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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 94
- 试验地点
- 2
- 主要终点
- Safety and Tolerability of TRE-515 as assessed by the Number of Participants with Adverse Events (AEs) as assessed by NCI-CTCAE v5.0Safety and tolerability of oral TRE-515
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
Open Label
In the dose escalation portion, will enroll up to 46 subjects in five or more cohorts. The dose expansion portion will enroll up to 48 subjects. The actual number of subjects enrolled will depend on the safety data and additional evidence of antitumor activity.
干预措施: TRE-515 (Drug)
结局指标
主要结局
Safety and Tolerability of TRE-515 as assessed by the Number of Participants with Adverse Events (AEs) as assessed by NCI-CTCAE v5.0Safety and tolerability of oral TRE-515
时间窗: up to 60 months
as assessed by NCI-CTCAE v5.0
Incidence of dose-limiting toxicities
时间窗: Treatment cycle of to 21 days
determine maximum tolerated dose of TRE-515
次要结局
- Pharmacokinetic characterization of TRE-515- AUC(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Pharmacokinetic characterization of TRE-515- Cmax(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Pharmacokinetic characterization of TRE-515-Cmin(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit , through the study duration up to 18 months)
- Pharmacokinetic profile of TRE-515- T-1/2(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Pharmacokinetic characterization of TRE-515- T-Max(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Pharmacokinetic Characterization of TRE-515-V/F(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Pharmacokinetic Characterization of TRE-515-CL/F(At each Cycle ( each cycle is 21 days) Day 1,8 and 15 and at study completion visit, through the duration of the study up to 18 months)
- Preliminary evaluation of antitumor activity(baseline up to study duration of 18 months)
- Recommend phase 2 dose (RP2D) of TRE-515(up to 18 months)