Open-Label, Dose-Escalation With Expansion to Assess the Safety, Tolerability, and PK of TRE-515 in Subjects With Solid Tumors
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|ClinicalTrials.gov Identifier: NCT05055609|
Recruitment Status : Recruiting
First Posted : September 24, 2021
Last Update Posted : August 2, 2022
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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
|Condition or disease||Intervention/treatment||Phase|
|Solid Tumor, Adult Oncology||Drug: TRE-515||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||This is an open label, multi-center, nonrandomized, first in human dose escalation trial of TRE-515 to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and RP2D of TRE-515 as monotherapy in subjects with advanced solid tumors.The dose escalation phase uses a conventional 3+3 dose escalation study design, where in each cohort, 3 subjects will be initially treated and each subject will be followed for full DLT assessment before the next dose cohort may open. The dose expansion phase will begin once the RP2D is determined and additional subjects will receive TRE-515 at the RP2D to gain additional experience with the safety profile and additional evidence of activity of TRE-515.|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||September 23, 2021|
|Estimated Primary Completion Date :||May 2023|
|Estimated Study Completion Date :||July 2023|
Experimental: Open Label
In the dose escalation portion, it is estimated that approximately 12-24 subjects will be enrolled in four dose cohorts. The dose expansion portion will enroll 6-12 subjects.
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.
- 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 [ Time Frame: up to 18 months ]as assessed by NCI-CTCAE v5.0
- Incidence of dose-limiting toxicities [ Time Frame: Treatment cycle of to 21 days ]determine maximum tolerated dose of TRE-515
- Pharmacokinetic characterization of TRE-515- AUC [ Time Frame: 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 ]area under the plasma concentration curve time -concentration curve
- Pharmacokinetic characterization of TRE-515- Cmax [ Time Frame: 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 ]the maximum observed plasma concentration
- Pharmacokinetic characterization of TRE-515-Cmin [ Time Frame: 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 ]Minimum observed plasma concentration
- Pharmacokinetic profile of TRE-515- T-1/2 [ Time Frame: 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 ]The time in hours required for the plasma level of the study drug to decrease by one-half during the terminal elimination phase
- Pharmacokinetic characterization of TRE-515- T-Max [ Time Frame: 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 ]Tmax is the time in hours to reach Cmax following dosing
- Pharmacokinetic Characterization of TRE-515-V/F [ Time Frame: 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 ]volume of distribution and bioavailability of TRE-515
- Pharmacokinetic Characterization of TRE-515-CL/F [ Time Frame: 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 ]oral clearance of TRE-515
- Preliminary evaluation of antitumor activity [ Time Frame: baseline up to study duration of 18 months ]based on RECIST v1.1
- Recommend phase 2 dose (RP2D) of TRE-515 [ Time Frame: up to 18 months ]The recommended phase 2 dose of TRE-515 will be determined based on pharmacokinetics, safety and tolerability
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05055609
|Contact: Shari A Burgess, RNemail@example.com|
|Contact: Sharon Larryfirstname.lastname@example.org|
|United States, California|
|Santa Monica, California, United States, 90404|
|Contact: Lisa Yonemoto 310-633-8400|
|Principal Investigator: Zev Wainberg, MD|
|United States, North Carolina|
|Carolina BioOncology Institute||Recruiting|
|Huntersville, North Carolina, United States, 28078|
|Contact: Sydney Noldin 704-947-6599|
|Principal Investigator: John Powderly, MD|
|Other Study ID Numbers:||
|First Posted:||September 24, 2021 Key Record Dates|
|Last Update Posted:||August 2, 2022|
|Last Verified:||July 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|