A Phase 1, Open-Label, First-In-Human, Dose-Escalation Study With Expansion to Assess the Safety, Tolerability, and Pharmacokinetics of Orally Administered TRE-515 in Subjects With Solid Tumors
Trethera
Summary
TRE-515 is a first-in-class small molecule inhibitor of deoxycytidine kinase (dCK) that is being developed for oral administration in patients with solid tumors. In cancer cells, rapid and upregulated DNA replication creates high replication stress, as such, cancer cells are more susceptible than normal cells to perturbations in nucleotide metabolism by DNA-targeting treatments such as TRE-515. The Primary objective is to determine the safety and maximum tolerability of TRE-515 when administered orally once daily as a single agent. The secondary objectives are to establish a recommended phase 2 dose (RP2D), to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of TRE-515, preliminary evaluation of antitumor activity, and to determine the effect of an acid reducing agent (ARA) on TRE-515 exposure. The exploratory objectives are to evaluate the relationship between TRE-515 exposure and plasma deoxynucleoside concentrations, evaluate the relationship between TRE-515 exposure and reductions in intracellular dCK on-target knockdown as measured by a \[18F\]-clofarabine (CFA) positron emission tomography (PET) probe, to evaluate the relationship between TRE-515 treatment and dCK and CDA gene expression in archived tumor tissue when available, to evaluate the relationship between tumor CDA and plasma deoxynucleoside (dC and dU) concentrations, and to explore the effect of TRE-515 treatment on gene expression in white blood cell populations.
Description
This is a Phase 1, open label, multi-center, nonrandomized, first in human, dose escalation trial of TRE-515 designed to evaluate safety and tolerability and determine the MTD and RP2D of orally administered TRE-515 as monotherapy in subjects with advanced solid tumors. Safety assessments will include adverse events (AEs), dose limiting toxicities (DLTs), clinical laboratory values, vital signs, body weight, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status . Dose-limiting toxicities will be assessed over the first 21 days on study. The PK and prelim…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: 1. Have a histologically or cytologically confirmed solid tumor. Subjects with tumors that have known biomarkers, such as PSA or CA-125, will have status recorded. 2. Subjects with advanced refractory cancer for which standard curative or palliative measures do not exist or are no longer effective. There is no limitation on the number or types of prior therapy. 3. Measurable disease, per RECIST v1.1, with the exception of patients without measurable disease but with a known biomarker of progression, such as prostate cancer (PSA) or ovarian cancer (CA-125), with a positive…
Interventions
- DrugTRE-515
TRE-515 will be administered orally once daily at least 1 hour prior or 2 hours after eating at approximately the same time each day. Dosing will be continuous with no breaks between cycles. Subjects will continue to receive successive cycles of TRE-515 treatment as long as they do not demonstrate progressive disease, experience an unacceptable toxicity, and both the Sponsor and PI consider additional treatment with TRE-515 to be within the best interest of the subject.
Locations (2)
- UCLASanta Monica, California
- Carolina BioOncology InstituteHuntersville, North Carolina