- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03366116
5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors
Phase I Trial of 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in Patients With Advanced Solid Tumors
Background:
Blood, tissue, and tumor cells contain genes. Genes are made up of DNA. DNA is the instruction book for each cell. In some people with cancer, the genes that might have slowed the growth of their tumor were turned off. Researchers want to see if a new drug can turn the genes back on and slow the tumor growth. The drug is called Aza-TdC.
Objective:
To test the safety of Aza-TdC, and to find out the dose of this drug that can be safely given to humans.
Eligibility:
People ages 18 and older who have advanced cancer that has gotten worse after standard treatment, or for which no effective therapy exists
Design:
Participants will be screened with:
Medical history
Blood and urine tests
Scans to measure their tumors
Test to measure the electrical activity of the heart
Participants will take the study drug by mouth. The drug is given in cycles. Each cycle is 21 days (3 weeks) long.
Week 1 and week 2: participants will take the study drug once a day for 5 days. Then they will have 2 days without the drug. Week 3: no study drug is taken. This completes one cycle of treatment.
For cycle 1, participants will repeat the screening tests several times. For all other cycles, participants will have blood tests and pregnancy tests. They will have scans of their tumor every 6 weeks.
The cycle will be repeated as long as the participant tolerates the drug and the cancer is either stable or gets better.
Sponsoring Institute: National Cancer Institute
Study Overview
Detailed Description
Background:
Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes. Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias.
The nucleoside analog 5-aza-4 -thio-2 -deoxycytidine (Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in re-activation of tumor suppressor genes.
Data suggest a correlation between Aza-TdC activity in solid tumor xenograft models and decreased levels of DNMT1.
Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; Aza-TdC has greater antitumor activity than another recently developed DNMT1 inhibitor, TdCyd, in some solid tumor xenograft models. Treatment with Aza-TdC is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.
Primary Objective:
To establish the safety, tolerability, and MTD of oral Aza-TdC administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles, to patients with refractory solid tumors
Secondary Objectives:
To determine the pharmacokinetics of oral Aza-TdC
To document preliminary evidence of Aza-TdC activity
To determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
To determine the effects of Aza-TdC on DNA damage response (DDR) signaling and on genome-wide DNA methylation in tumor biopsy tissue
Exploratory Objective:
To determine the effects of Aza-TdC on global RNA expression and on levels of DNMT1, DNMT3a, DNMT3b, and other select proteins in tumor biopsy tissue
To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with Aza-TdC response or resistance
Eligibility:
Patients >= 18 years of age must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy
Study Design:
Aza-TdC will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles.
The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. Intrapatient dose escalation will be allowed.
Blood samples will be obtained for pharmacokinetic analysis and to isolate circulating tumor cells to assess re-expression of genes silenced by methylation.
Up to 21 patients will be accrued to a PD expansion cohort at the MTD to further assess pharmacodynamic endpoints in tumor and blood.
Study Type
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: James H Doroshow, M.D.
- Phone Number: (240) 781-3320
- Email: doroshoj@mail.nih.gov
Study Contact Backup
- Name: DTC Referral Coordinators
- Phone Number: (240) 781-3400
- Email: dtcreferralcoordinators@nih.gov
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- Recruiting
- National Institutes of Health Clinical Center
-
Contact:
- For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
- Phone Number: 888-624-1937
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
- INCLUSION CRITERIA:
- Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy.
- Age greater than or equal to 18 years of age.
- ECOG performance status < 2
Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count greater than or equal to 1,500/mcL
- platelets greater than or equal to100,000/mcL
- total bilirubin less than or equal to 1.5 X institutional upper limit of normal (<=3 (SqrRoot) upper limit of normal in the presence of documented Gilbert s syndrome)
- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal
OR
- AST(SGOT)/ALT(SGPT) less than or equal to 5 X institutional upper limit of normal for patients with liver metastases
- creatinine less than or equal to 1.5X institutional upper limit of normal
OR
creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with creatinine levels above 1.5X institutional normal
- Because nucleoside analogs are known to be teratogenic, women of child-bearing potential and men must agree to use two forms of contraception (hormonal or barrier method of birth control; abstinence; sterilization) prior to study entry, for the duration of study participation, and for 3 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use two forms of contraception prior to the study, for the duration of study participation, and for 3 months after completion of administration of Aza-TdC.
- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior palliative radiation or cyberknife therapy. Patients must have recovered to grade 1 from prior toxicity or adverse events. Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment prior to study entry may continue this treatment.
- Ability to understand and the willingness to sign a written informed consent document.
- Willingness to provide blood and urine samples for research purposes.
- Ability to swallow pills/capsules.
- Left ventricular ejection fraction greater than 45% or the institutional lower limit of normal by either ECHO or MUGA at entry.
- For patients enrolled on the expansion cohort, patients must have tumor amenable to biopsy (excisional or incision biopsies of skin or H & N lesions under visualization) and willingness to undergo tumor biopsies.
EXCLUSION CRITERIA:
- Patients who are receiving any other investigational agents.
- Pregnant women and women who are breastfeeding are excluded from this study.
- Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, known HIV infection requiring protease inhibitor therapy, known Hepatitis B, known Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 1 month after treatment of the brain metastases.Patients should not be on anti-seizure medications. These patients may be enrolled at the discretion of the Principal Investigator.
- Malabsorption syndrome or other conditions that would interfere with intestinal absorption.
INCLUSION OF WOMEN AND MINORITIES:
Both men and women of all races and ethnic groups are eligible for this trial.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1
Aza-TdCyd will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles
|
Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes.
The nucleoside analog 5-aza-4'-thio-2'- deoxycytidine (Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to hypermethylation and silencing of tumor suppressor genes.
Aza-TdC offers an improvement over traditional DNMT inhibitors via higher incorporation into DNA and lower cytotoxicity; Aza-TdC has greater antitumor activity than another recently developed DNMT1 inhibitor, TdCyd, in some solid tumor xenograft models.
Treatment with Aza-TdC is anticipated to yield inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To determine the safety, tolerability, and MTD of oral aza-TdCyd administered daily for 5 days a week for 2 weeks, with one week off, in 21-day cycles
Time Frame: Cycle 1 and Cycle 2
|
To determine the safety, tolerability, and MTD of oral aza-TdC administered daily for 5 days a week for 2 weeks, with one week off, in 21-day cycles
|
Cycle 1 and Cycle 2
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To determine the pharmacokinetics of oral aza-TdCyd
Time Frame: Cycle 1
|
To determine the pharmacokinetics of oral aza-TdC
|
Cycle 1
|
To document preliminary evidence of aza-TdCyd activity
Time Frame: Cycle 1 and 2
|
To document preliminary evidence of aza-TdC activity
|
Cycle 1 and 2
|
To determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
Time Frame: Cycle 1 and 2
|
To determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
|
Cycle 1 and 2
|
To determine the effects of Aza-TdC on DNA damage response (DDR) signaling and on genome-wide DNA methylation in tumor biopsy tissue
Time Frame: Pre-treatment, Cycle 1 Day 2, Cycle 2 Day 10
|
To determine the effects of Aza-TdC on DNA damage response (DDR) signaling and on genome-wide DNA methylation in tumor biopsy tissue
|
Pre-treatment, Cycle 1 Day 2, Cycle 2 Day 10
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: James H Doroshow, M.D., National Cancer Institute (NCI)
Publications and helpful links
General Publications
- Cowan LA, Talwar S, Yang AS. Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics. 2010 Feb;2(1):71-86. doi: 10.2217/epi.09.44.
- Thottassery JV, Sambandam V, Allan PW, Maddry JA, Maxuitenko YY, Tiwari K, Hollingshead M, Parker WB. Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4'-thio-2'-deoxycytidine and 5-aza-4'-thio-2'-deoxycytidine. Cancer Chemother Pharmacol. 2014 Aug;74(2):291-302. doi: 10.1007/s00280-014-2503-z. Epub 2014 Jun 8.
- Tiwari KN, Cappellacci L, Montgomery JA, Secrist JA 3rd. Synthesis and anti-cancer activity of some novel 5-azacytosine nucleosides. Nucleosides Nucleotides Nucleic Acids. 2003 Dec;22(12):2161-70. doi: 10.1081/ncn-120026872.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 180014
- 18-C-0014
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Neoplasms
-
European Association for Endoscopic SurgeryWithdrawn
-
Moscow Clinical Scientific CenterRecruitingCecal Neoplasms | Colonic Neoplasms MalignantRussian Federation
-
Chang Gung Memorial HospitalNational Science and Technology CouncilRecruiting
-
John M. BuattiNational Cancer Institute (NCI); National Institutes of Health (NIH)CompletedUterine Cervical Neoplasms | Prostatic Neoplasms | Rectal Neoplasms | Endometrial Neoplasms | Anus NeoplasmsUnited States
-
GlaxoSmithKlineCompleted
-
Royal North Shore HospitalNorthern Sydney and Central Coast Area Health ServiceNot yet recruiting
-
Instituto Nacional de Cancer, BrazilCompletedHead Neck NeoplasmsBrazil
-
Fudan UniversityShanghai Zhongshan Hospital; RenJi Hospital; First Hospital of China Medical... and other collaboratorsNot yet recruitingRectal Cancer | RECTAL NEOPLASMS
-
Sun Yat-sen UniversityPeking Union Medical College Hospital; RenJi Hospital; Shengjing Hospital; First... and other collaboratorsRecruitingSurgery | Rectal Neoplasms MalignantChina
-
NovartisBayerCompletedColorectal Neoplasms | Rectal Neoplasms | Colonic NeoplasmsBelgium, Germany, Italy, United States, Taiwan, Switzerland, Spain, Canada, Slovakia, United Kingdom, New Zealand, Australia, Portugal, Brazil, Hungary, Czechia, France, Netherlands, Sweden
Clinical Trials on aza-TdC
-
Roswell Park Cancer InstituteWithdrawnCastration-Resistant Prostate Carcinoma | Stage IV Prostate Cancer AJCC v8 | Stage IVA Prostate Cancer AJCC v8 | Stage IVB Prostate Cancer AJCC v8 | PSA Progression | Metastatic Prostate Carcinoma in the Soft Tissue | Castration Levels of Testosterone | Prostate Carcinoma Metastatic in the Bone | PSA...United States
-
Centre Hospitalier Universitaire de NiceWithdrawn
-
Nova Southeastern UniversityCompletedLymphedema, SecondaryUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)CompletedRecurrent Acute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Myelodysplastic/Myeloproliferative Neoplasm | Blasts More Than 20 Percent of Bone Marrow Nucleated Cells | Blasts More Than 20 Percent of Peripheral Blood White CellsUnited States
-
Nova Southeastern UniversitySurgical Specialists of MiamiCompleted
-
Northwestern UniversityCompletedNarcolepsy | Narcolepsy Type 1 | Narcolepsy Without Cataplexy | Narcolepsy With Cataplexy | Narcolepsy Type 2United States
-
University of OklahomaVA Office of Research and DevelopmentTerminatedBrain Ischemia | Brain InfarctionUnited States
-
Abant Izzet Baysal UniversityThe Scientific and Technological Research Council of TurkeyWithdrawnBreast Cancer | LymphedemaTurkey
-
University of PennsylvaniaTeleflex; Arrow InternationalCompletedRenal Failure Chronic Requiring Hemodialysis | Chronic Renal InsufficiencyUnited States
-
Shanghai Jiao Tong University School of MedicineRecruitingRefractory Acute Myeloid LeukemiaChina