Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy.

Abstract

TPS573 Background: Fibrolamellar carcinoma (FLC) is a rare, aggressive form of primary liver cancer predominantly affecting children and young adults under the age of 30. There is no established standard therapy and most patients with advanced disease succumb to their illness with a median prognosis of only 12 months. A chimeric transcript between DNAJB1 and PRKACA, which encodes the catalytic subunit of protein kinase A (PKA), was identified as a signature genomic event in FLC. However, pharmacological inhibition of PKAc for FLC with traditional small molecule inhibitors has been infeasible due to unacceptable on-target toxicity. Preclinical work from our laboratory and others has revealed that the DNAJB1- PRKACA fusion results in a metabolic rewiring of the tumor characterized by glutamine dependence. This glutamine dependence also creates a nutrient-depleted tumor immune microenvironment (TiME) enriched in immunosuppressive metabolites (e.g., ammonia, acidosis) that prohibits an effective antitumor immune response. Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME. Methods: We are conducting a single-arm phase 1b/2 clinical trial of glutamine antagonist DRP-104 in combination with durvalumab in children (age ≥ 12) and adults with advanced FLC who have progressed on prior anti-PD(L)1 therapy. Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days). The primary clinical endpoints are safety and objective response rate (ORR), defined as the percentage of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates. Key eligibility criteria include histologically confirmed FLC that is metastatic or unresectable; demonstrated radiographic progression on at least one line of prior anti-PD(L)1 therapy; Age ≥ 12 years; ECOG performance status of ≤2; measurable disease according to RECIST 1.1; and adequate end organ function. Patients will undergo fresh core tumor biopsy pre-treatment and at approximately week 4. Biopsies will be used to prepare paraffin embedded and flash-frozen samples. Research bloodwork will be collected prior to dosing at baseline, prior to dosing on cycles 2-5, and every 3 months thereafter to be processed for PBMC isolation. This study has been registered under NCT06027086 and is expected to begin enrollment in December 2023. Clinical trial information: NCT06027086 .