(P 541) ETCTN 10563: PHASE 1 STUDY OF PEPOSERTIB AND LIPOSOMAL DOXORUBICIN FOR ADVANCED OR METASTATIC LEIOMYOSARCOMA AND OTHER SARCOMAS

Objective: Soft tissue sarcomas (STS) are mesenchymal malignancies comprised of over 80 subtypes with distinct tumor biology and clinical behaviors. STS with complex genomes have chromosomal instability (CIN) that is associated with aggressiveness, but also renders them vulnerable to therapies that cause further genotoxic stress. Leiomyosarcomas (LMS) are among the most common STS and are frequently characterized by CIN and DNA damage response (DDR) dysregulation. Preclinical evidence showed that the gene encoding the catalytic subunit of DNA-PK (PRKDC) is essential in LMS models, suggesting dependency on DNA-PK mediated non-homologous end joining (NHEJ) DNA repair. In preclinical LMS models, low dose anthracycline synergized with the DNA-PK inhibitor peposertib to inhibit tumor growth in vitro and in vivo. We hypothesized that a low, sensitizing dose of liposomal doxorubicin may enhance tumor DNA damage and safely synergize with DNA-PK inhibition in patients with LMS and other STS with CIN and DDR deficits.

Methods: This is a phase 1, open label, multicenter dose escalation and dose expansion study (NCT05711615) evaluating low-dose liposomal doxorubicin given intravenously (IV) on day 1 of 28-day cycles in combination with peposertib given orally twice daily continuously (Table 1). Up to 18 patients over 18 years-old with advanced or unresectable LMS, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), dedifferentiated liposarcoma (DDLPS), and synovial sarcoma, ECOG performance status ≤2, who have received at least 1 prior line of systemic therapy (including anthracycline up to 300 mg/m2) are eligible for dose escalation (Figure 1). Dose expansion will be restricted to 12 patients with LMS (Figure 2). The primary objective is to determine the recommended phase 2 dose (RP2D) of the combination based on the DLT rate. The Bayesian Optimal Interval (BOIN) design will inform dose escalation decisions. Secondary endpoints for the expansion cohort include adverse event rate, progression-free survival (PFS), and objective response rate (ORR) per RECIST v1.1. Tumor biopsies during screening and at cycle 1 days 7-10 will be used to evaluate potential predictive biomarkers and assess for changes in DNA damage and repair biomarkers. Circulating tumor DNA (ctDNA) will be collected prior to treatment (dose escalation and dose expansion) and at several timepoints on treatment and at progression (dose expansion only) to correlate ctDNA levels with disease activity and response.

Results: N/A (form would not allow me to submit without including 10 characters minimum)

Conclusion: This ongoing phase 1 dose escalation and dose expansion study is evaluating low dose liposomal doxorubicin combined with the DNA-PK inhibitor peposertib in LMS and select STS with embedded correlative studies to identify predictive biomarkers and explore mechanism of action.

Note: Research support for correlative studies and peposertib supply were provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).