Inclusion Criteria for patients with recurrent /progressive medulloblastoma (stratum I)
1. Age: Patients must be ≥3 and ≤25 years of age at the time of study enrollment. 2. Diagnosis: Recurrent medulloblastoma: Patients must have a diagnosis of
medulloblastoma that is recurrent, progressive or refractory. All patients must have
histological verification of a medulloblastoma, at original diagnosis or relapse.
- - Patients must have adequate pretrial tumor material available.
- - Patients must have measurable disease defined as a lesion that can be measured in
two perpendicular diameters on MRI.
3. Metastatic Disease: Patients with M+ disease are eligible.
4. Performance Status:
Karnofsky ≥ 50% for patients >16 years of age or Lansky ≥ 50 for patients ≤ 16 years
of age. Patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score. See Appendix
- I.
Adequate neurologic function defined as:
- Patients with neurological deficits should have deficits that are stable for a
minimum of 2 weeks prior to enrollment.
- - Patients with current seizure disorders may be enrolled if seizures are
well-controlled on antiepileptic therapies.
5. Prior Therapy:
1. Radiotherapy: prior radiotherapy requirements Patients must have received prior
disease-directed therapy including radiotherapy for their initial diagnosis of
medulloblastoma unless patients are less than 4 years of age at the time of
enrollment.
For those less than 4 years of age at the time of enrollment, prior disease
directed therapy does not have to include prior radiotherapy.
Patients must have had their last fraction of:
- - Craniospinal irradiation, total body irradiation or radiation to ≥ 50% of
pelvis > 3 months prior to enrollment.
- - Focal irradiation > 4 weeks prior to enrollment.
2. Myelosuppressive anticancer therapy: Patients must have received their last dose
of myelosuppressive anticancer therapy at least 21 days prior to enrollment. 3. Immunotherapy: Patients must have received their last dose of any immunotherapy
agents at least 30 days prior to enrollment. 4. Non-myelosuppressive anticancer agents: Patients must have received their last
dose of non-myelosuppressive anticancer agents at least 7 days prior to study
enrollment.
5. Antibodies: Patients must have received their last dose of any antibodies at
least 21 days prior to enrollment.
6. Hematopoietic growth factors: Patients must have received their last dose of
hematopoietic growth factors at least 14 days prior to enrollment for a
long-acting growth factor (e.g. pegfilgrastim) or 7 days prior to enrollment for
short-acting growth factor.
7. Autologous stem cell infusion: At least 90 days must have elapsed after an
autologous stem cell infusion. 6. Organ Function Requirements:
1. Adequate bone marrow function defined as:
- - ANC (Absolute neutrophil count) ≥ 1000/µl.
(may be supported)
2. Adequate Renal Function defined as: Creatinine clearance or radioisotope GFR ≥
70ml/min/1.73 m2 or A serum creatinine based on age/gender as follows:
Age: Maximum Serum Creatinine (mg/dL)
- - 2 to < 6 years: 0.8 (Male) 0.8 (Female)
- 6 to < 10 years: 1 (Male) 1 (Female)
- 10 to < 13 years: 1.2 (Male) 1.2 (Female)
- 13 to < 16 years: 1.5 (Male) 1.4 (Female)
- ≥ 16 years: 1.7 (Male) 1.4 (Female)
3.
Adequate Liver Function Defined as.
- - Total bilirubin ≤1.5 times institutional ULN.
- - AST(SGOT) ≤3 × institutional upper limit of normal.
- - ALT(SGPT) ≤3 × institutional upper limit of normal.
4. Patients of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while
being treated on this study.
5. Signed informed consent according to institutional guidelines must be obtained
prior to registration.
Inclusion Criteria for Patients with Newly-Diagnosed High-Grade Gliomas (HGG) (stratum II)
and Newly-Diagnosed (DIPG) (stratum III)
1. Age: Patients must be ≥3 and ≤25 years of age at the time of study enrollment. 2. Diagnosis. 1. Stratum II: patients must have histologically confirmed, newly-diagnosed HGG
(such as anaplastic astrocytoma, glioblastoma, H3K27M mutant diffuse midline
glioma, etc.).
- - Patients with a newly-diagnosed HGG must enroll within 6 weeks of their
final dose of standard radiation therapy with or without chemotherapy.
- - Patients with primary spinal cord tumors are eligible.
2. Stratum III: Patients with a newly-diagnosed DIPG:
- - Patients with a radiographically typical DIPG, defined as a tumor with a
pontine epicenter and diffuse involvement of more than 2/3 of the pons, are
eligible without histologic confirmation.
- - Patients with brainstem lesions that do not meet these radiographic criteria
will be eligible if there is histologic confirmation of an infiltrating
astrocytoma WHO grades II-IV.
3. Metastatic Disease: Patients with M+ disease are eligible.
4. Performance Status:
Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years
of age (See Appendix I). Patients who are unable to walk because of paralysis, but who
are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score.
Adequate neurologic function defined as:
• Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to enrollment.
5. Prior Therapy requirements: Patients must have received no prior therapy other than
surgery, radiation, chemotherapy during radiotherapy and/or steroids (dexamethasone
with goal to wean dexamethasone throughout protocol therapy).
Patients with a newly diagnosed high-grade glioma or DIPG must enroll within 6 weeks
of their final dose of standard of care radiation therapy with or without
chemotherapy.
1. Patients with HGG or DIPG are permitted, but not required, to have received
chemotherapy during radiation. Bevacizumab is permitted prior to enrollment in
patients with DIPG or HGG. Patients must have received their last dose of
bevacizumab at least 14 days prior to enrollment.
2. For HGG patients, Patients must have received radiotherapy at a standard dose of
54 Gy in 1.8 Gy fractions for approximately 6 weeks with an acceptable variance
of 10%. Radiation therapy must have begun no later than 30 days after the date
definitive surgery.
3. Patients must enroll within 42 days of their final dose of standard radiation
therapy. 4. For patients with DIPG, Patients must have received radiotherapy at a standard
dose of radiotherapy of 54 Gy in 1.8 Gy daily fractions for approximately 6 weeks
with an acceptable variance rate of 10%. Radiation therapy must have begun no
later than 30 days after the date of radiographic diagnosis or biopsy. 5. For patients with spinal cord HGG: Patients must have received radiotherapy at a
standard dose of 54 Gy in 1.8 Gy fractions for approximately 6-7 weeks with an
acceptable variance of 10%
6. For patients with metastatic disease: Patients may have received standard dose
craniospinal therapy. 6. Organ Function Requirements:
1. Adequate bone marrow function defined as.
- - ANC (Absolute neutrophil count) ≥ 1000/µl.
(may be supported)
2. Adequate Renal Function defined as: Creatinine clearance or radioisotope GFR ≥
70ml/min/1.73 m2 or A serum creatinine based on age/gender as follows:
Age: Maximum Serum Creatinine (mg/dL)
- - 2 to < 6 years: 0.8 (Male) 0.8 (Female)
- 6 to < 10 years: 1 (Male) 1 (Female)
- 10 to < 13 years: 1.2 (Male) 1.2 (Female)
- 13 to < 16 years: 1.5 (Male) 1.4 (Female)
- ≥ 16 years: 1.7 (Male) 1.4 (Female)
3.
Adequate Liver Function Defined as:
- - Total bilirubin ≤1.5 times institutional ULN.
- - AST(SGOT) ≤3 × institutional upper limit of normal.
- - ALT(SGPT) ≤3 × institutional upper limit of normal.
4. Patients of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while
being treated on this study.
5. Signed informed consent according to institutional guidelines must be obtained
prior to registration.
Exclusion Criteria for all strata:
1. Pregnancy or Breast-Feeding:
1. Pregnant or breast-feeding women will not be entered on this study due to known
or unknown risks of fetal and teratogenic adverse events as seen in animal/human
studies. Pregnancy tests must be obtained in girls who are post-monarchal. Males
or females of reproductive potential may not participate unless they have agreed
to use an effective contraceptive method.
2. Pregnancy Prevention Patients of childbearing or child fathering potential must
be willing to use a medically acceptable form of birth control, which includes
abstinence, while being treated on this study and for 3 months after drug
cessation.
2. Study Specific:
1. Active infection requiring treatment. 2. Patients with malignancy related to HIV or solid organ transplant: known history
of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible.
Viral testing is not required unless clinically indicated in patients without a
known history. 3. Known immunosuppressive disease. 4. Patients with active renal, cardiac (congestive cardiac failure, myocardial
infarction, myocarditis), or moderate to severe pulmonary problems generally
defined by need for medical intervention (e.g., oxygen, medications) and/or
limiting activities of daily living (generally CTCAE Grade 2 or higher) or
shortness of breath with limited exertion are not eligible. Pulmonary conditions
include (but are not limited to) COPD, asthma, and hemi-pneumectomy. 5. Patients receiving concomitant immunosuppressive agents for medical conditions;
inhaled corticosteroids for asthma are allowed.
6. Patients receiving concomitant tumor-directed therapy. 7. Patients receiving any other investigational drug therapy.
8. Patients on dexamethasone > 0.1 mg/Kg/day up to maximum dose of 4 mg/day or
equivalent.
9. Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ
dysfunction).
10. Patients with inability to return for follow-up visits or obtain follow-up
studies required to assess toxicity to therapy. 11. Patients at high risk for imminent neurologic decline due to extensive bulk
disease, midline shift, or herniation on MRI. These patients should be discussed
with the study chairs.
