(P 402) A PILOT STUDY OF BTX-A51 IN PATIENTS WITH METASTATIC AND/OR RECURRENT LIPOSARCOMAS CHARACTERIZED BY MDM2 AMPLIFICATIONS

Objective: Liposarcomas account for ~20% of all soft tissue sarcomas. The well differentiated and de-differentiated subtypes of LPS are characterized by MDM2 amplifications, usually with co-amplification of CDK4, with no mutations in TP53 (wild type). BTX-A51 is an oral small molecule kinase inhibitor designed to block Casein Kinase 1α (CK1α) as well as transcriptional CDKs (CDK7/CDK9). In preclinical models of human liposarcoma, BTX-A51 transcriptionally represses MDM2 expression with consequent increased levels of p53, while also activating DNA damage repair pathways through CK1α inhibition. The primary objective of this trial is to confirm the safety and tolerability of BTX-A51 in patients (pts) with metastatic and/or recurrent liposarcomas. Exploratory objectives are to assess evidence of anti-tumor activity in study participants. We will also assess study drug exposure and proof-of-mechanism pharmacodynamic biomarkers of BTX-A51 activity, adaptive changes in tumor biology in response to administration of BTX-A51 by RNA transcriptomic analysis, and potential changes in microenvironment and immune markers in serial tumor biopsy samples.

Methods: The primary objective of this pilot study is to confirm the safety and tolerability of the recommended phase 2 dose and schedule of BTX-A51 in this population. Of note, phase Ib studies have previously been done in advanced refractory AML pts and pts with solid tumors other than liposarcomas. Those studies suggested a recommended phase 2 dose and schedule of 21 mg/day given 3 days per week (MWF). Descriptive statistics will be used to summarize results in the present study. Safety and tolerability will be monitored through continuous reporting of treatment-emergent and treatment-related adverse events, laboratory abnormalities, and incidence of subjects experiencing dose modifications, delays, interruptions, or premature discontinuation of BTX-A51 due to an adverse event. All treated pts will be included in the safety analysis. AEs will be graded by NCI CTCAE v5.0. Physical examination, vital signs, laboratory assessments (standard clinical chemistry and hematology), and ECOG performance status will be monitored. Planned correlative testing is described in Table 1. Biopsies will be taken before and during treatment, and optionally following disease progression to assess potential mechanisms of resistance. Key pharmacodynamic markers will include tumor immunohistochemistry for p53, MDM2, MCL-1, Ki-67, and p21 on serial biopsies, as well as MIC-1 levels in peripheral blood. Transcriptomic changes in serial tumor biopsies will be measured by RNA-seq. Changes in the tumor microenvironment and immune cell composition associated with BTX-A51 administration will be assessed with Cyclic immunofluorescence (CyCIF). Dynamic BH3 profiling for pro-apoptotic effects will also be performed on fresh biopsy samples serially. Preliminary efficacy assessments will include determination of objective response rate by RECIST v1.1 and progression-free and overall survival at 12 months. NCT06414434

Results: N/A Trial in Progress.

Conclusion: N/A Trial in Progress.