Background: NAB-S (ABI-009, nab-rapamycin) is approved for treatment of adults with unresectable or metastatic perivascular epithelioid cell tumors. Albumin binding improves sirolimus solubility and may target it to tumoral cells. mTOR inhibition may enhance PAZO activity directly and by overcoming resistance. We assess feasibility and safety of the combination. Methods: Eligible patients (≥18y) had: advanced, unresectable, non-adipocytic STS progressing after 1-5 prior therapies; adequate end-organ function; ECOG performance status 0-1; measurable target lesions (RECIST v1.1); and no prior mTOR or angiogenesis inhibitor treatment. The study was conducted according to a 3+3 design. Initial cohorts received 800 or 400 mg PAZO daily and 60, 45 or 30 mg/m² of NAB-S on days 1 and 8 on a 21-day cycle. Subsequently, NAB-S was administered only on day 1 based on preliminary analysis of adverse events (AEs) and pharmacokinetics (PK). Primary endpoint was determination of maximally tolerated dose (MTD). Dose-limiting toxicities (DLT) were grade 3-5 adverse events (AE) during the first cycle not due to PAZO. Secondary endpoints included AE characterization (CTCAE v5.0), descriptive evaluation of responses and their duration, and correlative/PK studies. Results: 19 patients were treated; initially, 13 received NAB-S on days 1 and 8. DLT included thrombocytopenia (TCP, n = 7), decreased WBC/neutrophils (n = 2), increased lipase (n = 1), and proteinuria (n = 1). Due to overlapping AEs or possible NAB-S/PAZO interaction, further cohorts received 400 mg PAZO daily and either 30 or 45 mg/m² NAB-S (n = 6). There were no DLTs in the 30 mg/m² cohort (n = 3). In the 45 mg/m² cohort, 2 out of 3 patients had TCP meeting DLT definition. Grade 3-4 AEs in more than 10% included: TCP (58%), neutropenia (11%), leukopenia (11%), lymphopenia (11%), and diarrhea (11%). Any grade AEs in > 50% included: TCP (74%), mucositis (63%), fatigue (58%), and acneiform rash (53%). There was no grade 5 AEs. Of 19 treated, 11 (58%) discontinued due to disease progression, 3 (16%) due to AE (TCP-2, transaminitis-1), and 1 (5%) due to death from disease. Four (21%) remain on study as of 2/2023. 18 were evaluable for best response: 3 partial responses (PR; leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 stable disease (SD), 2 progressive disease. Clinical Benefit Rates (CBR = PR+SD) at 3 and 6 months were 61% (11/18) and 50% (9/18). Among the leiomyosarcoma subset, CBR at 3 and 6 months were 70% (7/10) and 60% (6/10). Correlative and pharmacokinetic results will be presented. Conclusions: Thrombocytopenia was the most prominent DLT when studying the NAB-S/PAZO combination. 3 patients out of 19 discontinued therapy due to AEs; the remainder continued therapy after adjustment. MTD and RP2D is NAB-S 30 mg/m² day 1 and PAZO 400 mg days 1-21. Preliminary evidence of activity of the combination was observed. Clinical trial information: NCT03660930.