Clinical trial NCT03366116: 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors
Official title: Phase I Trial of 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Solid Tumors
Keywords: Pharmacodynamics
DNA Methylation
Pharmacokinetics
Nucleoside Analog
Epigenetics
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2017-12-08
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: * 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 x 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.

Primary outcomes:
measure: 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
timeFrame: Cycle 1 and Cycle 2
Secondary outcomes:
measure: To determine the pharmacokinetics of oral aza-TdCyd
timeFrame: Cycle 1
measure: To document preliminary evidence of aza-TdCyd activity
timeFrame: Cycle 1 and 2
measure: To determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
timeFrame: Cycle 1 and 2
measure: To determine the effects of Aza-TdC on DNA damage response (DDR) signaling and on genome-wide DNA methylation in tumor biopsy tissue
timeFrame: Pre-treatment, Cycle 1 Day 2, Cycle 2 Day 10
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: James H Doroshow, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.