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

Inclusion criteria

• 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.
• 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, 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 status.
• Male or female 18 years of age or older
• Capable of giving signed informed consent
• 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
• Able to receive the positron emission tomography (PET) isotope and undergo PET scans, with the exception if the site lacks access to the PET diagnostic machine.
• Recovered from prior treatment-related toxicity based on Investigator and Medical Monitor assessment.
• 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 ≥60 mL/min from a blood sample
• 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.

Exclusion criteria

• 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-melatomatous skin cancer, carcinoma in situ of the cervix, Stage 1 prostate cancer, or Stage 1 bladder cancer. Subjects who have completed therapy for cancers other than the solid tumor that qualifies the subject for inclusion in the study should be disease-free for ≥ 5 years following completion of treatment for the secondary cancer. An exception may be made if treatment for the secondary cancer was completed between 1 and 5 years prior to enrollment and the PI and study Medical Monitor, upon review of all relevant medical records, jointly determine that the treatment was curative and the secondary cancer is unlikely to relapse during study participation.
• Subjects with a prior organ transplant.
• Subjects with QTc corrected by Bazett's (QTcB) prolongation of \>470 msec (confirmed on triplicate ECGs performed at least 2 minutes apart) at screening and confirmed prior to dose administration on Day 1
• 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
• Known hypersensitivity to the drug or excipients contained within the drug formulation.
• Use of or requirement for any of the prohibited medications
• For subjects enrolled into the gastric ARA substudy only, history within the past 12 months, or presence of, Stage 3 or 4 gastroesophageal reflux disease (GERD) or history of gastric reduction surgery, including a Whipple procedure or gastric bypass. Prior use of gastric ARA drugs is acceptable.