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
- Have a histologically or cytologically confirmed solid tumor.
- 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.
- Measurable disease, per RECIST v1.1
- Male or female 18 years of age or older
- Able to swallow oral capsules and tolerate intravenous blood sampling for PK, has no known intolerance or hypersensitivity to TRE-515 or excipients, and able to comply with study requirements
- Ability to receive positron emission tomography (PET) isotope and undergo PET scans,
with the following exceptions:
- The subject declines or is unable or unwilling to remain still for a prolonged period of time
- The subject is claustrophobic
- The site unable to schedule the test in the required timelines per the protocol
- The site lacks access to the PET diagnostic machine
- Recovered from prior treatment-related toxicity.
- ECOG performance status of 0 to 2.
- Adequate laboratory parameters including:
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) and ≤5 × ULN if liver metastatic disease is present
- Total bilirubin ≤1.5 × ULN unless considered due to Gilbert's syndrome in which case, ≤3 × ULN
- Calculated creatinine clearance ≥50 mL/min
- Platelet count ≥75,000/mm3
- Neutrophil count ≥1500/mm3
- Hemoglobin ≥9 g/dL
- Albumin >2.8 g/dL
- Willingness to use adequate contraception throughout study and for a period of 3 months after last dose of TRE-515.
- Candidate for potentially curative therapy.
- Subjects receiving anticancer therapy or adjuvant therapy for other cancers or subjects with other known active cancer(s) with the exception of limited stage surgically curable non melanomatous skin cancer, carcinoma in situ of the cervix, Stage 1 prostate cancer, or Stage 1 bladder cancer. Subjects who completed therapy for other known cancers must be disease free for 5 years following completion of their anticancer treatment.
- Subjects with a prior organ transplant.
- QTcB prolongation of >470 msec (confirmed on triplicate ECGs performed at least 5 minutes apart).
- Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
- Fewer than 28 days (or fewer than 5 half-lives, whichever is shorter) from prior anticancer therapy such as chemotherapy, hormonal therapy (hormonal therapy for control of prostate cancer allowed), investigational therapies, and biological therapies.
- Major surgery other than diagnostic surgery within 28 days of Study Day 1, radiation therapy within 28 days of Study Day 1, or palliative radiation therapy within 14 days of Study Day 1.
- Pregnant or currently breast-feeding.
- Known HIV-positive or active Hepatitis B or Hepatitis C infection.
- Psychiatric illness/social situations that would interfere with compliance with study requirements.
- History of clinically significant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure (New York Heart Association classification ≥2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry.
- Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would impart, in the judgement of the PI and/or Sponsor, excess risk associated with study participation or study drug administration, which would make the subject inappropriate for entry into this study.
- Cerebrovascular accident (transient ischemic attack/stroke) in the 6 months prior to study entry.TRE515-T-02, Version 2.0 Confidential 07 April 2021 Page 15 of 56
- Known hypersensitivity to the drug or excipients contained within the drug formulation.
- Use of or requirement for any of the prohibited medications
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