Phase 1b study of vactosertib in combination with oxaliplatin with 5FU/LV (FOLFOX) in patients with metastatic pancreatic cancer who have failed first-line gemcitabine/nab-paclitaxel.
Authors: Kim Seung Tae , Hong Jung Yong , Park Young Suk , Kim Seong-Jin , Park Joon Oh 
Published: June 2022

e16299 Background: TGF-β is strongly involved in the tumor microenvironment of PDAC, and dysregulation of TGF-β signaling is a frequent molecular disturbance in pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. Vactosertib is an orally bioavailable TGF-β signaling inhibitor that targets the TGF-β type I receptor kinase. In preclinical studies, vactosertib in combination with FOLFOX improves pancreatic cancer survival by suppressing cell migration, invasion, and epithelial-mesenchymal transition (EMT), highlighting a potential clinical application of this approach for PDAC patients. We performed a phase 1b study to determine the recommended phase 2 dose (RP2D) and to evaluate the safety of vactosertib in combination with FOLFOX in patients with metastatic PDAC who have failed first-line gemcitabine/ 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 (phase 1b), 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 5.6 months [95% confidence interval (CI), 2.27–8.93]. Conclusions: 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, ORR, PFS and overall survival, will be presented. Clinical trial information: NCT03666832.