Open-Label, Dose-Escalation With Expansion to Assess the Safety, Tolerability, and PK of TRE-515 in Subjects With Solid Tumors

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 too determine the safety and maximum tolerability of TRE-515 when administered orally once daily as a single agent.

The secondary objective is to establish a recommended phase 2 dose (RP2D), to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of TRE-515 preliminary evaluation of antitumor activity

The exploratory objectives are to evaluate the relationship between TRE-515 exposure and plasma deoxynucleoside concentrations of deoxycytidine (dC), evaluate the relationship between TRE-515 exposure and intracellular dCK on-target knockdown as measured by a [18F]-clofarabine (CFA) positron emission tomography (PET) probe and to evaluate the relationship between TRE-515 treatment and dCK gene expression in archived tumor tissue when available

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 preliminary tumor response analyses will be conducted throughout the study.

Preliminary tumor responses will be assessed by the Principal Investigator (PI) based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) using an appropriate modality (computer tomography [CT]/magnetic resonance imaging [MRI]) every 8 weeks.

In the dose escalation phase, subjects will be enrolled in sequential cohorts to receive TRE-515 as a daily oral dose using continuous 21-day cycles at escalating dose levels, as outlined in.

Subjects will continue to receive TRE-515 in the absence of progressive disease as defined by RECIST v1.1 or unacceptable toxicity. Following determination of an RP2D, an additional 6 subjects will receive TRE-515 at the RP2D to gain additional experience with the safety profile and additional evidence of activity.

In the dose escalation phase, a minimum of 3 subjects will be treated in each dose cohort using a conventional 3+3 dose escalation study design, starting at Cohort 1 . Cohort (-1) represents a contingency de-escalation dose level in the event that tolerance issues are encountered in Cohort 1. In each cohort, 3 subjects will be initially treated, and each subject will TRE515-T-02, be followed for the full DLT assessment period . In the absence of a DLT in the 3 subjects within a cohort, dose advancement will proceed through the successive cohorts. All subjects in each cohort must have completed the DLT observation period before the next dose cohort may open. Depending upon the tolerance at a particular dose level, intermediate dose levels may be studied to more closely characterize DLTs and more accurately identify the MTD as recommended by the Safety Review Committee (SRC). Individual subjects may continue receiving additional TRE-515 treatment until disease progression, unacceptable toxicity, or other reason for treatment discontinuation.

The MTD of TRE-515 is defined as the highest dose at which less than 2 of 6 subjects experience DLT. Subjects considered to be evaluable for the MTD determination must have received at least 14 of 21 doses (67% of scheduled doses) or who have discontinued the study drug earlier than 21 days because of a DLT. A Cohort dose will be declared to be above the MTD if two or more subjects demonstrate DLT. With the determination that a Cohort dose exceeds the MTD, the next lower Cohort will be expanded to 6 subjects (if not already expanded to 6 subjects). In the event that an MTD is not reached, the safety committee shall elect to define a RP2D that is consistent with the maximally administered tolerated dose.

The RP2D will be determined by an appointed SRC prior to initiation of the dose expansion phase of the study and will be no higher than the MTD determined in the dose escalation phase of the study. The SRC may elect to define an RP2D lower than the MTD based on an overall assessment of the PK and safety data available. The SRC may elect to modify the RP2D during the dose expansion phase if new data become available that suggest a modification is indicated.In the event that the RP2D is increased during the dose expansion phase of the study, subjects currently receiving TRE-515 may have their dose increased to the higher RP2D provided the following criteria are met:

• The subject has received TRE-515 for at least 3 weeks (21 days) at the current dose
• The subject is not experiencing any TRE-515 related toxicity ≥ Grade 2
• A dose escalation to the higher RP2D is considered to be in the subject's best interest by both the subject's investigator and the medical monitor
• The Sponsor agrees with the dose escalation In the event that the RP2D is decreased during the dose expansion phase of the study, subjects currently receiving TRE-515 may have their dose decreased to the lower

RP2D provided the following criteria are met:

• A dose reduction to the lower RP2D is considered to be in the subject's best interest by both the subject's investigator and the medical monitor (subjects who appear to be benefitting from their current dose are not required to dose reduce)
• The Sponsor agrees with the dose reduction Individual subjects may continue receiving additional TRE-515 treatment until disease progression, unacceptable toxicity, or other reason for treatment discontinuation.