This is a platform trial for children, adolescents and young adults with recurrent/progressive ATRT. Following successful screening, participants will enroll on a trial arm based on open slot availability and treatment arm-specific inclusion criteria.

This study will enroll participants with recurrent/progressive ATRT. Following successful screening, participants will enroll on a trial arm based on open slot availability and treatment arm-specific inclusion criteria.

Arm A treatment agents will be gemcitabine and paxalisib.

ATRT is a highly aggressive central nervous system (CNS) tumor that afflicts mostly young children (median age at diagnosis, two years). It is a relatively new entity, formally termed in 1996, and is characterized by genetic alterations in SMARCB1, or more rarely, in SMARCA4. (1,2) Once considered nearly incurable, gradual advances in therapeutic intensity have led to improved survival. However, less than 50% of patients will become long-term survivors despite intensive multi-modal therapies such as multi-agent chemotherapy, radiotherapy, high-dose chemotherapy with autologous stem cell rescue and intrathecal chemotherapy. (3–6) Despite these advances, many patients still suffer recurrent disease with abysmal prognoses. Equally concerning is the long-term morbidity associated with the intensive treatments administered to the youngest ATRT patient population. (7) Therefore, novel approaches for the treatment of ATRT are urgently needed to both improve patient survival and the quality-of-life of survivors. At the time of recurrence, the prognosis for patients with ATRT is dismal. (8,9) There is a paucity of therapeutic options for patients with recurrent ATRT, secondary to the rarity of this disease and the challenges in treating a very aggressive disease in a young, vulnerable patient. Building on the recent advances in our understanding of ATRT biology and leveraging the extensive infrastructure of the Pediatric Neuro-Oncology Consortium (PNOC), the PNOC ATRT working group has designed this study to provide a platform for the translation of novel therapies for recurrent ATRT. Within this clinical trial, we aim to address these key issues by working with laboratories around the world to select the most promising novel therapies and combination strategies. Our platform study will offer phase 2 trials based on evolving preclinical data and clinical experience. When appropriate, there will be a safety lead-in/phase 1 component to investigate the incorporation of novel combinations and/or where the pediatric recommended phase 2 dose (RP2D) has not been determined. This platform design will allow for estimations of efficacy and toxicity for different treatment arms, allowing resource-sharing (regulatory infrastructure), thus shortening the timeline between different therapeutic options. Given the limited treatment options for participants with recurrent ATRT, we aim to offer trial re-enrollment for patients who progress on any interventional.

Primary Objective(s):

• To assess efficacy of each treatment arm based on arm-specific endpoints.
• To evaluate the safety and tolerability of each treatment arm for patients with recurrent/progressive ATRT.

Inclusion Criteria

In addition to the below, investigators are to refer to arm-specific inclusion criteria in the appendix.

• Participants must have pathologic diagnosis of CNS ATRT, with confirmation of SMARCB1 (INI1) loss by IHC and/or biallelic loss of function of SMARCB1 by molecular report. Loss of SMARCA4 as confirmed by IHC or molecular report is also acceptable but requires study chair approval
• Participants must have confirmation of methylation report, co-enrollment on PNOC-030 or sufficient tumor tissue available for methylation-based subgrouping (refer to Section 7.1)
• Participants must have recurrent or progressive ATRT.
• Participants age must be ≥1 and ≤ 39 years at the time of study enrollment. Please refer to arm specific inclusion criterial for potential variations in lower age eligibility limit.
• Prior Therapy: Participants must have fully recovered from the acute effects of prior anti-cancer therapy, and the following wash-out periods need to be observed prior to enrollment:
  • Systemic myelosuppressive therapy: ≥ 21days after the last dose (42 days for nitrosoureas or mitomycin C)
  • Intrathecal/intraventricular chemotherapy: ≥ 7 days after the last dose
  • Small molecule/targeted/biologic agent: ≥ 7 days after the last dose
  • Monoclonal antibodies: ≥ 21 days after the last dose. Other non-myelosuppressive anti-cancer agents: ≥ 3 drug half-lives after the last dose
• CAR-T cell therapy (systemic or intraventricular): > 21 days
• Previous radiotherapy. Participants will be eligible following radiotherapy, if they meet the following criteria:
  • Previous craniospinal or total body radiotherapy: Participants must have received their last fraction ≥ 12 weeks prior to enrollment and have evidence of progressive/recurrent evaluable disease post radiation.
  • Previous focal radiotherapy to target lesions: Participants must have received their last fraction to target lesions ≥ 12 weeks prior to enrollment and have evidence of progressive/recurrent evaluable disease post radiation; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression.
  • Focal therapy to non-target lesions: Participants may have received therapy to non-target lesions as long as the last fraction was ≥ 14 days prior to enrollment. Participants must have at least one non-irradiated lesion that is evaluable for response.
• Performance Score: 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: Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment. Please also refer to arm-specific inclusion criteria for potential variations in steroid limitations.
• Organ Function Requirements
• 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).
• Adequate Renal Function Defined as:
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) based on age and gender
• 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 ≤ 1.5 x ULN
  • ALT ≤ 3 x ULN
  • AST ≤ 3 x ULN
• Adequate Neurologic Function Defined as:
  • Participants with seizure disorder may be enrolled if well controlled. See arm-specific recommendations for potential interactions between anticonvulsant agent(s) with study drug. See Appendix B for a list of recommended non-enzyme inducing anticonvulsants.
• Effect on the developing fetus:
  • Recommendations on the potential effect of interventional agents on the developing human fetus will be specified in each study arm’s details of therapeutic agents. Unless otherwise specified, the effects of study interventions should be considered potentially teratogenic. Thus, 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 treatment and four months after its completion. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, or should a male participant’s partners become pregnant during study participation, they should inform the treating physician immediately.
• A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
• Participants must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.

Please see arm-specific appendix for additional inclusion criteria.

Arm A – Additional Inclusion Criteria

• Subjects must meet all inclusion criteria for the overall study outlined in section 3.5
• Patients must be evaluable per RAPNO criteria for medulloblastoma and other leptomeningeal seeding tumors to be evaluated for the primary endpoint (Warren et al. 2018, also see section 7); patients with evaluable but non-measurable disease, including leptomeningeal disease or positive CSF cytology only are eligible. Patients with recurrent of progressive ATRT who receive surgery only for their disease progression and do not have evaluable disease may be eligible for study treatment but would not be included towards the primary efficacy endpoint (to be discussed with study chairs).
• Subjects must be able to swallow intact capsules
• Adequate Metabolic Function Defined as:
  • Non-fasting glucose ≤ 140 mg/dL without the use of antihyperglycemic agents.
  • If non-fasting glucose > 140 mg/dL a fasting glucose should be done. If fasting glucose ≤ 125 mg/dL without the use of antihyperglycemic agents, participant will meet adequate metabolic function criteria.
  • Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl – can be on lipid lowering medications as needed to achieve.

• Adequate Cardiac Function Defined as:
  • ECG must be obtained to verify QTC. If an abnormal reading is obtained, the ECG should be repeated in triplicate.
  • QTC < 470 msec.

Exclusion Criteria

• Evidence of synchronous tumors or other extra-CNS malignancy
• Participants who are receiving any other investigational agents
• Participants who are currently receiving other anti-cancer agents
• Participants with uncontrolled infection or other uncontrolled systemic illness
• Female participants of childbearing potential who are pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy and throughout study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition as the intended treatment regimen, as detailed in that arm’s treatment description.

Please see arm-specific appendix for additional exclusion criteria, including age limits and the use of concomitant medications.

Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.

Arm A – Additional Exclusion Criteria

In addition to not meeting any of the exclusion criteria of the overall study (section 3.4), participation on arm A will also require that subjects do not meet any of the following:

• Previous exposure to gemcitabine or paxalisib
• Concomitant use of antihyperglycemic agent (e.g. metformin)
• Chronic diarrhea greater than Grade 2

Note: Concomitant use of potent CYP3A4/5 inhibitors or potent CYP3A4/5 inducers is prohibited. This may include enzyme inducing antiepileptic drugs (EIAEDs: see Appendix B). Subjects must have discontinued the use of such drugs  ≥ 72 hours prior to starting therapy.

Funding is provided by Rally Foundation, The Truth 365 Foundation, and the PNOC Foundation.