5-Azacytidine Infusion for Brain Cancer

(5-AZA Trial)

Overseen by David Sandberg, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Other treatment protocol, Infection, Pregnancy, others

No Placebo Group

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing the safety and effectiveness of a drug called 5-Azacytidine for patients with recurring brain tumors. The goal is to find the best dose and see if the drug can help reduce the tumors.

Will I have to stop taking my current medications?

The trial requires a minimum of 7 days between your last dose of systemic chemotherapy or radiation therapy and the first infusion of 5-Azacytidine. It doesn't specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug 5-Azacytidine for brain cancer?

5-Azacytidine has been approved by the FDA for treating myelodysplastic syndrome (MDS), where it showed benefits like reducing the need for blood transfusions and improving blood counts. However, in studies for other cancers like melanoma and sarcomas, it did not show significant antitumor activity. ^{1 2 3 4 5}

What safety data exists for 5-Azacytidine in humans?

5-Azacytidine has been studied in humans and is known to cause some side effects, mainly affecting blood cells, such as leukopenia (low white blood cell count) and thrombocytopenia (low platelet count), which are usually reversible. Other common side effects include nausea and mild diarrhea, and in some cases, there have been serious toxicities like infections and bleeding. The drug's safety profile varies with dosage and administration method. ^{2 6 7 8 9}

What makes 5-Azacytidine unique for treating brain cancer?

5-Azacytidine is unique because it can be administered as a continuous infusion, which maintains higher plasma concentrations with fewer side effects compared to a bolus (single large dose) administration. This drug is also being explored for its ability to penetrate the cerebrospinal fluid, potentially offering a pharmacokinetic advantage for treating brain cancer. ^{1 2 10 11 12}

Research Team

David Sandberg, M.D.

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

This trial is for patients with a specific brain cancer called recurrent posterior fossa ependymoma. They must have an implanted catheter or agree to one, a life expectancy of at least 12 weeks, stable neurological conditions, and adequate bone marrow function. Pregnant women, those with untreated infections or recent treatments from other trials are excluded.

Inclusion Criteria

My ependymoma cancer has come back or gotten worse in my brain or spine.

Life expectancy of at least 12 weeks in the opinion of the principal investigator

Patients with either measurable or evaluable tumor as assessed by MRI of the brain and total spine

Exclusion Criteria

Pregnant or lactating women

Enrolled in another treatment protocol

Evidence of untreated infection

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Placement

Surgical placement of a ventricular catheter into the fourth ventricle attached to a subcutaneously placed reservoir

1 week

1 visit (in-person)

Treatment

Participants receive 8 weeks of intraventricular 5-Azacytidine infusions into the fourth ventricle

8 weeks

16-32 visits (in-person) depending on dose group

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

2 visits (in-person)

Treatment Details

Interventions

• 5-Azacytidine (5-AZA) (Anti-metabolites)

Trial Overview The study tests different dosing frequencies of the drug 5-Azacytidine (5-AZA) infused directly into the fourth ventricle of the brain to find the safest maximum dose and assess its effectiveness against tumor activity through imaging studies.

Participant Groups

Group I: group 3 Experimental Treatment 1 Intervention

5-Azacytidine (5-AZA) group 3: Enrolled patients will undergo surgical placement of a ventricular catheter into the fourth ventricle that will be attached to a subcutaneously placed reservoir. Patients will be divided into 3 dose groups and receive 8 weeks of intraventricular 5-AZA (12 mg) into the fourth ventricle. Patients in Group 3 will receive four 5-AZA infusions every week.

Group II: group 2 Experimental Treatment 1 Intervention

5-Azacytidine (5-AZA) group 2: Enrolled patients will undergo surgical placement of a ventricular catheter into the fourth ventricle that will be attached to a subcutaneously placed reservoir. Patients will be divided into 3 dose groups and receive 8 weeks of intraventricular 5-AZA (12 mg) into the fourth ventricle. Patients in Group 2 will receive three 5-AZA infusions every week.

Group III: group 1 Experimental Treatment 1 Intervention

5-Azacytidine (5-AZA) group 1: Enrolled patients will undergo surgical placement of a ventricular catheter into the fourth ventricle that will be attached to a subcutaneously placed reservoir. Patients will be divided into 3 dose groups and receive 8 weeks of intraventricular 5-AZA (12 mg) into the fourth ventricle. Patients in Group 1 will receive two 5-AZA infusions every week.

5-Azacytidine (5-AZA) is already approved in Canada, Japan for the following indications:

Approved in Canada as Vidaza for:

• Myelodysplastic syndrome
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndrome
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

Dr. LaTanya Love

The University of Texas Health Science Center, Houston

Interim President

MD from UT Medical Branch in Galveston

Dr. Jagat Narula

The University of Texas Health Science Center, Houston

Chief Academic Officer since 2023

MD, PhD

Findings from Research

In a phase I trial involving 21 patients with advanced solid tumors, 5-aza-2'-deoxycytidine (5-aza-dCyd) showed a dose-limiting toxicity of myelosuppression, indicating that while the drug has potential, careful monitoring of blood cell levels is necessary during treatment.

The study observed one partial response in a patient and recommended a dosing schedule of 75 mg/m2 in three infusions every 5 weeks for future phase II trials, suggesting that this regimen may be effective for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. van Groeningen, CJ., Leyva, A., O'Brien, AM., et al.[2018]

In a study involving 30 patients with advanced metastatic malignant melanoma who were resistant to previous treatments, 5-azacytidine was administered at a dosage of 100 mg/m2/day for 10 days.

The treatment resulted in significant toxicities, including hematologic, gastrointestinal, and cutaneous issues, but no antitumor activity was observed, indicating that 5-azacytidine may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma. Bellet, RE., Catalano, RB., Mastrangelo, MJ., et al.[2019]

Azacitidine was approved by the FDA for treating all subtypes of myelodysplastic syndrome (MDS) based on a randomized controlled trial showing a 16% overall response rate, with sustained responses lasting up to 17 months.

The treatment demonstrated a favorable safety profile, with no deaths attributed to azacitidine, although common side effects included gastrointestinal issues and hematologic complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Kaminskas, E., Farrell, AT., Wang, YC., et al.[2013]

In a study involving 30 patients with various solid tumors, treatment with 5-azacytidine resulted in objective remissions in 7 out of 11 breast cancer patients, 2 out of 5 melanoma patients, and 2 out of 6 colon cancer patients, indicating its potential efficacy against these cancers.

The major side effects included significant hematologic toxicity, such as leukopenia and thrombocytopenia, which were reversible and typically occurred 20-30 days after starting treatment, highlighting the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of 5-azacytidine (NSC-102816) . Weiss, AJ., Stambaugh, JE., Mastrangelo, MJ., et al.[2016]

In a Phase I trial involving 27 adult patients with refractory cancer, 1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC) showed dose-limiting toxicities, primarily reversible granulocytopenia and thrombocytopenia, with significant side effects observed at a dose rate of 1.96 mg/m2/h.

Despite the toxicity, minor clinical responses were noted in several patients, leading to a recommended dose of 2.0 mg/m2/h for future Phase II studies, indicating potential efficacy in treating certain types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). Surbone, A., Ford, H., Kelley, JA., et al.[2014]

In a phase II study of 5-azacytidine involving 191 eligible patients with solid tumors, only 2.6% showed partial regression of their tumors, indicating limited efficacy.

The treatment was associated with significant toxicities, including myelosuppression and gastrointestinal issues, leading to 13 deaths due to drug-related complications, highlighting safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in solid tumors. Quagliana, JM., O'Bryan, RM., Baker, L., et al.[2013]

A continuous intravenous infusion of 5-azacytidine at a dose of 150 mg/m2/day over 120 hours was found to be safe and effective, with no instances of nausea or vomiting reported in seven patients.

The treatment demonstrated antitumor activity in two patients, one with colon cancer and another with American Burkitt's lymphoma, while leukopenia was identified as the primary side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of 5-azacytidine (NSC-102816) using 24-hour continuous infusion for 5 days. Lomen, PL., Baker, LH., Neil, GL., et al.[2016]

Intrathecal and intraventricular administration of Arabinosyl-5-azacytosine (AAC) in nonhuman primates showed a significant pharmacokinetic advantage, achieving much higher concentrations in cerebrospinal fluid (CSF) compared to systemic administration, with a peak CSF concentration 150-fold greater than that from an intravenous dose.

The study found that AAC was well-tolerated with no clinically evident neurotoxicity, and only mild, transient systemic toxicity was observed in one animal, indicating a favorable safety profile for potential intrathecal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebrospinal fluid pharmacokinetics and toxicology of intraventricular and intrathecal arabinosyl-5-azacytosine (fazarabine, NSC 281272) in the nonhuman primate. Heideman, RL., McCully, C., Balis, FM., et al.[2019]

5-aza-2'-deoxycytidine (5-aza-dCyd) demonstrated significant antitumor activity in human head and neck cancer xenografts in nude mice, with complete tumor regression observed in 1 out of 6 tumors in the most sensitive lines.

The drug showed comparable or superior antitumor effects to conventional chemotherapy agents like cisplatin and methotrexate, suggesting its potential as an effective treatment option for head and neck cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical antitumor activity of 5-aza-2'-deoxycytidine against human and neck cancer xenografts [corrected]. Braakhuis, BJ., van Dongen, GA., van Walsum, M., et al.[2019]

In cancer patients, 5-azacytidine administered via continuous infusion resulted in higher plasma concentrations and fewer side effects compared to bolus administration, suggesting a safer and more effective delivery method.

The majority of 5-azacytidine was excreted through urine (73-98%) within three days, indicating efficient elimination from the body, while its stability was significantly enhanced at lower temperatures and pH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion. Israili, ZH., Vogler, WR., Mingioli, ES., et al.[2014]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates. [2014]

3. United States pubmed.ncbi.nlm.nih.gov

Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma. [2019]

4. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in sarcomas of bone. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I study of 5-azacytidine (NSC-102816) . [2016]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in solid tumors. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Phase I study of 5-azacytidine (NSC-102816) using 24-hour continuous infusion for 5 days. [2016]

10. United States pubmed.ncbi.nlm.nih.gov

Cerebrospinal fluid pharmacokinetics and toxicology of intraventricular and intrathecal arabinosyl-5-azacytosine (fazarabine, NSC 281272) in the nonhuman primate. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Preclinical antitumor activity of 5-aza-2'-deoxycytidine against human and neck cancer xenografts [corrected]. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion. [2014]