Tazemetostat+Nivo/Ipi in INI1-Neg/SMARCA4-Def Tumors

Inclusion Criteria:

• Diagnosis: Histologically confirmed tumors at diagnosis or at relapse (as applicable):
• Stratum A
• Atypical Teratoid Rhabdoid Tumor (ATRT)
• Other INI1- or SMARCA4-deficient primary CNS malignant tumors (with PI approval)
• Stratum B
• Malignant rhabdoid tumor (MRT)
• Rhabdoid tumor of the kidney (RTK)
• Epithelioid sarcoma
• Chordoma (poorly differentiated or de-differentiated)
• Other INI1- or SMARCA4-deficient malignant tumors (with PI approval)
• All subjects must have had tumor assessment at original diagnosis or relapse showingeither of the following: Loss of INI1 confirmed by immunohistochemistry (IHC) ORmolecular confirmation of tumor bi-allelic SMARCB1 (INI1) loss or mutation when INI1IHC is equivocal or unavailable
• Loss of SMARCA4 confirmed by IHC OR molecular confirmation of tumor SMARCA4 loss ormutation (with PI approval) Reports confirming these findings (including tumorsequencing if available) will be reviewed by the Sponsor-Investigator, PI or designeefor approval of eligibility prior to enrollment.
• Treatment status: All subjects must have completed planned upfront treatment for theirdisease for strata A1 or B1. Subjects need not have relapsed or have refractorydisease to be eligible for this protocol.
• Disease Status: For subjects under consideration for strata A1 or B1, subjects musthave evaluable disease Note: Leptomeningeal lesions/disease are allowed as evaluabledisease.
• For relapsed/refractory subjects under consideration for strata A2 or B2, subjectsmust have measurable disease as defined by RANO for stratum A2 or RECIST v1.1 forstratum B2. See Section 11.
• Note: the following do not qualify as measurable disease:
• malignant fluid collections (e.g., ascites, pleural effusions)
• bone marrow infiltration
• lesions only detected by nuclear medicine studies (e.g., bone, gallium or PETscans)
• elevated tumor markers in plasma or CSF
• previously irradiated lesions that have not demonstrated clear progression post-radiation therapy
• leptomeningeal lesions that do not meet the measurement requirements for RANO.
• For subjects under consideration for strata A3 or B3, subjects must have no evidenceof evaluable or measurable disease by exam or imaging.
• Pre-recurrent subjects to be enrolled in strata A1, B1, A3, or B3 must be enrolledwithin 8 weeks of completion of upfront therapy
• Age ≥ 6 months and ≤ 21years of age
• Karnofsky performance status ≥ 50% for subjects ≥16 years of age and Lanskyperformance status ≥ 50% for subjects <16 years of age (see Appendix A). Note:Neurologic deficits in subjects with CNS tumors must have been stable for at least 7days prior to study enrollment. Subjects who are unable to walk because of paralysis,but who are up in a wheelchair, will be considered ambulatory for the purpose ofassessing the performance score.
• Life expectancy of greater than 2 months.
• Prior Therapy: Subjects must have fully recovered from the acute toxic effects of allprior anti-cancer therapy. Subjects must meet the following minimum washout periodsprior to first day of study treatment:
• Myelosuppressive chemotherapy: ≥21 days after the last dose of myelosuppressivechemotherapy.
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated withreduced platelet or ANC counts): ≥ 7 days after the last dose of the agent.
• Small molecule biologic therapy: ≥7 days following the last dose of anon-monoclonal biologic agent.
• Monoclonal antibody: ≥21 days after the last dose, and toxicity related to priorantibody therapy must be recovered to Grade ≤1.
• Corticosteroids: If used to modify immune adverse events related to priortherapy, ≥ 14 days must have elapsed since last dose of corticosteroid. CNSsubjects receiving corticosteroids for neurologic symptom relief must be atstable or decreasing doses for at least 7 days prior to the first day of studytreatment. For all patients, corticosteroid doses of up to 0.12 mg/kg/dayprednisone equivalent may be approved after consultation with the PrincipalInvestigator. Treatment with topical, inhaled or ophthalmic corticosteroid isacceptable.
• Radiotherapy
• ≥14 days after focal XRT (small port)
• ≥90 days must have elapsed after prior TBI, craniospinal XRT or if >50%irradiation of pelvis
• ≥42 days must have elapsed if other substantial bone marrow irradiation
• ≥42 days must have passed since last radionuclide therapy (e.g. samarium orradium).
• Myeloid growth factors: ≥14 days following the last dose of long-acting growthfactor (e.g. Neulasta) or 7 days following short-acting growth factor.
• Autologous stem cell therapy, Autologous T Cell, or other CellularTherapy: ≥ 42days must have elapsed after any cellular therapy infusion. Prior allogeneic stemcell transplant is not allowable.
• Prior EZH2 inhibitor therapy: Subjects with relapsed/refractory disease (strataA2 and B2) may have received prior single agent tazemetostat or other EZH2inhibitors for up to 1 year, but subjects without prior progression/relapse mayNOT have received any prior EZH2 inhibitors.
• Subjects must have adequate organ function as defined below:
• Bone Marrow Function
• Absolute neutrophil count ≥1,000/uL
• Hemoglobin ≥8 g/dL (may receive RBC transfusions)
• Platelets: For non-relapsed subjects (Strata A1, A3, B1 or B3): >75K/uL, Forsubjects with relapsed disease (Strata A2 or B2): >50K/uL, For all subjects: mustbe platelet transfusion independent, defined as not receiving a platelettransfusion for at least 7 days prior to CBC documenting eligibility.
• Hepatic Function
• Total bilirubin ≤ 1.5 x upper limit of normal for age.
• ALT (SGPT) and AST (SGOT) ≤ 3 x upper limit of normal (for the purpose of thisstudy, the ULN for ALT is 45 U/L)
• Renal Function: A serum creatinine based on age/gender as follows: Maximum SerumCreatinine (mg/dL)
• Male: 6 months to 1 year-0.5,1 to < 2 years-0.6, 2 to < 6 years-0.8, 6 to < 10years-1, 10 to < 13 years-1.2,13 to < 16 years- 1.5, ≥ 16 years 1.7
• Female: 6 months to 1 year-0.5,1 to < 2 years-0.6, 2 to < 6 years-0.8, 6 to < 10years-1, 10 to < 13 years-1.2,13 to < 16 years- 1.4, ≥ 16 years1.4 OR
• Creatinine clearance ≥ 70 mL/min/1.73 m2 for subjects with creatinine levelsabove institutional normal.
• Adequate Pulmonary Function defined as: No evidence of dyspnea at rest, no exerciseintolerance due to pulmonary insufficient and a pulse oximetry > 92% while breathingroom air. -- Adequate Neurologic Function defined as: Subjects with seizure disorder may beenrolled if on anticonvulsants and well controlled. Nervous system disorders (CTCAEv5.0) resulting from prior therapy must be ≤ Grade 2, with the exception of decreasedtendon reflex (DTR). Any grade of DTR is eligible.
• Negative B-HCG pregnancy test (urine or serum) in females of childbearing potential.
• Women of childbearing potential (WOCBP) receiving the TAZNI combination agree toadhere to contraception for a period of 5 months after the last dose of eithertazemetostat, nivolumab, or ipilimumab
• Men receiving the TAZNI combination and who are sexually active with WOCBP will agreeto adhere to barrier contraception for a period of 3 months after the last dose ofeither tazemetostat, nivolumab or ipilimumab.
• Ability to understand and/or the willingness of the subject (or parent or legallyauthorized representative, if minor) to provide informed consent, documented using aninstitutionally approved informed consent procedure.

Exclusion Criteria:

• Concomitant Medications
• Subjects who are receiving any other investigational agents or other anti-canceragents are not eligible.
• CYP3A4 Agents: Subjects who are currently receiving drugs that are strong or moderateinducers or inhibitors of CYP3A4 are not eligible. Such inducers or inhibitors ofCYP3A4 are prohibited from 14 days prior to the first dose of tazemetostat to the endof the study. See Appendix C for a list of agents. Note:Dexamethasone for CNS tumorsor metastases, on a stable or decreasing dose, is allowed up to 0.12mg/kg/dayprednisone equivalents.
• Subjects with a known history of HIV, hepatitis B, and/or hepatitis C (testing notrequired as part of screening).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection or any other concurrent disease which in the judgment of the Investigatorwould make the subject inappropriate for enrollment on this study.
• Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.
• Has active autoimmune disease that has required systemic treatment in the past 12months, or a documented history of clinically severe autoimmune disease, or a syndromethat requires systemic steroids or immunosuppressive agents. Subjects with vitiligo orresolved childhood asthma/atopy are exceptions. Intermittent use of bronchodilators orlocal steroid injections are not excluded. Replacement therapy (e.g. thyroxine,insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. Autoimmunediagnoses not listed must be approved by the Principal Investigator.
• On screening CBC differential, subjects must not have any significant morphologicabnormalities concerning for MPN/MDS or ALL.
• Subjects must not have any prior history of myeloid malignancies, includingmyelodysplastic syndrome (MDS) or prior history of lymphoblastic lymphoma (LBL) orleukemia (ALL).
• Subjects who have received prior solid organ transplantation are not eligible.
• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered onthis study due to risks of fetal and teratogenic adverse events as there is yet noavailable information regarding human fetal or teratogenic toxicities.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4agent or with an agent directed to another stimulatory or co-inhibitory T-cellreceptor (e.g. OX40, CD137).
• Subjects who have received live / attenuated vaccine within 30 days of first dose ofstudy treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to tazemetostat or Orasweet.
• Subjects who, in the opinion of the investigator, may not be able to comply with thesafety monitoring requirements of the study are not eligible.