5-Azacytidine Infusion for Brain Cancer

(5-AZA Trial)

Overseen By David Sandberg, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Other treatment protocol, Infection, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 19

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called 5-Azacytidine (5-AZA) for brain cancer, specifically recurring ependymoma. The goal is to determine the best dose frequency for 5-AZA infusions directly into the brain's fourth ventricle and to evaluate its effectiveness against the tumor. Participants will be divided into groups receiving two, three, or four infusions per week. Ideal candidates have a history of ependymoma that has recurred or not responded to previous treatments and have a tumor in the posterior fossa of the brain. As a Phase 1 trial, this research aims to understand how 5-AZA works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that 5-Azacytidine infusions are likely to be safe for humans?

Research has shown that 5-Azacytidine (5-AZA) can be safely administered directly into the fourth ventricle of the brain without harming the nervous system. Patients usually tolerate this method well. However, as with any treatment, side effects or health changes may occur, and these are closely monitored during clinical trials. Participants should be aware of these possibilities and discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Unlike the standard treatments for brain cancer, which typically involve surgery, radiation, and chemotherapy, 5-Azacytidine (5-AZA) offers a novel approach by delivering the drug directly into the brain via a ventricular catheter. This method targets cancer cells more precisely and may reduce systemic side effects. Researchers are excited about 5-AZA because it works as a DNA methyltransferase inhibitor, potentially reactivating tumor suppressor genes and hindering cancer growth. Additionally, the tailored dosing regimens—ranging from two to four infusions per week—allow for flexibility in treatment intensity, which may optimize outcomes for different patient needs.

What evidence suggests that 5-Azacytidine infusions might be an effective treatment for brain cancer?

Research has shown that 5-Azacytidine (5-AZA) can be safely delivered directly into the fourth ventricle of the brain without harming the nervous system. This marks an important first step in exploring its potential to treat brain cancers like recurrent ependymoma. In this trial, participants will be divided into three groups, each receiving different frequencies of 5-AZA infusions. The researchers aim to determine if this method might work better specifically for brain tumors. While considered safe, the effectiveness against brain tumors is still under investigation. ^{1 2 3 5 6}

Who Is on the Research Team?

David Sandberg, M.D.

Principal Investigator

The University of Texas Health Science Center, Houston

Are You a Good Fit for This Trial?

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

Evidence of untreated infection

I haven't had any experimental drugs, chemotherapy, or radiation within the last week.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• 5-Azacytidine (5-AZA)

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Vidaza for:

• Myelodysplastic syndrome
• Acute myeloid leukemia
• Juvenile myelomonocytic leukemia

Approved in European Union as Vidaza for:

• Myelodysplastic syndrome
• Acute myeloid leukemia
• Chronic myelomonocytic leukemia

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+

Published Research Related to This Trial

In a study involving 15 patients with advanced metastatic osteogenic and Ewing's sarcoma, treatment with 5-azacytidine showed no significant antitumor activity, indicating it may not be an effective option for these types of cancer.

The treatment was associated with major toxicities, primarily hematologic and gastrointestinal, highlighting safety concerns despite the lack of efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in sarcomas of bone. Srinivasan, U., Reaman, GH., Poplack, DG., et al.[2019]

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]

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]

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]

In a study involving rhesus monkeys, arabinosyl-5-azacytidine (AAC) showed no clinically significant toxicity after various intravenous infusion durations, indicating a favorable safety profile for this treatment.

The pharmacokinetics of AAC revealed rapid plasma elimination with a complex decay pattern, and the drug demonstrated limited penetration into cerebrospinal fluid (CSF), which may inform future human studies on dosing and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates. Heideman, RL., Balis, FM., McCully, C., et al.[2014]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02940483

Infusion of 5-Azacytidine (5-AZA) Into the Fourth Ventricle ... The goal of this clinical research study is to establish the safety of direct administration of 5-Azacytidine into the fourth ventricle of the brain or ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30460634/

Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or ... Conclusion: 5-AZA can be infused into the fourth ventricle or posterior fossa tumor resection cavity without causing neurological toxicity.

3. withpower.com withpower.com/trial/phase-1-ependymoma-1-2019-dc81f

5-Azacytidine Infusion for Brain Cancer · Info for Participants In a study involving 15 patients with advanced metastatic osteogenic and Ewing's sarcoma, treatment with 5-azacytidine showed no significant antitumor activity, ...

4. researchgate.net researchgate.net/publication/329083012_Infusion_of_5-Azacytidine_5-AZA_into_the_fourth_ventricle_or_resection_cavity_in_children_with_recurrent_posterior_Fossa_Ependymoma_a_pilot_clinical_trial

Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or ... Conclusion 5-AZA can be infused into the fourth ventricle or posterior fossa tumor resection cavity without causing neurological toxicity. ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03572530?term=Azacitidine&rank=6

Infusion of 5- Azacytidine ( 5-AZA ) Into the Fourth Ventricle ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

6. 2024.sci-hub.se 2024.sci-hub.se/7238/592e40e4eb50b15085eec36616de94b6/sandberg2018.pdf

Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or ... Additionally, infusion into the fourth ventricle or tumor cavity will also enable drug distribution within the spinal subarachnoid space. This ...