Ultra-Rapid Profiling and Drug Screening for Treatment Selection in Patients With Relapsed or Recurrent Rare Brain Tumors

Following clinically indicated biopsy or resection, fresh tissue will be submitted for real-time high-throughput drug screening and tumor/paired-normal molecular profiling will be initiated. A specialized tumor board will issue a documented management recommendation within 28 days . Recommendations will integrate successful drug screening, all molecular/pathology data available at the time of review, prior therapy, and clinical context. Later molecular results may prompt an addendum. The treating physician retains responsibility for final treatment decisions.

• Personalized Treatment Recommendation (Other), also known as Individualized treatment plan, Specialized treatment plan: Specialized Treatment Plan of up to four FDA approved drugs based on participant's screening results will be assigned by Rare Brain Tumor specialized tumor board. Recommendations will be provided and to primary physician.

Primary outcomes

• Number of participants for whom a treatment recommendations are completed within 28 calendar days from tissue collection. [Up to 28 calendar days]: Time from tissue collection to generation of tumor board recommendations will be used to determine the feasibility of using the results of real-time high-throughput screening, WGS and RNAseq 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 ultra-rare brain tumors. Participants are expected to receive treatment plan within 28 calendar days.

Secondary outcomes

• Proportion of participants with Adverse events [Up to 1 year]: Proportion of participants with grade 3 or higher toxicities as per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Serious adverse events (SAEs), unexpected adverse reactions, and adverse events of special interest. Adverse events will be summarized by maximum grade and relationship to the drugs recommended by the tumor board.
• The preliminary clinical activity of tumor board-recommended treatment [Up to 2 years]: Best overall radiographic response (CR , PR, SD, PD) as per RAPNO criteria in patients receiving tumor board-recommended treatment.

Sex: All, ages: any to 45 Years

Inclusion Criteria:

1. Patients must have a relapse or recurrence of one of the following rare brain tumors:

   * CNS sarcoma (e.g. EWS, CIC, DICER1 altered)
   * BCOR altered tumors (e.g. BCOR ITD; BCOR, BCORL1, EP300, fused)
   * Mesenchymal tumors (e.g. FET::CREB altered tumors)
   * MN1::PATZ1 fused tumors
   * PLAG- altered tumors
   * Astroblastomas/MN-1 altered (e.g. EWSR2BEND2 altered)
   * Unclassifiable tumors
   * Other rare brain tumors: (e.g. recently described, poorly characterized, and/or ambiguous entities)
2. Participant must be a candidate for surgical resection or biopsy.

   • Participants must have surgically accessible disease.
3. Prior therapy

   • The participant must have a relapsed or recurrent rare brain tumor following at least one prior therapy for initial diagnosis or previous recurrence prior to study registration:
   * Surgery followed by observation.
   * Multi-modality therapy: surgery, radiation, and/or chemotherapy
4. Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

   * Biologic agent: Participant must have recovered from any toxicity potentially related to the agent.
   * Last radiation at least 7 days prior to therapy start
5. Karnofsky 50 for participants > 16 years of age and Lansky 50 for participants <16 years of age
6. Corticosteroids: Subjects who are receiving dexamethasone or equivalent must be on a stable or decreasing dose for at least 1 week prior to therapy start.
7. 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.
8. Adequate neurologic function defined as:

   • Participants with seizure disorders may be enrolled if seizures are well controlled. Participants on non-enzyme inducing anticonvulsants may be excluded pending interaction(s) with study drug.
9. A legal parent or guardian must be able to understand and agree to sign a written informed consent and assent document, as appropriate.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
2. Women of childbearing potential must not be pregnant or breast-feeding. A negative serum or urine pregnancy test is required prior to start of therapy.

• Adriana Fonseca, MD, Principal investigator, Children's National Research Institute