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Background <p>CFT8634, an orally bioavailable, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), showed robust and dose-dependent BRD9 degradation and antitumor activity in preclinical synovial sarcoma and <i>SMARCB1</i>-null tumor models. This study characterizes the safety, tolerability, and preliminary efficacy of CFT8634 in patients with these indications.</p> Methods <p>This first-in-human, open-label, multicenter, phase 1, dose-escalation clinical trial (NCT05355753) of CFT8634 enrolled patients with synovial sarcoma or <i>SMARCB1</i>-null tumors who received ≥1 prior line of systemic anticancer therapy. The primary endpoint was safety; secondary endpoints included assessment of pharmacokinetics, pharmacodynamics, and best overall response.</p> Results <p>Prior to enrollment completion, the trial was terminated due to insufficient efficacy. Here we show 23 out of 49 (47%) patients experience at least 1 grade ≥3, possibly treatment-related, treatment-emergent adverse event after receiving at least 1 dose of CFT8634, with a median duration of treatment of 1.7 months. Electrocardiogram data reveal frequent T-wave abnormalities during the treatment period across all dose levels, with 6 (12%) patients developing heart rate–corrected QT interval (QTc) prolongation. Plasma exposure of CFT8634 is dose proportional, and pharmacodynamic data show robust and continuous BRD9 degradation. These findings also show 1 patient (2%) achieving best overall response, which is a confirmed partial response, and 7 patients (14%) achieving stable disease during the dose-escalation phase.</p> Conclusions <p>CFT8634 effectively degrades BRD9, providing proof-of-principle that heterobifunctional degraders are a viable strategy for clinical development. However, further exploration of CFT8634 is inhibited due to patients experiencing unanticipated nonspecific T-wave abnormalities and QTc prolongation in this study.</p>

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Safety of the BRD9 heterobifunctional degrader CFT8634 in synovial sarcoma and SMARCB1-null tumors: an open-label, dose-escalation, phase 1 clinical trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Brian A. Van Tine,
  • William D. Tap,
  • Mark Agulnik,
  • Ravin Ratan,
  • Sant P. Chawla,
  • Steven Attia,
  • Anthony Elias,
  • Prabhjot Mundi,
  • Mohammed Milhem,
  • Joseph G. Pressey,
  • Amro Ali,
  • Ingrid Mintautas,
  • Riadh Lobbardi,
  • Huan Liu,
  • Eunju Hurh,
  • Len Reyno,
  • Gregory M. Cote

摘要

Background

CFT8634, an orally bioavailable, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), showed robust and dose-dependent BRD9 degradation and antitumor activity in preclinical synovial sarcoma and SMARCB1-null tumor models. This study characterizes the safety, tolerability, and preliminary efficacy of CFT8634 in patients with these indications.

Methods

This first-in-human, open-label, multicenter, phase 1, dose-escalation clinical trial (NCT05355753) of CFT8634 enrolled patients with synovial sarcoma or SMARCB1-null tumors who received ≥1 prior line of systemic anticancer therapy. The primary endpoint was safety; secondary endpoints included assessment of pharmacokinetics, pharmacodynamics, and best overall response.

Results

Prior to enrollment completion, the trial was terminated due to insufficient efficacy. Here we show 23 out of 49 (47%) patients experience at least 1 grade ≥3, possibly treatment-related, treatment-emergent adverse event after receiving at least 1 dose of CFT8634, with a median duration of treatment of 1.7 months. Electrocardiogram data reveal frequent T-wave abnormalities during the treatment period across all dose levels, with 6 (12%) patients developing heart rate–corrected QT interval (QTc) prolongation. Plasma exposure of CFT8634 is dose proportional, and pharmacodynamic data show robust and continuous BRD9 degradation. These findings also show 1 patient (2%) achieving best overall response, which is a confirmed partial response, and 7 patients (14%) achieving stable disease during the dose-escalation phase.

Conclusions

CFT8634 effectively degrades BRD9, providing proof-of-principle that heterobifunctional degraders are a viable strategy for clinical development. However, further exploration of CFT8634 is inhibited due to patients experiencing unanticipated nonspecific T-wave abnormalities and QTc prolongation in this study.