TAZNI: A Phase I/II Combination Trial of Tazemetostat with Nivolumab and Ipilimumab for Children with INI1-Negative or SMARCA4-Deficient Tumors

Protocol # :
Atypical Teratoid Rhabdoid Tumor
INI1 (SMARCB1)-Deficient Primary CNS Malignant Tumors
SMARCA4-deficient Primary CNS Malignant Tumors
Malignant Rhabdoid Tumor (MRT)
Rhabdoid Tumor of the Kidney (RTK)
Epithelioid Sarcoma
Disease Sites
Healthy volunteer
Transplanted organ and tissue status, unspecified
Disease not specified
Gastroesophageal Junction
Other specified personal risk factors, not elsewhere classified
Lip, Oral Cavity and Pharynx
Small Intestine
Other Digestive Organ
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Corpus Uteri
Other Female Genital
Other Male Genital
Urinary Bladder
Other Urinary
Eye and Orbit
Brain and Nervous System
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Chi, Susan, N
Site Research Nurses
Cavanaugh, Kerri, Lynn
Ezrre, Suzanne
McManus, Jeanine
Strachan, Marylynne

Trial Description

This research study involves a combination of three drugs given together as a possible
treatment for malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, epithelioid
sarcoma, chordoma or other tumors that are deficient in one of two possible proteins,
either INI-1 (SMARCB1) or SMARCA4.

The names of the study drugs involved in this study are:

- Tazemetostat (TAZVERIK)

- Nivolumab (OPDIVO)

- Ipilimumab (YERVOY)

Eligibility Requirements

Inclusion Criteria:

- Diagnosis: Histologically confirmed tumors at diagnosis or at relapse (as

- Stratum A

- Atypical Teratoid Rhabdoid Tumor (ATRT)

- Other INI1- or SMARCA4-deficient primary CNS malignant tumors (with PI

- 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 showing
either of the following: Loss of INI1 confirmed by immunohistochemistry (IHC) OR
molecular confirmation of tumor bi-allelic SMARCB1 (INI1) loss or mutation when INI1
IHC is equivocal or unavailable

- Loss of SMARCA4 confirmed by IHC OR molecular confirmation of tumor SMARCA4 loss or
mutation (with PI approval) Reports confirming these findings (including tumor
sequencing if available) will be reviewed by the Sponsor-Investigator, PI or
designee for approval of eligibility prior to enrollment.

- Treatment status: All subjects must have completed planned upfront treatment for
their disease for strata A1 or B1. Subjects need not have relapsed or have
refractory disease to be eligible for this protocol.

- Disease Status: For subjects under consideration for strata A1 or B1, subjects must
have evaluable disease Note: Leptomeningeal lesions/disease are allowed as evaluable

- For relapsed/refractory subjects under consideration for strata A2 or B2, subjects
must have measurable disease as defined by RANO for stratum A2 or RECIST v1.1 for
stratum 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 PET

- 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 evidence
of evaluable or measurable disease by exam or imaging.

- Pre-recurrent subjects to be enrolled in strata A1, B1, A3, or B3 must be enrolled
within 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 Lansky
performance 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 7
days 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 of assessing the performance score.

- Life expectancy of greater than 2 months.

- Prior Therapy: Subjects must have fully recovered from the acute toxic effects of
all prior anti-cancer therapy. Subjects must meet the following minimum washout
periods prior to first day of study treatment:

- Myelosuppressive chemotherapy: ≥21 days after the last dose of myelosuppressive

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or ANC counts): ≥ 7 days after the last dose of the agent.

- Small molecule biologic therapy: ≥7 days following the last dose of a
non-monoclonal biologic agent.

- Monoclonal antibody: ≥21 days after the last dose, and toxicity related to
prior antibody therapy must be recovered to Grade ≤1.

- Corticosteroids: If used to modify immune adverse events related to prior
therapy, ≥ 14 days must have elapsed since last dose of corticosteroid. CNS
subjects receiving corticosteroids for neurologic symptom relief must be at
stable or decreasing doses for at least 7 days prior to the first day of study
treatment. For all patients, corticosteroid doses of up to 0.12 mg/kg/day
prednisone equivalent may be approved after consultation with the Principal
Investigator. Treatment with topical, inhaled or ophthalmic corticosteroid is

- 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 or

- Myeloid growth factors: ≥14 days following the last dose of long-acting growth
factor (e.g. Neulasta) or 7 days following short-acting growth factor.

- Autologous stem cell therapy, Autologous T Cell, or other CellularTherapy: ≥ 42
days must have elapsed after any cellular therapy infusion. Prior allogeneic
stem cell transplant is not allowable.

- Prior EZH2 inhibitor therapy: Subjects with relapsed/refractory disease (strata
A2 and B2) may have received prior single agent tazemetostat or other EZH2
inhibitors for up to 1 year, but subjects without prior progression/relapse may
NOT 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, For
subjects with relapsed disease (Strata A2 or B2): >50K/uL, For all subjects:
must be platelet transfusion independent, defined as not receiving a platelet
transfusion 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 this
study, the ULN for ALT is 45 U/L)

- Renal Function: A serum creatinine based on age/gender as follows: Maximum Serum
Creatinine (mg/dL)

- Male: 6 months to 1 year-0.5,1 to < 2 years-0.6, 2 to < 6 years-0.8, 6 to < 10
years-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 <
10 years-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 levels
above institutional normal.

- Adequate Pulmonary Function defined as: No evidence of dyspnea at rest, no exercise
intolerance due to pulmonary insufficient and a pulse oximetry > 92% while breathing
room air.

-- Adequate Neurologic Function defined as: Subjects with seizure disorder may be
enrolled if on anticonvulsants and well controlled. Nervous system disorders (CTCAE
v5.0) resulting from prior therapy must be ≤ Grade 2, with the exception of
decreased tendon 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 to
adhere to contraception for a period of 5 months after the last dose of either
tazemetostat, nivolumab, or ipilimumab

- Men receiving the TAZNI combination and who are sexually active with WOCBP will
agree to adhere to barrier contraception for a period of 3 months after the last
dose of either tazemetostat, nivolumab or ipilimumab.

- Ability to understand and/or the willingness of the subject (or parent or legally
authorized representative, if minor) to provide informed consent, documented using
an institutionally approved informed consent procedure.

Exclusion Criteria:

- Concomitant Medications

- Subjects who are receiving any other investigational agents or other anti-cancer
agents are not eligible.

- CYP3A4 Agents: Subjects who are currently receiving drugs that are strong or
moderate inducers or inhibitors of CYP3A4 are not eligible. Such inducers or
inhibitors of CYP3A4 are prohibited from 14 days prior to the first dose of
tazemetostat to the end of the study. See Appendix C for a list of agents.
Note:Dexamethasone for CNS tumors or metastases, on a stable or decreasing dose, is
allowed up to 0.12mg/kg/day prednisone equivalents.

- Subjects with a known history of HIV, hepatitis B, and/or hepatitis C (testing not
required as part of screening).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or any other concurrent disease which in the judgment of the Investigator
would make the subject inappropriate for enrollment on this study.

- Has a history of (non-infectious) pneumonitis that required steroids or has current

- Has active autoimmune disease that has required systemic treatment in the past 12
months, or a documented history of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with
vitiligo or resolved childhood asthma/atopy are exceptions. Intermittent use of
bronchodilators or local steroid injections are not excluded. Replacement therapy
(e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment. Autoimmune diagnoses not listed must be approved by the Principal

- On screening CBC differential, subjects must not have any significant morphologic
abnormalities concerning for MPN/MDS or ALL.

- Subjects must not have any prior history of myeloid malignancies, including
myelodysplastic syndrome (MDS) or prior history of lymphoblastic lymphoma (LBL) or
leukemia (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 on
this study due to risks of fetal and teratogenic adverse events as there is yet no
available information regarding human fetal or teratogenic toxicities.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4
agent or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (e.g. OX40, CD137).

- Subjects who have received live / attenuated vaccine within 30 days of first dose of
study treatment.

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to tazemetostat or Orasweet.

- Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible.