Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.

Abstract

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma

“…Interestingly, this observation was unique to ASNS among the known DON target enzymes, as expression of well-studied targets such as GLS and GLS2 did not correlate in this way. Very little is known about what might dictate patient stratification for DON-based prodrugs that are currently in clinical trials 37 . Interestingly, in atypical teratoid/rhabdoid tumors (ATRT), which is a rare and aggressive cancer of the brain and spinal cord in infants, metabolic profiling revealed a unique dependence on glutamine for survival in ATRT cell lines with high MYC expression 38 .…”

Exploiting the Achilles’ heel of cancer: disrupting glutamine metabolism for effective cancer treatment

“…The immune regulation of DRP-104 showed great potential for combined use of DRP-104 with immunotherapy. In 2020, combined DRP-104 with atezolizumab (anti-PD-1) entered the clinical trial (NCT04471415) in the treatment of advanced solid tumors ( Johnson et al, 2021 ). A study has shown that DRP-104 can significantly inhibit the tumor growth of a variety of PDAC models in vivo ( Encarnación-Rosado et al, 2023 ).…”

Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors

“…[ 80 ] In a first-in-human phase 1/2a, multicenter, multicohort study, the safety, tolerability, and antitumor activity of DRP-104 alone and in combination with atezolizumab, a PD-L1 inhibitor, is being evaluated. [ 81 ]…”