Screening Criteria:
1. Tumor
a. Patient must have a diagnosis of medulloblastoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
2. Adequate Pre-trial Tumor Tissue a. Patient must have adequate pre-trial tumor material available for subgrouping.
3. Prior Therapy
a. Patient must have received and failed standard therapy for medulloblastoma.
4. Screening Consent a. Participant is willing to sign a screening consent. The screening consent is for subgroup testing for all participants and for bone age determination in subjects ≤ 18 years. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.
Inclusion Criteria:
1. Phase I Skeletally-immature:
1. Patient must be skeletally-immature at the time of study enrollment, defined as females with a bone age \< 14 years and males with a bone age \< 16 years.
2. Patients who participate in the expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions (Section 12.2.2). Patients with measurable extraneural disease only are also eligible.
3. Patient must be ≥ 3 and ≤ 18 years of age at the time of enrollment.
4. Patients enrolled on the Phase I study must have a BSA as noted below:
Dose Level 0 (400 mg/m2 BID): Minimum - 0.84m2; Maximum - 2.25m2 Dose Level 1 (600 mg/m2 BID): Minimum - 0.60m2; Maximum - 2.00m2 Dose Level 2 (800 mg/m2 BID): Minimum - 0.63m2; Maximum - 2.00m2
2. Phase II Skeletally-mature:
a. Patients must be skeletally-mature, defined as females with a bone age ≥14 years and males with a bone age ≥ 16 years OR have a chronological age \>18 years.
b. Patients must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions. Patients with measurable extraneural disease only are also eligible.
3. Surgical Study:
1. Surgical resection must be clinically indicated.
2. Must be ≥3 years at time of enrollment.
3. Must be amenable to receiving CX-4945 for 5-7 days prior to surgery
4. All Phases:
1. Patient must have a diagnosis of SHH medulloblastoma that is recurrent or progressive, confirmed histologically and by CLIA-certified methylation-based subgroup testing at Cincinnati Children's Hospital Medical Center (CCHMC), Memorial Sloan Kettering Cancer Center (MSKCC), National Cancer Institute (NCI), or Nationwide Children's Hospital (NCH). Results from prior testing at these designated sites using the same approaches described for this study will be accepted.
2. Prior Therapy
• Must have received prior therapy which included radiation therapy and recovered from acute treatment related toxicities.
• Must have received the last dose of myelosuppressive therapy at least 21 days prior to enrollment and at least 42 days if nitrosourea.
• Must have received the last dose of another investigational or biologic agent ≥7 days prior. For agents known to have adverse events occurring beyond 7 days, the period must be extended to accommodate the longer interval. For monoclonal antibodies with prolonged half-lives, at least 3 half-lives must have elapsed.
• Must have received last fraction of craniospinal or total body irradiation or radiation to ≥50% of the pelvis \>12 weeks prior to enrollment. Last fraction of focal irradiation must be \>4 weeks prior to enrollment.
• Must be ≥ 24 weeks since allogeneic stem cell transplant with no evidence of acute graft vs. host disease.
• Must be ≥12 weeks since autologous stem cell transplant.
3. Must be off all colony-forming growth factors at least 1 week prior to enrollment. Must be off 2 weeks if the subject received a long-acting formulation.
4. If neurological deficits are present, must have been stable for a minimum of 1 week prior to enrollment.
• Patients with seizure disorders may be enrolled if seizures are well controlled.
5. Must have a Karnofsky/Lansky Performance status ≥50%
6. Must have adequate organ and marrow function
7. Subjects receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment.
8. Female patients of childbearing potential must have a negative pregnancy test.
9. Patients of child-bearing or child fathering potential must be willing to use medically acceptable form of birth control while treated on this study and for 3 months after drug cessation.
10. Parent or legal guardian must be able to understand and willing to sign the written informed consent.
C. Exclusion Criteria:
1\. All Phases
1. Nursing mothers due to an unknown but potential risk for adverse events in nursing infants.
2. Patients with a history of any other malignancy with the exception of patients with a secondary brain tumor if the patient's prior malignancy has been in remission for at least 5 years from the end of treatment.
3. Patients with any of the following gastrointestinal disorders - difficulty swallowing or active malabsorption, uncontrolled diarrhea, gastritis, ulcerative colitis, Crohn's disease or hemorrhagic coloproctitis, history of gastric or small bowel surgery involving any extent of gastric or small bowel resection.
4. Patients with any clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate therapy, put them at additional risk for toxicity or interfere with the study procedures or results.
5. Corrected QT (QTc) interval is \>480ms
6. Patients who are receiving other anti-cancer or investigational drug therapy
7. Patients who are on warfarin or statins.
