SBIR-STTR Award

Trethera, a clinical stage biopharmaceutical company, has developed a small molecule drug, TRE-515, to target the nucleoside salvage pathway via a key rate-limiting enzyme, deoxycytidine kinase (dCK). We have shown that dCK is expressed at high levels in a variety of solid tumors, and TRE-515 selectively targets cancer cells based on their high expression of, and dependence on, dCK. Notably, TRE-515 is the only salvage pathway inhibitor currently in clinical development, and no salvage pathway inhibitors are approved as cancer therapeutics. Currently, Trethera is evaluating TRE-515 in a phase 1a open-label, dose escalation study in patients with solid tumors (IND #131939). Acceptable safety and tolerability have been demonstrated across three TRE-515 doses (40mg, 80mg, 160mg) in 10 patients. Preliminary pharmacokinetic (PK) data indicate an acceptable half-life, rapid absorption, and low variability among patients, and early and pharmacodynamic (PD) data demonstrate effective target inhibition. Notably, early signs of anti-tumor activity have been noted, with 50% of patients in the lowest dose cohorts showing stable disease. Our goal here is to perform a Phase 1 dose expansion trial deploying a quantitative LC/MS based assay to determine serum deoxycytidine (dC)/ deoxyuridine (dU) levels and a novel PET imaging approach as complementary biomarkers to monitor drug activity and assess preliminary antitumor activity. Whole-body dCK activity regulates the levels of serum dC and its metabolite dU, and reductions in dCK activity via TRE-515 inhibition can be routinely monitored by measuring changes in plasma dC/dU using an LC-MS assay we developed. [18F]CFA is a PET radiotracer that can be used to non-invasively measure dCK activity in tumors (IND #133911). As accepted by the FDA, male and female patients (N=12) with advanced refractory solid tumors will be administered 320 mg TRE-515 as a once daily oral dose. The LC/MS based assay to measure serum dC/dU levels will be further developed and used as an easily accessible biomarker to assess patient response to TRE-515 (Aim 1). Biomarker studies using the recently invented, IND- accepted positron emission tomography (PET) probe, [18F]Clofarabine ([18F]CFA), will be used for in vivo monitoring of the effects of TRE-515 on dCK activity (Aim 2). Safety assessments, biomarker studies, and Response Evaluation Criteria in Solid Tumors (RECIST) will be used to assess tumor responses in patients. Trial milestones include i) >1.5X increases in serum levels of dC + dU after initiating TRE-515 therapy, reflecting drug target inhibition and ii) greater than 33% reduction in [18F]CFA tumor uptake following TRE-515 treatment. Success in the proposed trial will support future Phase 1 and 2 clinical trials to determine efficacy, safety, combinations, patient selection, and optimal dose regimen of TRE-515.

Public Health Relevance Statement:
PROJECT NARRATIVE With cancer as the second leading cause of death in the US, there remains a pressing unmet need for new, more effective cancer therapeutics. Trethera has developed a small molecule drug, TRE-515, that inhibits deoxycytidine kinase (dCK), a rate limiting enzyme in the salvage pathway of nucleotide biosynthesis. Cancer cells utilize the salvage pathway to support rapid proliferation. TRE-515 holds an open IND and has been piloted in a dose escalation trial to establish preliminary dose, safety, and tolerability. The proposed Phase 1 dose expansion clinical trial will deploy a plasma deoxycytidine (dC) assay and a novel PET probe dCK imaging approach as complementary biomarkers to monitor drug activity and assess preliminary antitumor activity.

Project Terms:
absorption; After Care; After-Treatment; post treatment; Aftercare; inhibitor; Biological Assay; Assay; Bioassay; Biologic Assays; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cause of Death; Cell division; Clinical Protocols; Clinical Trials; Deoxycytidine; 2'-deoxy-cytidine; Cytosine Deoxyribonucleoside; Cytosine Deoxyriboside; Deoxycytidine Kinase; 2'-Deoxycytidine Kinase; ARA-C Kinase; EC 2.7.1.74; Deoxyribonucleosides; Deoxyuridine; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Female; Future; Goals; Half-Life; male; Methods; Nucleosides; Nucleotides; Patients; Drug Kinetics; Pharmacokinetics; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Positron-Emission Tomography; PET; PET Scan; PET imaging; PETSCAN; PETT; Positron Emission Tomography Medical Imaging; Positron Emission Tomography Scan; Rad.-PET; positron emission tomographic (PET) imaging; positron emission tomographic imaging; positron emitting tomography; Resources; Research Resources; Safety; Time; Work; Measures; Drug Monitoring; Mediating; Clofarabine; improved; Area; Clinical; Refractory; Phase; Ensure; Evaluation; Blood Serum; Serum; Measurement; Patient Selection; uptake; Solid Tumor; Solid Neoplasm; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Therapeutic; cancer cell; Malignant Cell; Companions; Hour; Dependence; Oral; deoxyribonucleoside triphosphate; radiotracer; radiolabel; radiolabels; success; DNA biosynthesis; DNA Replication; DNA Synthesis; tumor growth; cohort; Stable Disease; novel; Pharmacodynamics; Sampling; response; liquid chromatography mass spectrometry; LC/MS; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Nucleotide Biosynthesis; small molecule; Dose; Data; Proliferating; Qualifying; Cancer Patient; Validation; validations; Monitor; Development; developmental; Pathway interactions; pathway; open label; open label study; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Outcome; tumor; FDA approved; response to therapy; response to treatment; therapeutic response; therapy response; treatment response; new marker; novel biomarker; novel marker; bio-markers; biologic marker; biomarker; Biological Markers; clinical practice; Regimen; Drug Targeting; phase 1 trial; phase I trial; trial design; companion diagnostics; invention; stratified patient; patient stratification; response markers; response biomarker; small molecule inhibitor; clinical development; imaging based approach; imaging approach; patient specific response; responsive patient; patient response; in vivo monitoring; side effect; safety assessment; biopharmaceutical industry; biopharmaceutical company