Abstract CT057: Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I)
Authors: Ahnert Jordi Rodon , Schulte Brian , Demeure Michael J. , Deming Dustin , Federman Noah , McKean Meredith A. , Lee Elizabeth , Spira Alexander , Kwiatkowski David J. , Hussein Maen , Gordon Erlinda , Crockett David , Ganjoo Kristen , Cranmer Lee D. , Schmid Anita N. , Navarro Willis H. , Itri Loretta M. , Iyer Gopa 
Published: April 2023

Abstract
nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. 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 TSC1 and TSC2, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with long-term treatment of nab-sirolimus. PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 years old and mTORi-naïve, possess malignant solid tumors with TSC1 or TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, as determined by the investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 minutes 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 next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1 or TSC2 mutations; study access will be facilitated through a “just-in-time” approach to trial location activation. Based on the prevalence of TSC1 or TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table).
Est incidence of patients with TSC1 or TSC2 alterations available for 1L therapy in 2030 Tumor Type TSC1 Mutations, %a TSC2 Mutations, %a Eligible TSC1 or 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 Colorectal carcinoma 0.99 0.39 1.38 Pancreatic 0.57 — 0.57 Note: Estimated incidence of patients in the United States with definite impact TSC1 or TSC2 alterations available for 1L therapy in 2030. All gastrointestinal tumors (bolded) with known incidence of TSC1 or TSC2 and tumor types with combined incidence of TSC1 or TSC2 alterations of &gt;2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons). 1L, first-line.
Citation Format: Jordi Rodon Ahnert, Brian Schulte, Michael J. Demeure, Dustin Deming, Noah Federman, Meredith A. McKean, Elizabeth Lee, Alexander Spira, David J. Kwiatkowski, Maen Hussein, Erlinda Gordon, David Crockett, Kristen Ganjoo, Lee D. Cranmer, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Gopa Iyer. Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT057.