Phase I trial of LB-100 plus doxorubicin as first-line of advanced soft tissue sarcomas: A Spanish Sarcoma Group (GEIS) study.

Abstract

11572 Background: In sarcomas, blocking the phosphatase PP2A with LB-100 enhanced doxorubicin effectiveness, reducing tumor growth and metastases in in vivo experiments. Mechanistically, LB-100 inhibited ATM/ATR-activated DNA damage response. The combination of doxorubicin and LB-100 significantly shrank tumor xenographs compared with either compound alone. The recommended phase 2 dose (RP2D) for LB-100 in monotherapy was 2.33 mg/m 2 /d x3 days in a phase I in progressive solid tumors, reporting 1 partial response and 16 SD (including the 2 enrolled patients with sarcoma) out of 20 patients. Based on prior data, we designed a phase I trial (NCT05809830) combining doxorubicin (D) and LB-100 (L) for first-line advanced sarcomas. Methods: Adult patients with advanced soft tissue sarcomas and no prior anthracycline treatment were enrolled. The main endpoint was to determine the RP2D. Secondary endpoints were to evaluate the safety profile, efficacy (PFS, ORR,OS), QoL, and translational research. Dose levels were defined as follows, I: D 60 L 1.75; II: D 75 L 1.75; III: D 75 L 2.33; A -I dose-level was defined as D 60, L 1.25. L was administered on days 1 to 3 in a 2-hour IV infusion, followed by D in a 20-minute IV infusion on day 1 of each cycle. After 6 cycles of combination, L was administered as a maintenance phase until disease progression or unacceptable toxicity. Results: Between June 2023 and September 2024, 14 out of 17 screened patients were recruited, with 12 eligible for DLT evaluation. The non-DLT-evaluable patients were explained by the use of G-CSF and the altered sequence of drug administration during the first cycle. No DLTs were reported. Grade 3-4 treatment-related adverse events were neutropenia 42.9%, febrile neutropenia 21.4%, LVEF reduction 14.3%, and one patient each for nausea, anemia, and lymphopenia (7.1%). There were 2 partial responses (14%), 6 stabilizations (43%), and 6 progressions (43%) following RECIST criteria of 14 evaluable patients. Responses were seen in patients with UPS and myxofibrosarcoma. The mPFS was 5.7 months (95% CI 0-13.3), and the mOS was 16.7 months (95% CI NA). The only QoL items of EORTC-QLQ-C30 that significantly changed (impaired) between baseline and before the 3 rd cycle were nausea and diarrhea. There were 1SD and 2 PD of 3 patients in the first dose-level, 1 PR and 3SD of 4 patients in the second dose-level, and 1 PR, 2 SD, and 4 PD of 7 patients in the third dose-level. In our preclinical investigations, the highest concentrations of L induced an antagonistic effect with D. Conclusions: The RP2D is L1.75 and D 75 based on tolerance and activity, and it deserves to be tested in phase II trials. Clinical trial information: NCT05809830 .