Surgery and Combination Chemotherapy in Treating Younger Patients with Non-metastatic Standard-Risk Medulloblastoma

This pilot early phase I trial studies how well surgery and combination chemotherapy work in treating younger patients with a brain tumor called medulloblastoma that has not spread to another place in the body. Drugs used in chemotherapy, such as cisplatin, lomustine, vincristine sulfate, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) after surgery may kill any remaining tumor cells.

Inclusion Criteria

• SCREENING:
• Participants must have classical histology posterior fossa medulloblastoma as determined by institutional neuro-pathological evaluation
• Sufficient pathologic material must be available for central analysis and review
• Tumors will be deemed Wnt positive if, at the time of central analysis, there is: * Monosomy 6 as determined by array comparative genomic hybridization (CGH) * Gene transcript detection by NanoString supporting Wnt+ medulloblastoma * Absence of large-cell, anaplastic histology * Nuclear b-catenin immunohistochemistry (IHC) result will be determined, but not required for the diagnosis
• TREATMENT:
• Absence of residual or disseminated disease as defined by the following criteria: * Minimal residual disease as determined by post-operative imaging preferably performed within 48 hours of resection (and at most 28 days post-surgery), i.e. gross total resection or residual disease of < 1.5 cm^2 on post-operative imaging
• No evidence of metastatic disease in the brain, spine or cerebrospinal fluid (CSF); assessments must include magnetic resonance imaging (MRI) imaging of the brain and spine with and without contrast and a lumbar puncture for CSF cytology
• Diagnostic imaging (pre and post contrast) must be forwarded to Dana-Farber Cancer Institute (DFCI) for central review to confirm eligibility
• Patients must not have had any radiation therapy or chemotherapy for medulloblastoma prior to study enrollment
• Patients must have a Lansky performance status of >= 30 for children =< 10 years of age or a Karnofsky performance status of > 30 for children > 10 years of age
• Hemoglobin greater than 10 gm/dL (can be transfused); hemoglobin < 10 gm/dL due to operative blood loss is permitted
• Absolute neutrophil count >= 1,000/uL
• Platelets >= 100,000/uL (non-transfused)
• Total bilirubin < 1.5 x upper limit normal
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit normal for age
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70 ml/min/1.73 m^2 or normal serum creatinine for patient’s age and gender
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; pregnant or breast-feeding females are not eligible for study enrollment; all females of child-bearing age must have a negative pregnancy test before being enrolled on study; all patients of child-bearing age must practice an effective method of birth control whilst undergoing chemotherapy on study
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cisplatin, lomustine, vincristine (vincristine sulfate) or cyclophosphamide
• Ability to understand and the willingness to sign a written informed consent document for both screening and treatment; signed informed consent must be obtained prior to screening or treatment
• All Institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met
• Eligibility criteria cannot be waived

PRIMARY OBJECTIVES:

I. To determine the occurrence of relapse, progression, or death due to disease in the first two years after study enrollment of newly diagnosed children with non-metastatic, standard risk, Wnt positive medulloblastoma with a chemotherapy-only approach.

SECONDARY OBJECTIVES:

I. To describe overall survival of children with newly diagnosed non-metastatic, standard risk, Wnt positive medulloblastoma who are treated with a maximal surgical resection and chemotherapy-only approach.

II. To determine the pattern of failure in those children with progressive disease.

III. To correlate the frequency of nuclear beta (b)-catenin with other measures of Wnt-positivity.

OUTLINE:

Patients undergo surgery. Within 30 days, patients also receive Regimen A and Regimen B chemotherapy.

REGIMEN A: Patients receive cisplatin intravenously (IV) over 6 hours on day 1, lomustine orally (PO) on day 1, and vincristine sulfate IV on days 1, 8, and 15 during weeks 1 (course 1), 7 (course 2), 17 (course 4), 23 (course 5), 33 (course 7), and 39 (course 8). Courses repeat every 42 days in the absence of disease progression or unacceptable.

REGIMEN B: Patients receive cyclophosphamide IV over 1 hour on days 1 and 2 and vincristine sulfate IV on days 1 and 8 during weeks 13 (course 3), 29 (course 6), and 45 (course 9). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, and 9 months; 1, 1.5, 2, 2.5, and 3 years; and then annually for 2 years.

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Kenneth J. Cohen