Protocol Summary

Protocol No.: OCR16897

Sponsor Protocol No.: ACNS1422

Protocol Title: Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma

Principal Investigator: Slayton, William

Objective: This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, 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 reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Description: PRIMARY OBJECTIVES: I. To estimate the progression-free survival (PFS) of children >= 3 years of age with wingless-type MMTV integration site family (WNT)/WNT-driven average-risk medulloblastoma using reduced craniospinal radiotherapy (CSI) (18 Gray [Gy]) with a limited target volume boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no vincristine [vincristine sulfate] during radiotherapy and reduced-dose maintenance chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable. SECONDARY OBJECTIVES: I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation profiling will result in ?real-time? classification of WNT-driven medulloblastoma. II. To use the ALTE07C1 protocol to prospectively evaluate and longitudinally model the cognitive, social, emotional and behavioral functioning of children who are treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced chemotherapy (reduced cisplatin, vincristine and lomustine [CCNU]). TERTIARY OBJECTIVES: I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a ?real-time? predictive classification scheme for the Sonic Hedgehog (SHH), Group 3 and Group 4 medulloblastoma subgroups according to the Heidelberg classifier. OUTLINE: RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAITENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Phase: Phase II

Age Group: Both

Age: 3 Years - 21 Years

Gender: All

Scope: National

Treatment:
RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks.
MAITENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Detailed Eligibility:
INCLUSION CRITERIA:
1. Ages 3 to 21 years old
2. Patients must be newly diagnosed and have a confirmed molecular diagnosis of classical histologic type (non large cell/anaplastic [LC/A]) WNT medulloblastoma from rapid central pathology screening review on APEC14B1 (immunohistochemistry [IHC]/molecular screening [positive nuclear beta (B)-catenin by IHC and positive for catenin beta 1 [CTNNB1] mutation) and confirmation of =3. Patient must have negative lumbar cerebrospinal fluid (CSF) cytology; CSF cytology for staging should be performed preferably no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study
Note: patients with positive CSF cytology obtained prior to 14 days after surgery may have cytology repeated to determine eligibility and final CSF status
4. Patients must have eligibility confirmed by rapid central imaging review on APEC14B1; standard whole brain magnetic resonance imaging (MRI) with and without contrast (gadolinium) and spine MRI with contrast (gadolinium) must be performed at the following time points:
- Pre-operative to include an MRI of the brain with and without contrast (including post-contrast three-dimensional [3D] T1-weighted image [T1WI] and post-contrast fluid-attenuated inversion recovery [FLAIR])
- Pre-operative spinal MRI with gadolinium; post-operative staging spinal MRI may be obtained if pre-operative imaging is not possible or is suboptimal; pre-operative spine imaging is strongly preferred, due to the potential of post-operative sequelae, which could affect metastasis detection
- Post-operative brain MRI within 72 hours of surgery
5. Patients must be enrolled on ALTE07C1 prior to enrollment on ACNS1422
- Patients must be enrolled within 36 days of definitive diagnostic surgery (day 0)
Note: patients must begin treatment within 36 days of definitive surgery
6. Patients must have no previous radiotherapy or chemotherapy other than corticosteroids
7. Peripheral absolute neutrophil count (ANC) >= 1000/uL
8. Platelet count >= 100,000/uL (transfusion independent)
9. Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions)
10. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- 3 to - 6 to - 10 to - 13 to - >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
NOTE: The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
11. Total or direct bilirubin =12. Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =13. Central nervous system function defined as:
- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
- Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment
14. All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
15. All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Applicable Conditions:

  • Brain and Nervous System
  • Pediatric (Childhood) Cancer
  • Participation Institution:

  • UF Gainesville : Ashley Bayne
  • UF Jacksonville : Ashley Bayne
  • Contact:
    Ashley Bayne, RN
    Phone: +1 352-294-8745
    Email: abayne@ufl.edu

    More Information: View study listing on ClinicialTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02724579