(P 178) INITIAL RESULTS FROM A PHASE 1 STUDY OF CFT8634, A NOVEL BIFUCTIONAL DEGRADATION ACTIVATING COMPOUND (BIDAC) DEGRADER OF BRD9, IN SYNOVIAL SARCOMA AND SMARCB1-NULL TUMORS

Objective: CFT8634 is an orally bioavailable, selective, bifunctional degradation activating compound, or BiDAC™ degrader, of the Bromodomain-containing protein 9 (BRD9). BRD9 belongs to the non-canonical SWI/SNF complex and is essential to the proliferation of SMARCB1-perturbed cancers. These include synovial sarcoma, defined by the SS18-SSX fusion, and SMARCB1-null tumors such as epithelioid sarcoma. Synovial sarcoma is a rare soft tissue malignancy comprising ~10% of all soft tissue sarcomas. In the metastatic setting, therapeutic options are limited and outcomes are poor with a median overall survival of 17.0 months and 1-year survival rate of 59.7%. CFT8634 showed a robust and dose-dependent BRD9 degradation in preclinical tumor models of synovial sarcoma and SMARCB1-null tumor models and anti-tumor activity in patient-derived xenograft models of synovial sarcoma. Here we report pharmacokinetics (PK), pharmacodynamics (PD), and safety data from the first four cohorts of the CFT8634-1101 phase 1 trial where CFT8634 is being evaluated in patients with synovial sarcoma and SMARCB1-null tumors.

Methods: CFT8634-1101 (NCT05355753) is an ongoing first-in-human, open-label, multicenter, phase 1 dose-escalation and cohort-expansion (phase 2) clinical trial. Phase 1 primary objectives include safety, tolerability and RP2D/MTD of CFT8634. Secondary objectives include assessment of PK, PD , and preliminary efficacy endpoints of CFT8634. Key inclusion criteria are histologically or cytologically confirmed synovial sarcoma or SMARCB1-null tumors (SMARCB1 status ascertained by immunohistochemistry (IHC), fluorescent in situ hybridization, mutation analysis or other diagnostic tests), with unresectable or metastatic disease, following at least 1 prior line of standard-of-care systemic therapy.

Pharmacokinetic parameters on Cycle 1 Day 1 and Cycle 1 Day 15 were calculated using non-compartmental methods. Level of BRD9 degradation upon CFT8634 dosing were assessed by BRD9 IHC in tumor tissue at baseline and Cycle 1 Day 15 (on treatment biopsy) and by mass spectrometry in peripheral blood mononuclear cells at various timepoints.

Results: As of 17 May 2023, a total of 26 patients have been treated with CFT8634 in the 2 mg (n=2), 4 mg (n=5), 8 mg (n=6), 15 mg (n=7), and 30 mg (n=6) cohorts. Patients enrolled in the 30 mg cohort are under evaluation at the time of the data cutoff and are excluded from this analysis. From the first four dose cohorts, the median age was 37 (19-62) years, and most patients (85%) received at least 3 prior lines of therapy, ranging from one prior line to >4 prior lines of therapy. No dose limiting toxicities (DLTs) have been observed at any of the dose levels. The most common and predominately low-grade TEAEs (≥20%) include dry mouth (40%), anemia (30%), dysgeusia (30%), fatigue (30%), and neutropenia (25%). The most common ≥G3 TEAE (≥10%) observed was hyperbilirubinemia (10%). At the time of the data cutoff, there were two subjects who had dose escalated from 8 mg to 15 mg.

Plasma exposure of CFT8634 increased proportionally with dose after single- and repeat-dose administration and a half-life of 10-14 hours supports once-daily dosing. Pharmacodynamic data show a rapid (as early as 8 hours post first dose), robust and sustained BRD9 degradation, assessed in blood and tumor tissue, in most patients at different dose levels of CFT8634. These data confirmed CFT8634 is a potent BRD9 degrader as shown in the preclinical observations and analyses using synovial sarcoma and SMARCB1-loss in in vitro and in vivo models.

Conclusion: Preliminary findings from CFT8634-1101 indicate that CFT8634 demonstrated favorable tolerability and safety at early dose levels. Updated data to be presented at the conference.