A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of tazemetostat. Subjects will be screened for eligibility within 14 days of the planned first dose of tazemetostat. A treatment cycle will be 28 days. Response assessment will be evaluated after 8 weeks of treatment and subsequently every 8 weeks while on study. The study has two parts: Dose Escalation and Dose Expansion. Dose escalation for subjects with the following relapsed/refractory malignancies: Rhabdoid tumors: Atypical teratoid rhabdoid tumor (ATRT) Malignant rhabdoid tumor (MRT) Rhabdoid tumor of kidney (RTK) Selected tumors with rhabdoid features INI1-negative tumors: Epithelioid sarcoma Epithelioid malignant peripheral nerve sheath tumor Extraskeletal myxoid chondrosarcoma Myoepithelial carcinoma Renal medullary carcinoma Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) (with Sponsor approval) Synovial Sarcoma with a SS18-SSX rearrangement Dose Escalation cohorts are closed to enrollment. Dose Expansion at the MTD or the RP2D Cohort 1 - ATRT (closed to enrollment) Cohort 2 - MRT/RTK/selected tumors with rhabdoid features (closed to enrollment) Cohort 3 - INI-negative tumors: Epithelioid sarcoma Epithelioid malignant peripheral nerve sheath tumor Extraskeletal myxoid chondrosarcoma Myoepithelial carcinoma Renal medullary carcinoma Chordoma (poorly differentiated or de-differentiated) Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (closed to enrollment)

Official Title
-----------------
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Conditions
-----------------
Rhabdoid Tumors, INI1-negative Tumors, Synovial Sarcoma, Malignant Rhabdoid Tumor of Ovary

Intervention / Treatment
-----------------
* Drug: Tazemetostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age (at the time of consent/assent): ≥6 months to <18 years - Cohort 4 only: ≥10 years to <18 years Performance Status: If <12 years of age: Lanksy Performance Status >50% If ≥12 years of age: Karnofsky Performance Status >50% NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status. Has provided signed written informed consent/assent Has a life expectancy of >3 months Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion Is ineligible or inappropriate for other treatment regimens known to have effective potential Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment Has completed a prior therapy (ies) according to the criteria below: Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat) Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat) Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat) Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat) Monoclonal antibody (ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat) Immunotherapy (e.g., tumor vaccine) At least 6 weeks since last dose of immunotherapy agent(s) prior to first dose of tazemetostat) Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereotactic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥ 50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat) Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat) Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat) Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below: Hematologic (BM Function): Hemoglobin ≥ 8 g/dL Platelets ≥100,000/mm^3 (≥100 x 10^9/L) ANC ≥1,000/mm^3 (≥1.0 x 10^9/L) Hematologic (Coagulation Factors): INR/ PTd ≤1.5 ULN PTT ≤1.5 ULN Fibrinogen ≥0.75 LLN Renal Function (creatinine clearance or serum creatinine): Calculated creatinine clearance ≥50 mL/min/1.73m^2 Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L) Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L) Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L) Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L) Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L) Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L) Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L) Hepatic Function: Total bilirubin <1.5 x ULN ALT or AST <3 x ULN Eligibility can be determined by either total or conjugated bilirubin For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 7 days prior to enrollment NOTE: Subjects with leptomeningeal disease or brain tumors with positive cerebral spinal fluid cytology are eligible for this study. Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to enrollment. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram or multi-gated acquisition scan and New York Heart Association Class<2 Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec Is able to swallow and retain orally administered medication and does not have any uncontrolled gastrointestinal (GI) condition such as nausea, vomiting, or diarrhea, or any clinically significant GI abnormalities that may alter absorption such as malabsorption syndromes, hereditary fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltase insufficiency, or major resection of stomach and/or bowels NOTE: Nasogastric and gastrostomy tube administration of the oral suspension formulation of study drug is permitted. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of immunohistochemistry and/or cytogenetics/fluorescence in situ hybridization (FISH) and/or deoxyribonucleic acid mutation analysis (required for study entry but enrollment based on local results) Is willing and able to comply with all aspects of the protocol as judged by Investigator For female subjects of childbearing potential: Subject must: Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of Screening and within 72 hours prior to planned first dose of tazemetostat (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and Agree to use effective contraception, as defined in Section 8.6.11 start of Screening until 6 months following the last dose of study treatment and have a male partner who uses a condom, or Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.6.11, or Have a male partner who is vasectomized with confirmed azoospermia For male subjects with a female partner of childbearing potential: Subject must: Be vasectomized or Agree to use condoms as defined in Section 8.5.11 from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or Have a female partner who is NOT of childbearing potential For Dose Escalation Only: To be eligible for enrollment in dose escalation, a subject must meet ALL of the following criteria in addition to the inclusion criteria listed above for all subjects: Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination and other lesions such as bone lesions, leptomeningeal disease, ascites, hepatosplenomegaly from disease. Has one of the following histologically confirmed tumors: (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) Rhabdoid tumor: ATRT MRT RTK Selected tumors with rhabdoid features NI1-negative tumor: Epithelioid sarcoma Epithelioid malignant peripheral nerve sheath tumor Extraskeletal myxoid chondrosarcoma Myoepithelial carcinoma Renal medullary carcinoma Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval Synovial sarcoma with SS18-SSX rearrangement (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) (Closed to enrollment) For subjects with ATRT, MRT, RTK, or selected tumors with rhabdoid features only: the following test results must be available: Morphology and immunophenotypic panel consistent with rhabdoid tumor and Loss of INI1 or SMARCA4 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable For subjects with INI1 negative tumor only: the following test results must be available: Morphology and immunophenotypic panel consistent with INI1-negative tumors, and Loss of INI1 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable For subjects with synovial sarcoma only: The following test results must be available: Morphology consistent with synovial sarcoma, and Cytogenetics or FISH and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) Dose Escalation cohorts are closed to enrollment. For Dose Expansion Only: Note: To be eligible for enrollment in Dose Expansion, a subject must meet ALL of the following criteria in addition to the inclusion criteria for ALL subjects listed above Has measurable disease Has one of the following histologically confirmed tumors: Cohort 1 - ATRT (Closed to enrollment) Cohort 2 - MRT/RTK/selected tumors with rhabdoid features (Closed to enrollment) Cohort 3 - INI-negative tumors (Closed to enrollment): Epithelioid sarcoma Epithelioid malignant peripheral nerve sheath tumor Extraskeletal myxoid chondrosarcoma(EMC) Myoepithelial carcinoma Renal medullary carcinoma Chordoma (poorly differentiated or de-differentiated) Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Closed to enrollment) NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP or other Sponsor-approved certified laboratory must be available. For subjects with ATRT/MRT/RTK only - have the following test results available: Morphology and immunophenotypic panel consistent with rhabdoid tumor, and Loss of INI1 or SMARCA4 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable For subjects with INI1-negative tumors only: The following test results must be available: Morphology and immunophenotypic panel consistent with INI1-negative tumors, and Loss of INI1 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable For subjects with synovial sarcoma with SS18-SSX rearrangement (in Cohort 4 ONLY - Closed to enrollment): The following test results must be available: Morphology consistent with synovial sarcoma, and Cytogenetics or FISH and/or molecular confirmation (e.g., deoxyribonucleic acid [DNA] sequencing) of SS18 rearrangement t(X;18)(p11;q11) For subjects to be enrolled in Cohort 4 (Closed to enrollment): Able to swallow and retain orally administered tablets Exclusion Criteria: Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2 Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat Has had major surgery within 2 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 2 weeks prior to enrollment. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing. Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central lab at screening. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy. Has a prior history of T-LBL/T-ALL. Has clinically active heart disease including prolonged corrected QTcF (>450 msec) Is currently taking any prohibited medication(s) as described in Section 7.3. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study Has an active infection requiring systemic treatment Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV) Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA) Has had a symptomatic venous thrombosis within the 14 days prior to study enrollment NOTE: Subjects with a history of a deep vein thrombosis 14 days prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug,or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents 15.15. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben 16. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements 17. For female subjects of childbearing potential: Is pregnant or nursing For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of tazemetostat.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label Tazemetostat<br>Dose Escalation: Level 1 (Starting Dose) Oral Tazemetostat 240 mg/m^2 BID; Level 2 Oral Tazemetostat 300 mg/m^2 BID; Level 3 Oral Tazemetostat 400 mg/m^2 BID; Level 4 Oral Tazemetostat 520 mg/m^2 BID; Level 5 Oral Tazemetostat 700 mg/m^2 BID; Level 6 Oral Tazemetostat 900 mg/m^2 BID; Level 7 Oral Tazemetostat 1200 mg/m^2 BID Dose Expansion: Cohort 1: Oral tazemetostat 1200mg/m2 BID Cohort 2: Oral tazemetostat 520mg/m2 BID Cohort 3: Oral tazemetostat 520mg/m2 BID Cohort 4: Oral tazemetostat 800mg/m2 TID (2400mg/m2/day) | Drug: Tazemetostat<br>* Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.<br>* Other names: E7438;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the MTD or the RP2D (Dose Escalation) | The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 will guide establishment of the protocol defined RP2D and/or MTD | 1 cycle/28 days | 
| Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria |  | Assessed every 8 weeks for duration of study participation which is estimated to be 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria |  | Assessed every 8 weeks for duration of study participation which is estimated to be 24 months | 
| Dose Expansion: Progression-free survival (PFS) |  | At 24 and 56 weeks post treatment using Kaplan-Meier method | 
| Dose Expansion: Overall Survival (OS) |  | At 24 and 56 weeks post treatment using Kaplan-Meier method | 
| Incidence of treatment-emergent adverse events as a measure of safety and tolerability |  | Adverse events assessed from first dose through 30 days post last dose | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax |  | Days 1 and 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax |  | Days 1 and 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t) |  | Days 1 and 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12) |  | Days 1 and 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2 |  | Days 1 and 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F |  | Day 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F |  | Day 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka |  | Day 15 | 
| Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough |  | Day 1 of cycles 2, 3 and 4 |