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

4 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to establish the safety and tolerability of simultaneous infusions of 5-Azacytidine and trastuzumab into the fourth ventricle of the brain or resection cavity in patients with recurrent posterior fossa ependymoma and to assess the antitumor activity of simultaneous infusions of 5-Azacytidine and trastuzumab into the fourth ventricle of the brain or resection cavity in patients based upon imaging studies and lumbar cerebrospinal fluid (CSF) cytology.

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.

What data supports the idea that Chemotherapy for Ependymoma is an effective treatment?

The available research shows that chemotherapy for ependymoma has limited effectiveness. One study mentions that ependymomas are generally resistant to chemotherapy, and only one drug, Cisplatin, has shown some effectiveness with a response rate of 34%. Another study highlights that chemotherapy did not improve survival rates when added to radiation therapy in children. However, there is a case where a young child with metastatic ependymoma was successfully treated with intensive chemotherapy without radiation, remaining in remission for five years. Overall, chemotherapy alone is not consistently effective, and its use is often combined with other treatments or reserved for specific cases. ^{1 2 3 4 5}

What safety data exists for chemotherapy treatments like 5-Azacytidine and Trastuzumab?

The safety data for trastuzumab, a HER2-targeted therapy, includes potential cardiac toxicity, as indicated by a meta-analysis of trials showing a risk of congestive heart failure and left ventricular ejection fraction decline. Trastuzumab deruxtecan, another HER2-targeted therapy, has a generally manageable safety profile but carries a warning for interstitial lung disease and embryo-fetal toxicity. No specific safety data for 5-Azacytidine or its other names (Vidaza, Onureg, Azacitidine) is provided in the research. ^{6 7 8 9 10}

Is the drug 5-Azacytidine, Trastuzumab promising for treating ependymoma?

Based on the research, chemotherapy, including drugs like 5-Azacytidine and Trastuzumab, has not shown strong evidence of being effective for treating ependymoma. The response rates to chemotherapy are generally low, and it is not considered a standard or promising treatment for this type of tumor. ^{3 11 12 13 14}

Research Team

David Sandberg, M.D.

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 (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]

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]

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]

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]

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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

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

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

Ongoing Response in a Multiply Relapsed Metastatic Posterior Fossa Ependymoma A After Vorinostat and Concomitant Irradiation. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Childhood ependymoma: a systematic review of treatment options and strategies. [2022]

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

Global Reduction of H3K4me3 Improves Chemotherapeutic Efficacy for Pediatric Ependymomas. [2023]

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

Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review. [2023]

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

Incidence of HER2-expressing brain metastases in patients with HER2-null breast cancer: a matched case analysis. [2023]

7. England 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. [2023]

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

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

9. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

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

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. [2018]

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

Advances in Management of Pediatric Ependymomas. [2018]

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

Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma. [2019]

13. Germany pubmed.ncbi.nlm.nih.gov

Chemotherapy for intracranial ependymomas. [2022]

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

Ependymomas. [2022]