A phase 1b, open-label, safety, pharmacokinetic, and pharmacodynamic study of an anti–super-enhancer triptolide analogue with nab-paclitaxel plus gemcitabine in patients with metastatic adenocarcinoma of the pancreas.

Abstract

TPS769 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. Triptolide (TPL), a natural compound isolated from the Chinese herb has shown promising antitumor activity though the inhibition of HSP70 in a number of preclinical models including pancreatic cancer. In addition, TPL disrupt super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts to reprogram the cellular cross talk and signaling in tumor environment. Minnelide (ML), water soluble, novel prodrug of TPL, was recently reported to show promising activity in patients with gastrointestinal malignancies in phase I trial. Based on the strong synergism with nab-paclitaxel (A) plus gemcitabine (G), we designed this phase 1b study. Methods: Eligible patients will have histologically confirmed PDAC and have failed first-line FOLFIRINOX with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of ML (0.25 mg to 1.0 mg once a day) in combination with A plus G will be tested with 3+3 subjects recruited in each cohort. Patients in each cohort will receive ML 0.25 to 1.0 mg orally once a day on days 1-5, 8-12 and 15-19 with A 100-125mg/m2 intravenously plus G 800-1000mg/m2 IV on days 1, 8 & 15 of a 28-day cycle. The primary endpoint is to determine the safety of ML with A+G and to determine PFS by Independent Radiological Review (IRR). Once an MTD reaches, a total of 18 patients will be enrolled at MTD level in dose expansion part. The key secondary endpoints are to determine the pharmacokinetics, pharmacodynamics effect, the percentage of patients who achieve an objective confirmed overall response by IRR, maximum tolerated dose and recommended dose for phase 2 of ML in combination of A+G. As of September 2022, the study is just initiated for patient enrollment in first cohort. This study is prospectively registered on ClinicalTrials.gov, NCT05557851. Clinical trial information: NCT05557851 .