A phase I/II investigation of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma: Preliminary efficacy and safety results.

Abstract

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.