(P 540) PHASE 2, MULTICENTER, OPEN-LABEL BASKET TRIAL OF NAB-SIROLIMUS FOR MALIGNANT SOLID TUMORS HARBORING PATHOGENIC INACTIVATING ALTERATIONS IN TSC1 AND TSC2 (PRECISION I)

Objective: nab-Sirolimus, approved in the US for patients with advanced malignant PEComa, is a novel albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. TSC1 and TSC2 alterations have been observed in patients with various cancers. Clinically, in an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. In the Expanded Access Program (NCT03817515), patients with various malignancies bearing TSC1 or TSC2 alterations treated with nab-sirolimus showed evidence of response (partial response in 5/7 patients) and manageable toxicities. Based on the clinical observations from AMPECT and the Expanded Access Program, the PRECISION I trial (NCT05103358) was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of advanced cancers with TSC1 or TSC2 inactivating alterations.

Methods: Eligible patients are ≥12 years old and mTORi-naïve, possess advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator.

nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety.

Enrollment began March 2022. Collaboration with leading NGS providers will expedite the identification of patients with qualifying TSC1 and TSC2 mutations; ongoing study access is facilitated through a just-in-time approach to trial site activation. Based on the prevalence of TSC1 and TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table).

Results: Not applicable

Conclusion: Not applicable