A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.

Abstract

4033 Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B & C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .