This study will enroll children and young adults (age 12 months to 39 years of age) with relapsed medulloblastoma.

The current study will use a new treatment approach based on the molecular characteristics of each participant’s tumor. The study will test the feasibility in the pilot phase of performing real-time drug screening on tissue taken during surgery in patients with relapsed medulloblastoma, and of having a specialized tumor board assign a treatment plan based on the results of this screening and genomic sequencing.

In the efficacy phase, the study will evaluate the efficacy of the tumor board’s recommended treatment plan, guided by real-time drug screening, in patients with relapsed medulloblastoma and ependymoma.

The aim of this trial is to allow every child and young adult with relapsed medulloblastoma and ependymoma to receive the most effective and least toxic therapies currently available, and will pave the way for improved understanding and treatment of these tumors in the future. Moreover, if successful, it could serve as a paradigm for personalized medicine programs for other types of cancer.

Pilot Phase:

To determine the feasibility of using the results of real-time in vitro drug screening, whole exome sequencing, and RNA sequencing of participant-derived specimens to guide treatment recommendations by a specialized tumor board in a clinically actionable timeframe for children and young adults with recurrent medulloblastoma.

Efficacy Phase:

To determine the progression-free survival (PFS) in children and young adults with relapsed medulloblastoma and ependymoma who received the specialized tumor board recommendation and compare to historical cohorts.

Subjects must have baseline evaluations performed prior to the start of protocol treatment and must meet all inclusion and none of the exclusion criteria. In addition, the patient and/or their legal guardian must be thoroughly informed about all aspects of the study, including the study visit schedule, required evaluations, and all regulatory requirements. The written informed consent must be obtained from the patient or their legal guardian prior to enrollment. The following criteria apply to all patients enrolled in the study unless otherwise specified.

The Pilot Phase has reached full accrual. For details on the inclusion criteria, please refer to version 1.1.

The inclusion criteria for the efficacy phase are as follows:

• Participants must have recurrent medulloblastoma or recurrent ependymoma previously histologically confirmed. Participants must be experiencing their first or second relapse to be eligible.
• Participants must have the surgically accessible disease.
• Prior Therapy:

• • The participant must have received at least one prior therapy at the time of initial diagnosis.
  • Relapsed medulloblastoma or relapsed ependymoma are eligible.
  • Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and would be eligible for surgical resection per institutional guidelines.
    • Patients must have received their last chemotherapy or biologic agent at least 7 days prior to registration.
    • Monoclonal antibody treatment: > 21 days prior to registration
    • Bevacizumab participants must have received the last dose > 21 days prior to study registration.
• Participant must be a candidate for surgical resection or biopsy with anticipated ability to obtain the minimum tissue requirements for study as defined in Section 10.
• Radiation:
• Participants must have:
  • Had their last fraction of local irradiation to primary tumor ≥ 12 weeks prior to registration.
  • Had their last fraction of craniospinal irradiation or total body irradiation ≥ 12 weeks prior to registration.
  • At least 14 days after local palliative radiation (small-port).
• Age ≥12 months to ≤ 39 years of age
• Karnofsky ≥ 50 for participants > 16 years of age and Lansky ≥ 50 for participants ≤ 16 years of age (See Appendix A). Participants 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.
• Corticosteroids: Subjects who are receiving dexamethasone or equivalent must be on a stable or decreasing dose for at least 1 week prior to registration.
• Organ Function Requirements (within 7 days prior to study registration)
• Adequate Bone Marrow Function Defined as:
  • Peripheral absolute neutrophil count (ANC) >750/mm³
  • Platelet count > 75,000/mm³ (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
  • Hemoglobin ≥ 8 g/dl
• Adequate Renal Function Defined as:
  • Creatinine clearance or radioisotope GFR > 70mL/min/1.73 m² or
  • A serum creatinine based on age/sex as follows:

The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.¹

• Adequate Liver Function Defined as:
  • Total bilirubin < 1.5 x upper limit of normal (ULN) for age; in presence of Gilbert’s syndrome, total bilirubin < 3 x ULN or direct bilirubin <5 x ULN
  • ALT < 3 x ULN
  • AST < 3 x ULN.
• The effects of the agents used in this study on the developing human fetus are unknown.  For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of therapy administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Adequate neurologic function is defined as:
  • Participants with seizure disorder may be enrolled if seizures are well controlled.
  • Participants on non-enzyme-inducing anticonvulsants may be excluded pending interaction(s) with the study drug. See Appendix B for a list of recommended non-enzyme-inducing anticonvulsants.
• Patients must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.
• A legal parent/guardian or participant must be able to understand and willing to sign a written informed consent and assent document, as appropriate.

Exclusion Criteria

• Participants who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participants who are receiving any other investigational agents.
• Participants must be at least 7 days from the completion of therapy with a biologic or small molecule agent. For any agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants should also be discussed with the study chairs.
• Participants who are currently taking any anti-cancer direct therapy. Steroids are not considered anti-cancer therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
• Women of childbearing potential must not be pregnant or breastfeeding. A negative serum or urine pregnancy test is required prior to the start of therapy.
• Participants must not receive any tumor-directed therapy after enrollment, except for surgical resection/ biopsy

Support is provided by the Washington University, St. Louis, St. Baldrick’s Foundation, and the PNOC Foundation.