(P 312) A PHASE 1/2 STUDY OF CFT8634, A NOVEL BIFUNCTIONAL DEGRADATION ACTIVATING COMPOUND (BIDAC) DEGRADER OF BRD9, IN SYNOVIAL SARCOMA AND SMARCB1-NULL TUMORS

Objective: Background: SMARCB1-perturbed cancers are dependent on the chromatin factor BRD9. Two types of genetic alterations result in SMARCB1 perturbation: SS18-SSX gene fusion and SMARCB1 loss-of-function mutations. Driven by the presence of SS18-SSX chromosomal translocation, 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%. Other SMARCB1-null tumor types include malignant rhabdoid tumor (MRT), poorly differentiated chordoma, and epithelioid sarcoma.

CFT8634 is an orally bioavailable selective bifunctional degradation activating compound, or BiDAC™ degrader, that induces ternary complex formation with BRD9 and a cereblon E3 ligase, leading to the ubiquitination of BRD9 and its subsequent degradation by the proteasome. CFT8634 leads to robust and dose-dependent degradation of BRD9 in in vitro and in vivo models of synovial sarcoma and SMARCB1-null tumors, which translates to significant and dose-dependent anti-tumor activity in patient-derived preclinical xenograft models. These results provide rationale for a first-in-human, Phase 1 study to evaluate CFT8634 in synovial sarcoma and SMARCB1-null tumors.

Methods: Study Design: This is a first-in-human, open-label, multicenter, Phase 1/2 clinical trial with dose escalation and expansion phases. With a starting oral dose of 2 mg daily, the dose escalation phase of the trial will follow a Bayesian logistic regression model until determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). CFT8634 will be administered in 28-day cycles until disease progression or intolerable toxicity. Once the RP2D has been declared, expansion arms for synovial sarcoma and SMARCB1-null tumors will begin enrollment. The dose escalation phase of the trial will enroll approximately 40 patients with locally advanced or metastatic SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null tumors. Arm A of the dose expansion phase will enroll approximately 30 subjects with locally advanced or metastatic synovial sarcoma, while Arm B will enroll approximately 20 subjects with locally advanced or metastatic SMARCB1-null tumors.

Primary objectives include safety and tolerability, RP2D/MTD of CFT8634, and overall response rate during expansion arms. Secondary objectives include assessment of pharmacokinetics, pharmacodynamics, and additional efficacy endpoints.

Key inclusion criteria are synovial sarcoma or SMARCB1-null tumors confirmed by immunohistochemistry, fluorescent in situ hybridization, or other equivalent tests like gene mutation analysis, with unresectable or metastatic disease, following at least 1 prior line of standard-of-care systemic therapy. Patients must not be candidates for available therapies that are known to confer clinical benefit and must be ≥18 years of age, or ≥16 years old and weigh ≥50 kg. Key exclusion criteria include systemic anti-neoplastic therapy within 14 days or 5 half-lives, whichever is shorter, prior to the planned first dose of CFT8634.

Results: Not Applicable

Conclusion: Approximately 110 patients at approximately 10 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT05355753, and is open to enrollment.