Phase I trial of combination gemcitabine (gem) and nab-sirolimus (nab-S) in advanced leiomyosarcomas (LMS) or advanced soft-tissue sarcomas (STS) with <i>TSC1/2</i> alterations: Preliminary results.

11578 Background: Advanced LMS has limited effective therapies, with gem-based regimens being the most prescribed. Preclinical data suggest gemcitabine induces activation of the PI3K–mTOR pathway, supporting combination strategies with mTOR inhibition. Nab-S is a nanoparticle albumin-bound, IV formulation of sirolimus and has demonstrated greater intratumoral accumulation and antitumor activity in preclinical models compared to conventional mTOR inhibitors. Methods: This investigator-initiated, single-center phase I study evaluates gem (900mg/m2) plus nab-s (dose levels [DL]: DL1=75mg/m2 or DL2=100mg/m2) in patients (pts) using a Bayesian optimal interval (BOIN) design. Primary objective was to estimate the maximum tolerated dose (MTD) of the combination based on cycle 1 dose-limiting toxicities (DLT). Secondary objectives were to estimate objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST1.1 and adverse events (AE) graded per CTCAEv5. Results: As of 01/22/26, all 12 pts initially planned for accrual have completed the DLT period. The original dosing schedule consisted of drug administration on Days 1 and 8 of a 21-day cycle. After the first 6 pts were enrolled, the protocol was amended to administer drugs on Days 1 and 15 of a 28-day cycle. This modification was implemented for all pts due to hematologic toxicities. While expected based on the known safety profile of nab-s and of gem, this frequently prevented Day 8 administration under the original schedule. All pts had advanced LMS, 10 pts were female and 7 had uterine LMS, the median age at time of consent was 55 yo. Three pts were included at DL1, and there was no DLT. DL2 included 9 pts: only one pt experienced a DLT of mucositis and diarrhea grade (Gr) 3 lasting for 3 days. The most frequent treatment-related Gr3-4 AE was thrombocytopenia. One pt had Gr3 pneumonitis attributed to gem and discontinued trial after 2 cycles. There was no other concern for safety. Ten pts were evaluable for response (1 pt died of disease and 1 pt chose to discontinue the trial before their first evaluation). ORR is 30% (n=3/10) at time of data cutoff and 90% pt had clinical benefit: 6 pts had stable disease with 5 pts experiencing shrinkage of disease (range: -8% to -21%) and 1 pt with 0% change. Only 1 pt had progressive disease as best response. With a median follow-up of 4 months (mo) for PFS, the median PFS (95% confidence interval [CI]) is 8.38 (1.68, not reached) mo, the 3-mo PFS (95% CI) is 78% (36%,94%), and the 6-mo PFS (95% CI) is 58% (16%,85%). With a median follow-up of 5.8 mo for OS, the 6-mo OS (95% CI) is 80% (39%,95%). Conclusions: The MTD was determined to be gem 900mg/m2 with nab-s 100mg/m2 on Days 1 and 15 of a 28-day cycle. Based on this preliminary safety and efficacy, an expansion with an additional 6 pts at this DL is ongoing. Clinical trial information: NCT06308419 .