On May 25, 2023 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development, and commercialization of transformative targeted therapies, reported initial dose escalation data from the ongoing phase 1/2 trial of THE-630 in patients with advanced gastrointestinal stromal tumors (GIST) (Press release, Theseus Pharmaceuticals, MAY 25, 2023, View Source [SID1234632081]).

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Theseus will host a virtual investor webcast today at 5:30pm ET to discuss this update.

"THE-630 has shown strong clinical proof of mechanism through Cohort 6 with a safety and pharmacokinetic profile supportive of continued dose escalation," said Tim Clackson, Ph.D., President and Chief Executive Officer of Theseus. "Importantly, with dose-dependent activity observed against both major classes of KIT resistance mutations, coupled with the increased frequency of stable disease at the higher doses tested thus far, we believe THE-630 could have a best-in-class profile and provide a much-needed alternative to combat the complex resistance that drives rapid progression of GIST. We are also encouraged by the further validation of our PRA, with reductions in ctDNA observed for specific mutations consistent with our preclinical predictions. These data support our ability to reach target exposures in Cohort 8, and we look forward to reporting data through Cohort 8 later this year."

"The emerging potential activity in both classes of resistance mutations in the activation loop and ATP binding pocket is promising, as it is critically important to be active against both to provide a meaningful clinical benefit for patients," said Suzanne George, M.D., Associate Division Chief, Sarcoma Center, Dana-Farber Cancer Institute, and a principal investigator on the phase 1/2 trial.

Reporting data on THE-630 through Cohort 6 (n=23); currently dosing Cohort 7
•As of April 21, 2023, 25 patients have been treated in the dose escalation portion of the trial: 23 patients enrolled in Cohorts 1-6 (3, 4, 6, 9, 12, 18 mg); 2 patients enrolled in Cohort 7 (27 mg).
◦Following the data cutoff, both Cohort 7 patients subsequently cleared the dose-limiting toxicity (DLT) observation period without experiencing a DLT.
•All patients had metastatic KIT-mutant GIST.
•Patients in the trial had a median of 4 prior therapies (range 2 to 8); 70% of patients with ≥4 prior tyrosine kinase inhibitors (TKIs).
◦All patients received prior treatment with imatinib and sunitinib.
◦65% of patients received prior treatment with ripretinib and regorafenib.

Safety profile supportive of continued dose escalation; pharmacokinetics (PK) consistent with once-daily oral dosing
•The observed safety profile is consistent with the class and with preclinical data.
•Treatment-related adverse events (TRAEs) were observed in 65% of patients.
◦Of 89 TRAEs reported, 84 (94%) were grades 1-2 and 5 (6%) were grade ≥3 (3 of which occurred in Cohorts 1 and 2).
◦The most common TRAEs (occurring in ≥10% of patients) included fatigue, increased AST, diarrhea, nausea, dry mouth, and dyspnea.
•In Cohort 2 (4 mg), a 9th-line, 64-year-old patient with hyperlipidemia experienced a myocardial infarction (MI) on study day 6 after being hospitalized for adverse events unrelated to study drug, and subsequently died. The event was considered a DLT as the relationship between THE-630 and the MI could not be incontrovertibly ruled out.
◦No cardiac ischemic AEs of any grade have been reported in the other 22 patients in the study, including at significantly higher exposure levels.
•No additional DLTs or treatment-related serious adverse events have been observed, and the maximum tolerated dose (MTD) has not been reached.
•PK profile approximately linear and consistent with once-daily oral dosing.

Reductions in ctDNA of both classes of KIT resistance mutations, consistent with preclinical PRA predictions
•THE-630 reduced the allele frequency across all major classes of KIT activating and resistance mutations in a manner consistent with preclinical predictions seen in the Predictive Resistance Assay (PRA), including dose-dependent and potent reduction of exon 13 mutation V654A, the most common resistance mutation seen in GIST.
◦Pre- and post-baseline samples were available for 19 patients, including 2 in Cohort 6 (18 mg).
◦KIT mutations were detected in 84% of patients (16 out of 19); 5 patients had more than one resistance mutation at baseline (range 2 to 6).
◦ctDNA reductions were observed more frequently at higher doses, with 6 out of 6 patients treated in Cohorts 4-6 (9 to 18 mg) showing reductions in all KIT mutant variants present at baseline, including activating mutations detected in exons 9 and 11, and resistance mutations detected in exons 13, 14, and 17.
•Based on clinical PK through Cohort 6, and consistent with ctDNA observations to date, THE-630 is projected to achieve exposures consistent with pan-variant inhibition across all major classes of KIT mutations, as predicted by the PRA, in Cohort 8.

Evidence of prolonged stable disease observed
•Disease stabilization was observed more frequently at higher doses, with 8 out of 9 evaluable patients treated in Cohorts 4-6 (9 to 18 mg) achieving stable disease as best response, a disease control rate of 89%.
•A patient with 5 prior lines of therapy and KIT exon 11 and exon 17 (N822K) mutations detected in ctDNA at baseline had prolonged stable disease, receiving THE-630 for 36 weeks (enrolled in Cohort 2 [4 mg] with subsequent escalation to 6 mg and then 9 mg), with strong ctDNA reductions of both mutations observed.
•A patient with KIT exon 11 and exon 13 (V654A) mutations detected in pre-treatment tumor biopsy remains on therapy with stable disease maintained through at least 24 weeks (enrolled in Cohort 5 [12 mg] and subsequently escalated to 18 mg).

"Today’s data provide early clinical evidence that THE-630 could potentially meet a critical need in patients with refractory GIST," said David Kerstein, M.D., Chief Medical Officer of Theseus. "We are particularly excited by the observed dose-dependent reductions in KIT mutations, along with disease stabilization. With the encouraging early safety profile, we look forward to continuing dose escalation to a recommended phase 2 dose for THE-630."

Virtual Investor Event

Theseus will host a virtual investor event to review these initial clinical results today, beginning at 5:30pm ET. The event will be webcast live and can be accessed in the Events section of the Company’s investor relations website at ir.theseusrx.com. A replay of the webcast will be archived and available for 90 days following the event.

Date: Thursday, May 25, 5:30pm ET
Webcast link: View Source
Register for dial-in: https://register.vevent.com/register/BI54a9015fcbd64a6a996a40c017a76abf

About THE-630

THE-630 is a pan-variant tyrosine kinase inhibitor (TKI) of the receptor tyrosine kinase KIT, designed for patients with GIST that have developed resistance to earlier lines of therapy.

THE-630 Clinical Trial Background and Clinical Development Plan

Trial THE630-21-101 is a phase 1/2 open label, multicenter, first-in-human dose escalation and expansion trial designed to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral THE-630 (NCT Number: NCT05160168). The trial is expected to be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (phase 1) of the trial will include patients with unresectable or metastatic GIST who had disease progression on or are intolerant to imatinib therapy and have also received at least one of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of THE-630, including the dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose.

Once a recommended dose has been determined in the dose escalation phase, the dose expansion phase (phase 2) will enroll patients with unresectable or metastatic GIST into three cohorts defined by prior therapy including a second-line cohort and a fifth-line cohort. The primary objective of the expansion phase is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

Data from the phase 1/2 clinical trial is expected to inform further clinical development of THE-630 including the design of the planned registrational trials for THE-630. Theseus is prioritizing the development of THE-630 in second-line GIST, where a pan-variant KIT inhibitor with activity against all major classes of activating, or cancer-causing, and resistance mutations has the potential to deliver meaningful clinical benefit over the current standard of care. Theseus also plans to evaluate THE-630 in fifth-line GIST, where there is currently no available therapy and therefore a significant unmet need.