Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1/2 (PRECISION I)

MD Gopa Iyer,; MD Michael J. Demeure,; MS, MA Li Ding,; PhD Anita N. Schmid,; MD Willis Navarro,; MD, PhD David J. Kwiatkowski,; Ahnert, MD, PhD Jordi Rodon

doi:10.1530/endoabs.98.T4

Background: 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 occur in a range of common cancers. Clinically, in the AMPECT exploratory analysis 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. Most treatment-related adverse events in AMPECT were grade 1/2 (none grade ≥4), consistent with mTORi-class adverse events (Wagner, J Clin Oncol, 2021). Based on clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, PRECISION I (NCT05103358) was designed to assess nab-sirolimus safety and efficacy in a tumor-agnostic study of advanced cancers with TSC1 and TSC2 inactivating alterations.

Methods: Eligible patients are ≥12yo and mTORi-naïve, possess advanced malignant solid tumors with TSC1 and 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 D1 and D8 of each 21-day cycle. Primary endpoint: 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 QOL, 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 given in bold in the Table.Table. Estimated frequency of definite impact TSC1/TSC2 alterationsData are %. ^aProportion of patients with definite impact alterations (ie, alterations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) derived from analysis of TCGA and cBioPortal by Gulati et al. Data on file.

Results: N/A

Table Estimated frequency of definite impact TSC1/TSC2 alterations
Tumor Type	TSC1 Alterations^a	TSC2 Alterations^a	TSC1/TSC2 Combined
Bladder	6.33	1.70	8.03
Hepatobiliary	1.27	3.31	4.58
Endometrial	2.10	1.22	3.32
Soft tissue sarcoma	1.28	1.71	2.99
Ovarian	1.85	0.92	2.77
Esophagogastric	0.65	1.46	2.11
Non-small cell lung cancer	0.77	1.16	1.93
Colorectal carcinoma	0.99	0.39	1.38
Breast	0.41	0.10	0.51
Data are %. ^aProportion of patients with definite impact alterations (ie, alterations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) derived from analysis of TCGA and cBioPortal by Gulati et al. Data on file.

Conclusion: Trial in progress

Abstract ID 23649

Endocrine Abstracts

T4