Sargramostim and Trastuzumab in Treating Younger Patients with Recurrent Ependymoma
This phase I clinical trial studies the side effects and best dose of trastuzumab when given together with sargramostim in treating younger patients with ependymoma that have returned after a period of improvement. Monoclonal antibodies, such as trastuzumab, may block tumor growth in different ways by targeting certain cells. Colony-stimulating factors, such as sargramostim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving trastuzumab with sargramostim may work better in treating younger patients with recurrent ependymoma.
- Patients must be diagnosed with relapse of previously histologically confirmed PFEPN
- Magnetic resonance (MR) imaging of the brain (performed within 14 days of enrollment) must demonstrates no evidence of diffuse leptomeningeal spread beyond the primary relapse site in posterior fossa and no obstruction of cerebrospinal fluid flow (CSF) * Absence of CSF obstruction may be demonstrated by CSF flow study by MRI or stable ventricle size as compared to pre-relapse imaging
- MR imaging of the total spine (performed within 14 days of enrollment) demonstrates no evidence of spinal nodular metastatic disease that obstructs CSF flow * Surgical removal of spinal metastatic disease is permitted to achieve lack of nodular metastatic spinal disease if clinically indicated per treating neuro-oncologist/neurosurgeon and if lumbar punctures will not be contraindicated in the future
- Patients must have clinical indication for standard-of-care surgical resection of relapsed PFEPN tumor for enrollment in Stratum 1
- Eastern Cooperative Oncology Group (ECOG) performance status scores of 0, 1, or 2
- Karnofsky score of >= 50 for patients > 16 years of age; or
- Lansky score of >= 50 for patients =< 16 years of age
- All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * Age: maximum serum creatinine (mg/dL) * 1 month to < 6 months: 0.4 mg/dL (male and female) * 6 months to < 1 year: 0.5 mg/dL (male and female) * 1 to < 2 years: 0.6 mg/dL (male and female) * 2 to < 6 years: 0.8 mg/dL (male and female) * 6 to < 10 years: 1 mg/dL (male and female) * 10 to < 13 years: 1.2 mg/dL (male and female) * 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x upper limit of normal (ULN) for age
- Peripheral absolute neutrophil count (ANC) >= 1,000/uL
- Platelet count >= 100,000/uL (transfusion independent)
- Shortening fraction > 28% by echocardiogram or
- Ejection fraction > 50% by echocardiogram or radionuclide study
- Patients with a diagnosis of spinal cord ependymoma, myxopapillary ependymoma, subependymoma, ependymoblastoma, supratentorial ependymoma, or mixed glioma are NOT eligible for either Stratum
- Patients with evidence of nodular metastatic spinal disease by magnetic resonance imaging (MRI) are NOT eligible for Stratum 1 but may be eligible for STRATUM 2 if CSF flow study reveals no obstruction of flow and the patient is deemed safe for lumbar puncture by the medical team
- Patients with clinical contraindication against lumbar puncture or Ommaya placement are NOT eligible for either Stratum unless the patient has an ommaya reservoir
- Patients with non-programmable intact ventriculoperitoneal shunts are NOT eligible for either Stratum * Patients who have programmable ventriculoperitoneal (VP) shunts must be able to tolerate increased pressure setting to stop CSF flow diversion for 12-24 hour periods without symptoms of hydrocephalus
- At least 28 days must have elapsed (at time of starting protocol therapy) since completion of focal radiation therapy for current recurrence for Stratum 2; patients who have already undergone radiation therapy for current recurrence are NOT eligible for Stratum 1
- At least 21 days must have elapsed after the last dose of myelosuppressive chemotherapy; patients who have been treated with chemotherapy at time of recurrence are NOT eligible for either Stratum
- Adequate washout period based on half-life (excluding trastuzumab)
- Must have fully healed from any surgical procedure to be safe for lumbar puncture according to treating neurosurgeon and at least 14 days should have elapsed since the surgical procedure
- Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are NOT eligible for either Stratum
- Patients receiving systemic corticosteroids are NOT eligible for either Stratum
- Patients who are currently receiving another investigational drug are NOT eligible for either Stratum
- Patients who are currently receiving other anti-cancer/devices agents are NOT eligible for either Stratum
- Patients who are currently receiving medications that suppress immune responses are not eligible
- Pregnant or breast-feeding women are NOT eligible; pregnancy tests must be obtained in females who are post-menarchal
- Women of childbearing potential and male participants with partners of childbearing potential must agree to use a “highly effective,” non-hormonal form of contraception (including abstinence) or two “effective” forms of non-hormonal contraception by the patient and/or partner; contraception must continue for the duration of study treatment and for at least seven (7) months after the last dose of study treatment
- Patients who have an uncontrolled serious infection are NOT eligible for either Stratum
- Patients who have previously received solid organ or allogeneic stem cell transplantation are NOT eligible for either Stratum
- Patients who have a history of significant cardiac disease, cardiac disease risk factors or uncontrolled arrhythmias are NOT eligible for either Stratum
Locations & Contacts
Contact: Kathleen M. O'Toole Dorris
Trial Objectives and Outline
I. To detect presence of trastuzumab by mass spectroscopy in relapsed posterior fossa ependymoma (PFEPN) tumor specimen pre-treated with a single dose of intrathecal (IT) trastuzumab. (Stratum 1)
II. To evaluate toxicity of IT trastuzumab in combination with subcutaneous (subQ) granulocyte-macrophage colony stimulating factor (GM-CSF) (sargramostim) in children with relapsed PFEPN. (Stratum 2)
I. To evaluate toxicity and feasibility of preoperative IT trastuzumab in combination with subQ GM-CSF in children with relapsed PFEPN.
II. To determine if subQ GM-CSF and IT trastuzumab alter the microglia/macrophage (M/M) activity/tumor infiltration in children with relapsed PFEPN compared to the infiltration at their initial surgeries and to historical controls at first relapse.
III. To determine if subQ GM-CSF and IT trastuzumab alter the T-cell activity/tumor infiltration in children with relapsed PFEPN compared to the infiltration at their initial surgeries and to historical controls at first relapse.
IV. To evaluate for any association of human epidermal growth factor receptor 2 (HER-2) PFEPN tumor expression with change in M/M and/or T-cell activity/tumor infiltration in PFEPN tumor specimen treated with subQ GM-CSF and IT trastuzumab.
V. To compare progression-free survival (PFS) of children with relapsed PFEPN treated with subQ GMCSF and IT trastuzumab following surgical resection/radiation therapy to PFS of historical control group of relapsed PFEPN patients treated with standard of care surgical resection/radiation therapy only.
VI. To evaluate cerebrospinal fluid (CSF) pharmacokinetics of IT trastuzumab.
VII. To evaluate changes in CSF and serum complement levels and white blood cell numbers and types.
OUTLINE: This is a dose-escalation study of trastuzumab. Patients are assigned to 1 of 2 strata.
STRATUM I: Patients receive sargramostim subcutaneously (SC) once daily (QD) for 5 days. Patients then receive trastuzumab IT. Beginning 2-7 days after trastuzumab treatment, patients then undergo standard of care surgical resection of tumor.
STRATUM II: Patients receive sargramostim SC QD on days 1-3, 8-10, 15-17, and 22-24 of course 1 and days 1-3 and 15-17 of subsequent courses. Beginning 3 days after each dose of sargramostim, patients receive trastuzumab IT. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients who have measurable disease and demonstrate stable tumor size after 3 courses, may continue therapy and receive sargramostim SC QD for 3 days during course 4 and trastuzumab IT for up to 12 courses.
After completion of study, all patients are followed up for 30 days and patients enrolled in Stratum II are followed up for 5 years.
Trial Phase & Type
Children's Hospital Colorado
Kathleen M. O'Toole Dorris
Secondary IDs NCI-2016-00656
Clinicaltrials.gov ID NCT02774421