Chemotherapy for Ependymoma

Overseen By Bangning Yu, MD, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Other protocol, Resectable disease, Cardiac issues, Infection, Pregnant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of two drugs, 5-Azacytidine (a chemotherapy drug) and Trastuzumab (a targeted therapy), for treating recurrent ependymoma, a type of brain tumor. Researchers will directly infuse these drugs into the part of the brain where the tumor is located. The trial seeks participants whose ependymoma has returned or hasn't fully resolved despite earlier treatments and who have a tumor visible on an MRI. Participants must have a device implanted for drug infusion or agree to have one placed. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this novel approach.

Do I need to stop my current medications to join the trial?

The trial requires a minimum of 2 weeks between your last dose of any systemic chemotherapy and the first infusion of the trial drugs. It also requires a 4-week gap from any prior radiation treatments or bevacizumab infusions. The protocol does not specify other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 5-Azacytidine, administered directly into the brain, is well-tolerated by patients with ependymoma. One study reported no serious side effects or new brain issues related to the treatment, even after several doses.

For trastuzumab, commonly used in breast cancer treatment, the safety data is also encouraging. Studies indicate that while some patients have experienced serious side effects, these are uncommon. Trastuzumab has been used safely in various treatment settings.

Since this trial is in the early stages, the main goal is to determine if these treatments are safe for people. Existing research and their use in other conditions provide some confidence in their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments 5-Azacytidine and Trastuzumab for ependymoma because they offer a fresh approach compared to traditional therapies like surgery and radiation. 5-Azacytidine works by modifying the DNA to stop cancer cells from multiplying, which is different from conventional methods that physically remove or destroy cells. Trastuzumab targets specific proteins on cancer cells, potentially leading to more precise and less harmful treatment outcomes. These innovative mechanisms of action could pave the way for more effective and less invasive treatment options for patients with ependymoma.

What evidence suggests that this trial's treatments could be effective for ependymoma?

Research has shown that 5-Azacytidine might help treat ependymoma, a type of brain tumor, by delivering it directly into the fourth ventricle of the brain. In one study, all five patients experienced disease progression, but two showed some positive effects. Trastuzumab, a well-known treatment for breast cancer, targets a protein called HER2. Its effectiveness for brain conditions like ependymoma remains uncertain because it struggles to reach the brain. This trial will evaluate the effects of 5-Azacytidine alone and in combination with Trastuzumab to determine if these treatments can improve outcomes for ependymoma patients. ^{1 2 5 6 7}

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 children and adults with a type of brain cancer called posterior fossa ependymoma that has come back or didn't go away after treatment. They must have an implanted catheter in the brain, stable neurological conditions, good enough bone marrow function, normal heart (unless cleared by cardiology), kidney and liver functions, and not be pregnant or on other clinical trials.

Inclusion Criteria

I am mostly active and can do things for myself, regardless of my age.

It has been at least 4 weeks since my last radiation or bevacizumab treatment.

My kidney and liver tests are normal.

Exclusion Criteria

Pregnant or lactating women

I have an infection that hasn't been treated.

Enrolled in another treatment protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Simultaneous infusions of 5-Azacytidine and trastuzumab into the fourth ventricle or resection cavity

7 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-Azacytidine
• Trastuzumab

Trial Overview

The study tests the safety and effectiveness of infusing two drugs directly into the brain: 5-Azacytidine (5-AZA) and Trastuzumab. It aims to see if these drugs can shrink tumors or slow their growth when delivered straight to where they are located in patients with recurrent ependymoma.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 1 Intervention

5-Azacytidine is already approved in United States, European Union for the following indications:

Approved in United States as Vidaza for:

• Myelodysplastic syndromes (MDS)
• Acute myeloid leukemia (AML)

Approved in European Union as Vidaza for:

• Myelodysplastic syndromes (MDS)
• Acute myeloid leukemia (AML)
• Chronic myelomonocytic leukemia (CMML)

Approved in United States as Onureg for:

• Acute myeloid leukemia (AML)

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

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

A meta-analysis of six randomized trials found that dual HER2 blockade (combination therapy) has a comparable risk of cardiac adverse events, such as congestive heart failure (CHF) and left ventricular ejection fraction (LVEF) decline, when compared to anti-HER2 monotherapy.

The incidence of CHF was slightly lower in the combination therapy group (0.88%) compared to monotherapy (1.49%), suggesting that dual HER2 blockade does not significantly increase cardiac risks, which is important for treatment decisions in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Valachis, A., Nearchou, A., Polyzos, NP., et al.[2018]

Capmatinib (Tabrecta) is FDA-approved for treating metastatic non-small cell lung cancer in adults with specific mutations, but patients must be monitored for serious side effects like interstitial lung disease and hepatotoxicity.

Fam-trastuzumab deruxtecan-nxki (Enhertu) has also received accelerated FDA approval for a different type of metastatic non-small cell lung cancer, with warnings about risks such as interstitial lung disease and embryo-fetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two New Drugs Approved for Non-Small Cell Lung Cancer. Aschenbrenner, DS.[2023]

Trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2, is effective even in cases of lower HER2 expression, which is important for treating patients with previously HER2-null breast cancer.

In a study of 136 patients, 54% of those with HER2-null primary breast cancer showed detectable HER2 expression in brain metastases, highlighting a significant discordance that could affect treatment response and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of HER2-expressing brain metastases in patients with HER2-null breast cancer: a matched case analysis. Moss, NS., Singh, JM., Reiner, AS., et al.[2023]

In adults with intra-cranial ependymal tumors, there is a lack of universally accepted prognostic factors and treatment guidelines due to the rarity of these tumors and limited data.

Current evidence from a phase III trial in children shows that adding chemotherapy (lomustine, vincristine, and prednisone) to cranio-spinal irradiation does not improve survival compared to radiation therapy alone, suggesting that chemotherapy should only be used in controlled clinical trials for adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for the treatment of adult intra-cranial grade II-III ependymal tumours. Reni, M.[2004]

A 3-year-old boy with a recurrent posterior fossa ependymoma showed significant tumor reduction after treatment with Vorinostat, a histone deacetylase inhibitor, combined with craniospinal irradiation, leading to nearly complete resolution of the disease at 15 months.

Molecular analysis indicated specific epigenetic changes in the tumor, suggesting that targeting these alterations with epigenetic modifiers like Vorinostat could be a promising treatment strategy for select cases of ependymoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ongoing Response in a Multiply Relapsed Metastatic Posterior Fossa Ependymoma A After Vorinostat and Concomitant Irradiation. Gorsi, HS., Toll, SA., Sood, S., et al.[2022]

In pediatric ependymomas (EPNs), higher levels of the histone modification H3K4me3 are linked to more aggressive tumor grades and poorer patient outcomes, indicating its potential as a prognostic marker.

Targeting the enzyme responsible for adding H3K4me3, SETD1A, can enhance the effectiveness of chemotherapy in EPN cells, suggesting a new therapeutic strategy to improve treatment responses in these resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Global Reduction of H3K4me3 Improves Chemotherapeutic Efficacy for Pediatric Ependymomas. Lewis, R., Li, YD., Hoffman, L., et al.[2023]

Ependymal tumors are the third most common brain tumors in children under 14, and while metastatic cases are rare, they significantly impact young children, particularly those under 3 years old, with an overall survival rate of 50%-58%.

A case study of a 7-month-old boy with metastatic posterior fossa ependymoma revealed a novel gene fusion and demonstrated successful treatment with intensive chemotherapy and autologous stem cell rescue, achieving continuous remission for 5 years without radiation, highlighting potential new therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review. De Faria, FW., Schieffer, KM., Pierson, CR., et al.[2023]

Childhood intracranial ependymoma has a poor prognosis, particularly in young children and those who cannot undergo complete surgical resection, with about two-thirds experiencing recurrence even without visible tumor remnants.

Cisplatin is the only chemotherapy agent that has shown some effectiveness in treating ependymoma, but overall, these tumors are generally resistant to chemotherapy, highlighting the need for new treatment strategies and well-designed clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Childhood ependymoma: a systematic review of treatment options and strategies. Grill, J., Pascal, C., Chantal, K.[2022]

In a study of 25 adults with recurrent, platinum-resistant ependymoma, temozolomide (TMZ) showed limited efficacy, with only 4% of patients achieving a partial response and a median progression-free survival of just 2 months.

TMZ treatment resulted in various toxicities, including leukopenia and fatigue, but most were not severe (grade 3 or higher), indicating that while the drug is relatively safe, it does not provide significant benefits for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma. Chamberlain, MC., Johnston, SK.[2019]

Intrathecal trastuzumab, administered at a recommended dose of 80 mg twice weekly, was well-tolerated in patients with HER2-positive leptomeningeal disease, with only one case of significant toxicity (grade 4 arachnoiditis).

Among the 26 patients evaluated for efficacy, 19.2% showed a partial response, and the median overall survival for those treated was 8.3 months, indicating potential benefits for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics. Kumthekar, PU., Avram, MJ., Lassman, AB., et al.[2023]

Complete surgical resection of ependymomas is the only consistent factor that improves survival rates in pediatric patients, highlighting the importance of effective surgical intervention.

Recent genomic studies have identified unique molecular characteristics of ependymomas, suggesting that targeted therapies and personalized treatment approaches could enhance outcomes for patients with these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Management of Pediatric Ependymomas. Lin, FY., Chintagumpala, M.[2018]

Complete surgical resection of ependymomas significantly improves patient survival, making it crucial to evaluate the extent of disease through cerebrospinal fluid cytology and MRI before deciding on treatment.

For patients with residual disease who cannot undergo further surgery, limited-field radiotherapy is typically used, but the effectiveness of craniospinal irradiation remains debated due to the tendency for local recurrences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ependymomas. Chowdhary, S., Green, MR., Chamberlain, M.[2022]

Chemotherapy shows limited effectiveness in treating children with intracranial ependymoma, with a response rate of only 11% for single agents and less than 5% for complete responses, indicating a need for more effective treatment options.

Current evidence suggests that high-dose chemotherapy regimens and combinations may not significantly improve outcomes, particularly in infants and young children, highlighting the necessity for more rigorous clinical trials to better assess the role of chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for intracranial ependymomas. Bouffet, E., Foreman, N.[2022]

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