 10, 2023, a total of 32 patients received treatment with THE-630, spanning 7 dose levels which ranged from 3 mg to 27 mg.¹ A total of 6 patients experienced grade 1 to 3 HFSR; this included 3 patients who received the agent at 27 mg, 2 patients who received the agent at 18 mg, and 1 patient who was originally receiving the agent at 9 mg after intra-patient dose escalation to 18 mg. Only 1 case of grade 3 HFSR was reported, and that patient was in the 27-mg cohort. This toxicity was not detected in the cohorts of patients who received THE-630 at doses of 12 mg or lower.

Theseus shared that they are evaluating findings to inform the feasibility of developing low-dose THE-630 for other KIT-associated mast cell-driven inflammatory indications.

“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,” Tim Clackson, PhD, president and chief executive officer of Theseus, stated in the press release.

References

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 19, 2023. https://ir.theseusrx.com/2023-07-13-Theseus-Pharmaceuticals-to-Discontinue-Enrollment-in-Phase-1-2-Study-and-Terminate-Development-of-THE-630-in-Patients-with-GIST
2. Theseus Pharmaceuticals reports initial dose escalation data from ongoing phase 1/2 trial of THE-630 in patients with advanced GIST. News release. Theseus Pharmaceuticals, Inc. May 25, 2023. Accessed July 19, 2023. https://ir.theseusrx.com/2023-05-25-Theseus-Pharmaceuticals-Reports-Initial-Dose-Escalation-Data-from-Ongoing-Phase-1-2-Trial-of-THE-630-in-Patients-with-Advanced-GIST
3. THE-630 initial dose escalation data investor presentation. Theseus Pharmaceuticals, Inc. May 25, 2023. Accessed July 19, 2023. https://edge.media-server.com/mmc/p/izmfuvof/