Trastuzumab + GM-CSF for Ependymoma

Overseen By Deb Schissel, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must not be taking: Corticosteroids, Investigational drugs, Anti-cancer agents

Disqualifiers: Spinal cord ependymoma, Uncontrolled infection, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for children with relapsed posterior fossa ependymoma, a type of brain tumor. The researchers aim to determine if trastuzumab, administered into the spinal fluid, can be detected in the tumor and to assess the safety of using it with GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor), which boosts white blood cells. Participants should be children diagnosed with this specific relapsed brain tumor who plan to undergo surgery as part of their standard care. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

Yes, you will need to stop certain medications. You cannot take systemic corticosteroids, investigational drugs, or other anti-cancer agents while participating in the trial.

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

Yes, you will need to stop taking certain medications. Specifically, you cannot be on systemic corticosteroids, other investigational drugs, or anti-cancer agents to participate in the trial.

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

Research has shown that trastuzumab is usually well-tolerated when combined with chemotherapy for other conditions. One study found that patients taking trastuzumab did not experience more severe side effects than those who did not. However, the risk of heart problems necessitates careful monitoring.

GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) can cause side effects such as fever and skin rashes. Some patients may experience capillary leak syndrome, where fluid leaks from small blood vessels into nearby tissues, causing swelling and low blood pressure.

Limited information exists on using trastuzumab and GM-CSF together specifically for ependymoma, a type of brain tumor. However, both treatments have been studied separately, providing some insight into their safety. As this is an early-phase trial, it aims to determine safety and possible side effects. Participants will be closely monitored to manage any adverse events. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of trastuzumab and GM-CSF for ependymoma because it offers a novel approach compared to traditional treatments like surgery and radiation. Unlike standard therapies, trastuzumab targets specific cancer cell receptors, potentially offering a more precise attack on tumor cells. Additionally, GM-CSF is used to stimulate the immune system, enhancing the body's natural ability to fight the cancer. The unique delivery method, where trastuzumab is administered intrathecally (directly into the spinal fluid) after subcutaneous GM-CSF, aims to improve drug effectiveness and minimize systemic side effects, offering hope for better outcomes in this challenging condition.

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

In this trial, participants will receive either IT trastuzumab after a subQ GM-CSF course or IT trastuzumab combined with subQ GM-CSF. Research has shown that trastuzumab, a monoclonal antibody, can treat certain cancers with the HER2 protein. While it doesn't work for everyone, it has shown early success without causing serious side effects in children with brain tumors. GM-CSF boosts the immune system and is believed to enhance trastuzumab's effectiveness. Studies suggest that combining GM-CSF with trastuzumab can improve the immune response in patients with ependymoma, a type of brain tumor. Although direct evidence for this combination in relapsed posterior fossa ependymoma is still being gathered, the results so far are promising. ^{2 6 7 8 9}

Who Is on the Research Team?

Margaret Macy, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for children and young adults aged between 1 and 21 years with a specific type of brain tumor called relapsed posterior fossa ependymoma. They must have good organ function, no widespread cancer in the spine or brain, and be able to undergo surgery if needed. Participants need acceptable performance scores indicating they can perform daily activities.

Inclusion Criteria

I am between 1 and 20 years old.

My PFEPN cancer has come back.

My heart is functioning well.

Exclusion Criteria

I do not have any serious infections that are uncontrolled.

I have nodular metastatic spinal disease visible on MRI, making me ineligible for Stratum 1 but possibly eligible for Stratum 2.

I do not have a specific type of ependymoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of intrathecal trastuzumab following a 5-day course of subcutaneous GM-CSF, with surgical resection planned 2-7 days after IT trastuzumab dosage.

2 weeks

Dose Finding

Participants receive IT trastuzumab in combination with GM-CSF to establish a maximum tolerated dosage.

1 month

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• GM-CSF
• Trastuzumab

Trial Overview

The study tests how well trastuzumab, given through the spinal canal after a dose of GM-CSF under the skin, works on this kind of brain tumor. It aims to see if trastuzumab reaches the tumor and assesses any side effects when combined with GM-CSF.

How Is the Trial Designed?

Group I: IT trastuzumab in combination with subQ GM-CSF Experimental Treatment 1 Intervention

Patients with localized recurrent PFEPN will be treated with IT trastuzumab in combination with GM-CSF to establish a maximum tolerated dosage. GM-CSF will be administered at 250 mcg/m2/dose subQ daily for three (3) days prior to the IT trastuzumab dose.

Group II: IT trastuzumab after subQ GM-CSF Experimental Treatment 1 Intervention

Patients with localized recurrent PFEPN will be treated with IT trastuzumab following 5-day course of subQ GM-CSF. Surgical resection should be planned (based on institutional surgical scheduling standards) for ideally 2-7 days after IT trastuzumab dosage.

GM-CSF is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Leukine for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma
• HIV Infection

Approved in European Union as Sargramostim for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma

Approved in Canada as Leukine for:

• Neutropenia
• Bone Marrow Transplantation
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Children's Hospital Colorado

Collaborator

Trials

121

Recruited

5,135,000+

Published Research Related to This Trial

Intrathecal trastuzumab, when combined with systemic therapy, showed rapid symptomatic improvement and radiological response in two women with HER2 positive breast cancer and leptomeningeal carcinomatosis.

Both patients remained progression-free for at least seven months, suggesting that intrathecal trastuzumab may be a promising treatment option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer. Gulia, S., Gupta, S., Singh, A.[2020]

In a study involving 35 patients (18 receiving GM-CSF and 17 controls), GM-CSF did not enhance T cell or natural killer cell recovery after allogeneic stem cell transplantation, contrary to expectations.

However, GM-CSF administration improved dendritic cell reconstitution in patients undergoing autologous stem cell transplantation, suggesting its benefits may vary based on the type of transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granulocyte-macrophage colony-stimulating factor increases the proportion of circulating dendritic cells after autologous but not after allogeneic hematopoietic stem cell transplantation. Eksioglu, EA., Kielbasa, J., Eisen, S., et al.[2018]

A 39-year-old woman with HER2-overexpressing metastatic breast cancer and leptomeningeal carcinomatosis showed significant improvement after receiving intrathecal trastuzumab, indicating its potential efficacy in this rare condition.

The use of an Ommaya reservoir for intrathecal administration allowed for effective delivery of trastuzumab, leading to low cell counts in cerebrospinal fluid for 11 months, suggesting a well-tolerated treatment approach for patients with compromised blood-brain barriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Stemmler, HJ., Schmitt, M., Harbeck, N., et al.[2019]

In a study of 32 patients with non-Hodgkin's lymphoma and myeloma, the use of rhGM-CSF or rhG-CSF significantly reduced the duration of severe neutropenia after high-dose etoposide treatment, with patients recovering 5 days earlier than those who did not receive growth factors.

The treatment was well-tolerated, with minimal nonhematologic toxicity observed, and 58% of patients showed antitumor activity within a month, suggesting that these growth factors can enhance the safety and efficacy of high-dose chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor infusion makes high-dose etoposide a safe outpatient regimen that is effective in lymphoma and myeloma patients. Gianni, AM., Bregni, M., Siena, S., et al.[2017]

In a study of 5510 women aged 65 and older with breast cancer, those treated with granulocyte colony-stimulating factors (G-CSF) had a doubled risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) compared to those not treated with G-CSF, although the overall risk remained low.

Specifically, 1.77% of women receiving G-CSF developed AML or MDS within 48 months, compared to 1.04% of those who did not receive the treatment, indicating that while G-CSF can support chemotherapy, it is important to consider potential long-term risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. Hershman, D., Neugut, AI., Jacobson, JS., et al.[2020]

In a study of 10 patients with leptomeningeal metastasis from HER2-positive breast cancer, the combination of neratinib and capecitabine showed a 60% overall survival rate at six months and a median overall survival of 10 months, indicating potential efficacy in a challenging patient population.

The treatment resulted in neurological benefits for 70% of patients, with a median duration of response of 6.5 months, suggesting that neratinib and capecitabine could be a safe and effective option for patients who have exhausted other treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program. Pellerino, A., Soffietti, R., Bruno, F., et al.[2022]

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]

A 4-week study in cynomolgus monkeys showed that intrathecal administration of trastuzumab (at doses of 3 and 15 mg) did not cause any adverse effects on body weight, neurological function, or other health indicators, suggesting a good safety profile for this method of delivery.

The study achieved cerebrospinal fluid (CSF) concentrations of trastuzumab that were higher than those seen in patients, indicating that intrathecal administration could be a promising approach for treating brain metastases in patients with HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys. Braen, AP., Perron, J., Tellier, P., et al.[2015]

Intrathecal administration of trastuzumab, combined with methotrexate and cytarabine, was safely given to two patients with leptomeningeal carcinomatosis from metastatic breast cancer, with doses of trastuzumab reaching up to 100 mg.

Both patients experienced good control of their leptomeningeal disease for 6 to 13.5 months, suggesting that this treatment combination may offer a promising therapeutic option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal administration of trastuzumab with cytarabine and methotrexate in breast cancer patients with leptomeningeal carcinomatosis. Mego, M., Sycova-Mila, Z., Obertova, J., et al.[2015]

The administration of recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) in a 20-year-old man with a peripheral primitive neuroectodermal tumor led to the development of capillary leak syndrome, indicating a potential toxic effect even at low doses.

Despite the intention to accelerate granulocyte reconstitution after chemotherapy, the patient's condition worsened, ultimately resulting in death from invasive aspergillosis, highlighting the risks associated with rh GM-CSF in immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capillary leak syndrome during low dose granulocyte-macrophage colony-stimulating factor (rh GM-CSF) treatment of a patient in a continuous febrile state. Emminger, W., Emminger-Schmidmeier, W., Peters, C., et al.[2019]

In a clinical trial with 21 patients undergoing chemotherapy, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) significantly improved white blood cell and neutrophil counts, reducing the incidence and duration of leukopenia and neutropenia.

While rhGM-CSF effectively supported recovery of white blood cells, it had minimal impact on platelet counts, and the most common side effect was fever, experienced by 43% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical study of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced leukopenia]. Shi, YK., Sun, Y., Su, M.[2013]

Intrathecal trastuzumab, used alongside methotrexate and systemic anti-HER-2 therapy, has shown effectiveness in treating leptomeningeal metastases in a patient with HER-2 positive breast cancer, indicating its potential as a targeted treatment for this challenging condition.

Recent evidence suggests that intrathecal trastuzumab can cross the blood-brain barrier, achieving serum concentrations comparable to systemic therapy, which supports its safety and efficacy in managing brain-related metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab. Kordbacheh, T., Law, WY., Smith, IE.[2017]

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