Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m²/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m²/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m²/dose, DL-1: 20mg/m²/dose, and DL-2: 15mg/m²/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m²/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m²/dose and oral irinotecan 90 mg/m²/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.