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History of Changes for Study: NCT02601937
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
Latest version (submitted December 23, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 November 9, 2015 None (earliest Version on record)
2 December 9, 2015 Study Status and Contacts/Locations
3 January 7, 2016 Recruitment Status, Study Status, Contacts/Locations and Oversight
4 January 13, 2016 Contacts/Locations and Study Status
5 January 28, 2016 Contacts/Locations and Study Status
6 February 25, 2016 Study Status and Contacts/Locations
7 March 17, 2016 Contacts/Locations and Study Status
8 March 31, 2016 Contacts/Locations and Study Status
9 April 13, 2016 Contacts/Locations and Study Status
10 April 21, 2016 Contacts/Locations and Study Status
11 April 25, 2016 Contacts/Locations and Study Status
12 May 2, 2016 Contacts/Locations and Study Status
13 May 12, 2016 Contacts/Locations and Study Status
14 June 9, 2016 Contacts/Locations and Study Status
15 June 22, 2016 Contacts/Locations and Study Status
16 June 23, 2016 Contacts/Locations and Study Status
17 June 28, 2016 Contacts/Locations and Study Status
18 August 5, 2016 Study Status and Contacts/Locations
19 August 17, 2016 Contacts/Locations and Study Status
20 August 22, 2016 Contacts/Locations and Study Status
21 September 1, 2016 Contacts/Locations and Study Status
22 September 20, 2016 Contacts/Locations and Study Status
23 October 20, 2016 Contacts/Locations and Study Status
24 November 9, 2016 Contacts/Locations and Study Status
25 November 18, 2016 Contacts/Locations and Study Status
26 November 22, 2016 Study Status and Contacts/Locations
27 November 23, 2016 Study Design and Study Status
28 December 14, 2016 Study Status and Contacts/Locations
29 December 15, 2016 Contacts/Locations and Study Status
30 March 15, 2017 Study Status and Contacts/Locations
31 April 12, 2017 Study Status and Contacts/Locations
32 August 2, 2017 Contacts/Locations, Study Status, Eligibility, Arms and Interventions and Study Description
33 December 4, 2017 Contacts/Locations and Study Status
34 January 12, 2018 Study Status and Contacts/Locations
35 February 5, 2018 Study Status and Contacts/Locations
36 March 6, 2018 Study Status and Contacts/Locations
37 May 18, 2018 Recruitment Status, Study Status, Contacts/Locations and Study Design
38 July 23, 2018 Study Status
39 August 15, 2018 Study Status
40 January 30, 2019 Recruitment Status, Study Status, Contacts/Locations, Eligibility, Study Design and Study Description
41 March 20, 2019 Contacts/Locations and Study Status
42 April 18, 2019 Contacts/Locations and Study Status
43 June 17, 2019 Study Status
44 July 1, 2019 Study Status
45 August 20, 2019 Contacts/Locations and Study Status
46 September 27, 2019 Contacts/Locations and Study Status
47 April 1, 2020 Contacts/Locations, Study Status, Eligibility, Arms and Interventions and Study Description
48 May 7, 2020 Contacts/Locations and Study Status
49 January 13, 2021 Contacts/Locations, Study Status, Eligibility and Study Description
50 May 4, 2021 Recruitment Status, Study Status, Contacts/Locations, Study Design and Eligibility
51 May 20, 2021 Contacts/Locations and Study Status
52 June 29, 2021 Study Status
53 August 10, 2021 Study Status
54 August 31, 2021 Study Status
55 September 23, 2021 Study Status
56 December 8, 2021 Study Status
57 December 23, 2021 Recruitment Status and Study Status
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Study NCT02601937
Submitted Date:  November 9, 2015 (v1)

Open or close this module Study Identification
Unique Protocol ID: EZH-102
Brief Title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
Official Title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
Secondary IDs:
Open or close this module Study Status
Record Verification: November 2015
Overall Status: Not yet recruiting
Study Start: November 2015
Primary Completion: October 2017 [Anticipated]
Study Completion: January 2018 [Anticipated]
First Submitted: October 21, 2015
First Submitted that
Met QC Criteria:
November 9, 2015
First Posted: November 11, 2015 [Estimate]
Last Update Submitted that
Met QC Criteria:
November 9, 2015
Last Update Posted: November 11, 2015 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Epizyme, Inc.
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: No
Open or close this module Study Description
Brief Summary:

This is a Phase I, open-label, dose escalation and dose expansion study with a BID 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 Expansion at the MTD or the RP2D, for subjects with rhabdoid tumors (MRT/ATRT/RTK/selected tumors with rhabdoid features).

Detailed Description:
Open or close this module Conditions
Conditions: Rhabdoid Tumors
INI1-negative Tumors
Synovial Sarcoma
Malignant Rhabdoid Tumor of Ovary
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 44 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Open-label Tazemetostat
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
Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.
Other Names:
  • EPZ-6438
  • E7438
Open or close this module Outcome Measures
Primary Outcome Measures:
1. To determine the MTD or the RP2D (Dose Escalation)
[ Time Frame: 1 cycle/28 days ]

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
2. Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria
[ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]

Secondary Outcome Measures:
1. Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria
[ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]

2. Dose Expansion: Progression-free survival (PFS)
[ Time Frame: At 24 and 56 weeks post treatment using Kaplan-Meier method ]

3. Dose Expansion: Overall Survival (OS)
[ Time Frame: At 24 and 56 weeks post treatment using Kaplan-Meier method ]

4. Incidence of treatment-emergent adverse events as a measure of safety and tolerability
[ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]

5. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax
[ Time Frame: Days 1 and 15 ]

6. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax
[ Time Frame: Days 1 and 15 ]

7. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)
[ Time Frame: Days 1 and 15 ]

8. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)
[ Time Frame: Days 1 and 15 ]

9. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2
[ Time Frame: Days 1 and 15 ]

10. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F
[ Time Frame: Day 15 ]

11. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F
[ Time Frame: Day 15 ]

12. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka
[ Time Frame: Day 15 ]

13. Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough
[ Time Frame: Day 1 of cycles 2, 3 and 4 ]

Open or close this module Eligibility
Minimum Age: 6 Months
Maximum Age: 21 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Age (at the time of consent/assent): ≥6 months to ≤21 years
  2. Performance Status:
    • If <12 years of age: Lanksy Performance Status >50%
    • If ≥12 years of age: Karnofsky Performance Status >50%
  3. Has a life expectancy of >3 months
  4. 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
  5. Is ineligible or inappropriate for other treatment regimens known to have effective potential
  6. 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
  7. 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 21 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 3 half-lives 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)
  8. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below:
    • Hematologic (BM Function):
      • Hemoglobin ≥ 8 mg/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):
      • PT ≤1.5 ULN
      • PTT ≤1.5 ULN
      • Fibrinogen ≥0.75 LLN
    • Renal Function (creatinine clearance or serum creatinine):
      • Calculated creatinine clearance ≥60 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:
      • Conjugated bilirubin <1.5 x ULN
      • ALT or AST <3 x ULN
  9. 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 brian 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.

  10. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram or multi-gated acquisition scan
  11. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec
  12. 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
  13. 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)

For Dose Escalation Only:

  1. 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.
  2. 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
  3. 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
  4. 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
  5. 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)

For Dose Expansion Only:

  1. Has measurable disease
  2. Has one of the following histologically confirmed rhabdoid tumors:
    • ATRT
    • MRT
    • RTK
    • Selected tumors with rhabdoid features
  3. Has 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

Exclusion Criteria:

  1. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2
  2. Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy
  3. 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
  4. Has had major surgery within 2 weeks prior to enrollment
  5. 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
  6. Has clinically active heart disease including prolonged corrected QT interval
  7. Is currently taking any prohibited medication(s)
  8. Has an active infection requiring systemic treatment
  9. Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus
  10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
  11. Has had a symptomatic venous thrombosis within the 3 months prior to study enrollment - NOTE: Subjects with a history of a deep vein thrombosis >3 months prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study
  12. For subjects with CNS involvement (primary tumor or metastatic disease): Have ≥3 foci of punctate hemorrhage, any active bleeding, or intratumoral hemorrhage at time of enrollment or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents
Open or close this module Contacts/Locations
Central Contact Person: Blythe Thomson, MD
Telephone: 855-500-1011
Email: clinicaltrials@epizyme.com
Central Contact Backup: Peter Ho, MD, PhD
Telephone: 855-500-1011
Email: clinicaltrials@epizyme.com
Locations:
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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