Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).

Authors

null

Dustin A. Deming

University of Wisconsin, Madison, WI;

Dustin A. Deming , Jordi Rodon Ahnert , Michael J. Demeure , Noah Federman , Meredith McKean , Elizabeth Katherine Lee , Alexander I. Spira , David J. Kwiatkowski , Maen A. Hussein , Erlinda Maria Gordon , David G. Crockett , Kristen N. Ganjoo , Brian Schulte , Lee D. Cranmer , Anita N. Schmid , Willis H. Navarro , Loretta Marie Itri , Gopa Iyer

Organizations

University of Wisconsin, Madison, WI; , MD Anderson Cancer Center, Houston, TX; , Hoag Family Cancer Institute, Hoag Memorial Hospital Presbyterian, Newport Beach, CA; , University of California, Los Angeles, CA; , Sarah Cannon and HCA Research Institute, Nashville, TN; , Dana-Farber Cancer Institute, Boston, MA; , Virginia Cancer Specialists, Fairfax, VA; , Brigham and Women's Hospital, Boston, MA; , Florida Cancer Specialists North Division, St Petersburg, FL; , Sarcoma Oncology Research Center, Santa Monica, CA; , Nebraska Cancer Specialists, Omaha, NE; , Stanford Cancer Center GI Surgical Oncology, Stanford, CA; , UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; , University of Washington/Fred Hutchinson Cancer Consortium, Seattle, WA; , Aadi Bioscience, Pacific Palisades, CA; , Memorial Sloan Kettering Cancer Center, New York, NY;

Research Funding

Pharmaceutical/Biotech Company
Aadi Bioscience

Background: Albumin-bound (nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358.

Incidence numbers estimate of US patients with definite impact TSC1 and TSC2 alterations available for first-line therapy in 2030.

Tumor TypeTSC1 MutationsaTSC2 MutationsaEligible TSC1 and TSC2 Combined
Bladder6.33%1.70%8.03%
Hepatobiliary1.27%3.31%4.58%
Endometrial2.10%1.22%3.32%
Soft tissue sarcoma1.28%1.71%2.99%
Ovarian1.85%0.92%2.77%
Esophagogastric0.65%1.46%2.11%
Colorectal carcinoma0.99%0.39%1.38%
Pancreatic0.57%--0.57%

All gastrointestinal tumors (bolded) with known incidence of TSC1/TSC2, and tumor types with combined incidence of TSC1/TSC2 alterations of >2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact; this includes 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).

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Abstract Details

Meeting

2023 ASCO Gastrointestinal Cancers Symposium

Session Type

Trials in Progress Poster Session

Session Title

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Track

Esophageal and Gastric Cancer,Other GI Cancer

Sub Track

Therapeutics

Clinical Trial Registration Number

NCT05103358

Citation

J Clin Oncol 41, 2023 (suppl 4; abstr TPS818)

DOI

10.1200/JCO.2023.41.4_suppl.TPS818

Abstract #

TPS818

Poster Bd #

P8

Abstract Disclosures