(P 313) A 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)

Objective: Loss-of-function alterations of the tumor suppressor genes TSC1 and TSC2 upstream of mechanistic target of rapamycin (mTOR) are found at low frequency in many tumor types. However, across all tumors, inactivating TSC1 and TSC2 alterations combined are actually more frequent than all but 5 of the 24 targetable biomarkers for which there are FDA-approved therapies (Gulati, AACR 2022 #5799). There is no specific treatment approved for tumors harboring TSC1 or TSC2 inactivating alterations, and patients with these tumors represent a substantial unmet medical need. mTOR pathway inhibition may be a promising therapeutic approach, but first-generation mTOR inhibitors (mTORi) have shown clinical success in only a limited number of cancers, possibly due to insufficient target suppression (PMID: 33727259); improved therapies targeting mTOR are therefore needed.
Albumin-bound (nab)-sirolimus is a novel mTORi that utilizes nanoparticle technology to preferentially target tumors. In preclinical studies (Hou, AACR 2019 #348), treatment with nab-sirolimus resulted in significantly higher tumor uptake, greater suppression of the mTOR targets S6K and 4EBP1, reduced tumor growth, and a distinct pharmacokinetic profile relative to oral mTORi in animal models. These properties may enable nab-sirolimus to overcome the limitations of conventional mTORi. nab-Sirolimus is approved in the US for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Methods: In a registrational trial of nab-sirolimus in advanced malignant PEComa (PMID: 34637337), exploratory analysis of 31 evaluable patients suggested association of TSC2 or TSC1 inactivating alterations and response with nab-sirolimus: 89% of patients (8/9) with TSC2 inactivating alterations and 20% (1/5) with TSC1 inactivating alterations had confirmed response. Another 20% (1/5) of patients with TSC1 alterations had complete resection of a previously inoperable locally advanced tumor after receiving nab-sirolimus. The safety profile, antitumor activity, and duration of response in patients with TSC1 or TSC2 alterations (DOR; median not reached after 3 years of follow-up for responders) warrant further studies of nab-sirolimus safety and efficacy in patients with solid tumors harboring TSC1 or TSC2 inactivating alterations.
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) (Figure 1).
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 naïve to mTORi will be eligible.
nab-Sirolimus will be administered IV at 100 mg/m2 weekly 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. Key secondary endpoints include DOR, disease control rate, progression-free survival, overall survival, and safety.
Enrollment is ongoing. The most prevalent tumor types in this tissue-agnostic trial are expected to be lung, bladder, soft tissue sarcomas, uterine, colon, kidney, melanoma, liver, and esophageal, based on prevalence of TSC1 or TSC2 alterations in tumors from the NIH NCI Genomic Data Commons and Surveillance, Epidemiology, and End Results database (Table 1).

Results: Trial in progress abstract

Conclusion: Trial in progress abstract



Table 1.docx