Background: Advanced pretreated OSS has a very poor prognosis. Metronomic CP and MTX have shown little activity in pediatric cancers, including OSS. Preclinical data suggest that ZA could have a synergic effect when combined with mTOR inhibition in OSS. Methods: This is a prospective phase Ib study investigating the combination of SIR with CP, MTX and ZA trough a dose-escalation phase (3 + 3 design) in patients ≥ 18 years with bone metastatic solid tumors (part I) and an expansion cohort dedicated to patients ≥ 13 years with advanced pretreated OSS (part II). SIR was given at two dose levels (4 mg and 6 mg) continuously, in combination with CP 50 mg x 2 per day, 1 week on / 1 week off, MTX at 2.5 mg x 2 per day, on day 1 and day 4 every week, and ZA 4mg IV every 4 weeks. Primary endpoints were dose limiting toxicities (DLT), maximum tolerated dose and recommended phase II dose (RP2D) of SIR combined with CP, MTX and ZA for Part I, and 6-month non-progression rate (NPR) according to RECIST v1.1 for part II. Secondary endpoints included safety, 6-month objective response rate (ORR), one-year progression-free (PFS) and overall survivals (OS), and pharmacodynamics biomarker analyses. At least one non-progression at 6 months after centralized review of imaging was needed among 14 patients to consider activity of the combination. Results: From February 2015 to March 2021, 23 patients were included in the three participating centers. In part I, nine patients with breast (56%), prostate (33%) or biliary duct carcinoma (11%) were included. Median number of cycles was 2 (1-6). Two DLT were reported at dose level 2: one grade 3 neutropenia and one grade 3 anemia, therefore dose level 1 was the RP2D for part II. In part II, 14 OSS patients were included. Median age was 27 years (14 - 80). Median number of previous lines in the advanced disease was 1 (1-3). At the time of analysis, 11 patients had died. Reason for study discontinuation was progressive disease for 10 patients (72%), toxicity for two (14%) (one grade 2 platelet count decrease and one grade 5 unrelated lung infection), and investigator decision for two (14%), including one for cryotherapy of a residual lesion after an excellent partial response. Overall, 64 adverse events related to study drugs were reported, of which 14 (22%) grade 3, and 2 grade 4 (3%). They were mainly asthenia, nausea, mucositis oral, anemia, lymphocyte and platelet count decrease. Median follow up was 27.5 months [95% CI : 12.8-27.5]. Two non-progressions at 6 months (14%) were observed, including a partial response (7%). One-year PFS was 21.4% [95%CI 5.2-44.8] and median OS was 12.8 months [95% CI : 2.8-20.4]. Conclusions: The combination of SIR at 4 mg daily with CP, MTX and ZA has an acceptable toxicity profile and reached the initial targeted efficacy rate in advanced pretreated OSS patients. Clinical trial information: NCT02517918.