Safety and Clinical Efficacy of IOA-289, a Novel Autotaxin Inhibitor, Plus Gemcitabine and Nab-Paclitaxel (gnp) in Patients with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma (Mpdac).

e15130 Background: Autotaxin (ATX) plays a critical role in inflammation and resistance mechanisms in a wide range of malignancies. IOA-289 is a novel inhibitor of ATX, with anti-fibrotic, immune-enhancing and anti-tumour activity. This first-in-human trial evaluated safety and tolerability, pharmacokinetic (PK)/pharmacodynamic (PD) profile of IOA-289 in combination with GnP. Methods: IOA-289 was investigated, in untreated mPDAC, in a dose escalation study evaluating the continuous twice daily dosing (BID). IOA-289 was initially administered for 7 days as a monotherapy (Cycle 0) before adding GnP at standard doses in 3 weekly schedule followed by 1 week pause (Cycle 1 onwards). Primary objective: Safety and tolerability. Secondary objectives: PK; PD (e.g., plasma LPA and serum CA19-9); radiographic responses (RECIST 1.1); PFS and OS. Results: Cohort 1 assessed the safety at 100 mg BID (n = 4), cohort 2 at 200 mg (n = 4), and cohort 3 at 400 mg (n = 5). Safety assessment shows no treatment-emergent adverse events led to study drug discontinuation, or a dose limiting toxicity. Most toxicities were consistent with the known toxicity profile of GnP. Median time on treatment for cohort 1 was 4.8 months, for cohort 2 and cohort 3 patients are still under treatment and clinical outcomes are not yet established but are projected to surpass the observation from cohort 1. Five patients are currently remain active on treatment No clinical responses were observed in cohort 1. In cohort 2, 2 out of 4 patients (50%) achieved a Partial Response (PR) at cycle 5 and 7 respectively, which was confirmed and durable. No mature data is available yet for later cohorts. Exposure to the compound resulted in reductions in multiple LPA species, with a protocol-defined inhibition of > 50% for over 24 hrs. Consistent reductions in levels of CA19-9 have been observed since cohort 2 (200 mg BID), with > 50% reduction already from cycle 2, with durable reductions lasting longer than 4 months. No mature data is available for later cohorts. Conclusions: IOA-289 is well tolerated at all dose levels in combination with standard GnP. Patients in the higher dose cohorts are experiencing robust CA19-9 reductions consistent with ORR. Occurrence of PRs occurred later than compared to historical controls and were durable, suggesting a differentiated mode of action. Clinical trial information: NCT05586516 .