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Protocol Details

Phase I Trial of 5-aza-4'-thio-2'-Deoxycytidine (Aza-TdC) in Patients with Advanced Solid Tumors

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

18-C-0014

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: 120 Years

Referral Letter Required

No

Population Exclusion(s)

Children

Keywords

Pharmacodynamics;
DNA Methylation;
Pharmacokinetics;
Nucleoside Analog;
Epigenetics

Recruitment Keyword(s)

None

Condition(s)

Neoplasms;
Solid Tumors

Investigational Drug(s)

Aza-TdC

Investigational Device(s)

None

Intervention(s)

Drug: aza-TdC

Supporting Site

National Cancer Institute

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

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Eligibility

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.


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Citations:

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

James H. Doroshow, M.D.
National Cancer Institute (NCI)
NIHBC 31 BG RM 3A44
31 CENTER DR
BETHESDA MD 20892
(240) 781-3320
doroshoj@mail.nih.gov

DTC Referral Coordinators
National Cancer Institute (NCI)

(240) 781-3400
dtcreferralcoordinators@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937
ncimo_referrals@mail.nih.gov

Clinical Trials Number:

NCT03366116

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