Abstract A017: Phase 1b Study of 2nd line vactosertib plus oxaliplatin with 5FU/LV (FOLFOX) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who have failed first-line gemcitabine with nab-paclitaxel
Authors: Park Joon Oh , Kim Seung Tae , Hong Eunji , Hong Jung Yong , Park Young Suk , Kim Seong-Jin 
Published: November 2022

Abstract
Background: Despite of recent advances in chemotherapies, PDAC remains aggressive malignancies and the leading cause of cancer-related death in the world. TGF-β is strongly involved in the tumor microenvironment in PDAC, and dysregulation of TGF-β signaling is a frequent molecular disturbance in progression and metastasis. Vactosertib is an orally bioavailable TGF-β signaling inhibitor that targets the TGF-β type I receptor kinase. In in vivo studies, vactosertib in combination with FOLFOX improves pancreatic cancer survival by suppressing cell migration, invasion, and EMT, highlighting a potential clinical application of this approach for PDAC patients. Based on this preclinical study, we develop a phase 1b study to determine the RP2D and to evaluate the safety of vactosertib in combination with FOLFOX in patients with metastatic PDAC who have failed first-line gemcitabine with nab-paclitaxel. Methods: Eligible patients have histologically confirmed PDAC who have failed first-line gemcitabine/nab-paclitaxel with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part, different dose levels of vactosertib (50 mg bid, 100 mg bid, and 200 mg bid) for escalation were tested, starting with dose level 0 (DL 0, 100 mg bid) with 3 to 6 subjects recruited in each cohort. DL -1 was only planned to test when DL 0 was unacceptable. In the dose expansion part, an additional backfill cohort was planned to open for determination of the final RP2D. Patients in each cohort were planned to receive vactosertib 50-200 mg orally twice per day 1-5 & day 8-12 with oxaliplatin 85 mg/m2 on day 1, LV 200mg/m2 IV on day 1, 5FU 200mg/m2 bolus on day 1 and continuous 5-FU 2400mg/m2 infusion over 48 hours every 2 weeks. The primary endpoints were to determine RP2D and to evaluate safety of this combination. The key secondary endpoints were progression free survival (PFS), overall response rate (ORR), disease control rate (DCR) based on RECIST 1.1 and overall survival. Results: A total of 16 patients were enrolled, 3 in DL 0, 4 in DL 1 and 9 in DL 1 backfill cohort. No dose limiting toxicities (DLTs) were observed and the RP2D was established as vactosertib 200 mg orally twice per day 1-5 & day 8-12 with FOLFOX. The vactosertib related adverse events (AEs) of any grade included fatigue, nausea, vomiting and anorexia. Three of 13 patients (23.1%) had partial response and 5 (38.5%) stable disease as best response, with clinical benefit rate of 61.5 % in DL 1, while there were no PR or SD in DL 0. Median PFS was 4.2 months [95% confidence interval (CI), 1.3–7.1] and median OS was 9.3 months [95% confidence interval (CI), 4.86–13.7]. Conclusion: In this phase Ib study, we demonstrated the feasibility and safety of adding vactosertib to FOLFOX in 2nd line setting, which needs to be further investigated. Updated results, including PK analyses, safety profiles, and clinical outcomes will be presented. This study was prospectively registered on ClinicalTrials.gov, NCT03666832.
Citation Format: Joon Oh Park, Seung Tae Kim, Eunji Hong, Jung Yong Hong, Young Suk Park, Seong-Jin Kim. Phase 1b Study of 2nd line vactosertib plus oxaliplatin with 5FU/LV (FOLFOX) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who have failed first-line gemcitabine with nab-paclitaxel [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A017.