Abstract PO033: A phase 1b/2 trial of PXS-5505 combined with first line atezolizumab plus bevacizumab for treating patients with unresectable or metastatic hepatocellular carcinoma
Authors: Burchard Paul R , Ruffolo Luis I , Ullman Nicholas , Dave Yatee , Belt Brian A , Linehan David C , Hernandez-Alejandro Roberto , Badri Nabeel 
Published: September 2022

Abstract
Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver malignancies with just 20-30% resectable at presentation. Combination of atezolizumab and bevacizumab has brought immunotherapy to the forefront of combating this disease and represents an attractive immunotherapeutic backbone for pairing HCC therapy with means to improve intratumoral drug delivery and boost response. Lysyl oxidases (LOX) are a family of 5 secreted amine oxidases that catalyze the cross-linking of collagen and elastin in the extracellular matrix. PXS-5505 is a novel pan-LOX inhibitor that we have utilized in a pre-clinical model of primary liver malignancy and demonstrated improved survival when combined with systemic therapy through increased intratumoral drug delivery and enhanced host anti-tumor immunity. To study the impact of PXS-5505 in HCC, we designed a phase Ib/II trial of PXS-5505 in combination with atezolizumab and bevacizumab for treating patients with unresectable or metastatic HCC.Methods: This phase Ib/II trial includes patients with newly diagnosed, systemic therapy naïve, unresectable or metastatic HCC. Patients who received previous locoregional therapies remain eligible. Phase Ib consists of an open-label safety and tolerability assessment of PXS-5505 with a dose escalation design incorporating first-line combination therapy with atezolizumab and bevacizumab. The primary endpoint will be the maximal tolerated dose (MTD) of PXS-5505 through the Bayesian optimal interval (BOIN) design, targeting a dose limiting toxicity (DLT) rate of 30%. Secondary endpoints include the confirmed objective response rate (ORR) in evaluable patients after completing at least 4 cycles (12 weeks) of treatment. Once 12 patients have accrued to a particular dose, the MTD dose is established. Based on Simon’s two-stage design, if there are 4 or more responses with the MTD cohort, an expansion cohort will begin for phase II. Phase II will enroll an additional 30 patients at the MTD for a total evaluable sample size of 42. The primary endpoint will be the confirmed ORR in evaluable patients after completing at least 4 cycles of treatment. Assessment of ORR will be performed 3-6 months after start of treatment at the MTD with confirmatory assessment 28-56 days afterwards. If there are 15 or more responses among these 42 patients, we reject the null hypothesis and claim that the treatment is promising. A confirmed ORR of 45% will afford a 10% type 1 error with 80% power to detect a difference. Secondary endpoints include assessment of progression free survival (median from time of enrollment) and overall survival (median overall survival from time of enrollment). Exploratory endpoints include paired biopsies (at baseline and after the 4th cycle of treatment) for assessment of immunophenotypic and stromal changes to the tumor microenvironment in response to treatment with immunohistochemistry, flow cytometry, and RNA qRT-PCR analysis. The trial identification number is NCT05109052 and is expected to start enrollment in May of 2022.
Citation Format: Paul R Burchard, Luis I Ruffolo, Nicholas Ullman, Yatee Dave, Brian A Belt, David C Linehan, Roberto Hernandez-Alejandro, Nabeel Badri. A phase 1b/2 trial of PXS-5505 combined with first line atezolizumab plus bevacizumab for treating patients with unresectable or metastatic hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO033.