Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02601937




Registration number
NCT02601937
Ethics application status
Date submitted
21/10/2015
Date registered
11/11/2015
Date last updated
27/12/2021

Titles & IDs
Public title
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
Scientific title
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
Secondary ID [1] 0 0
EZH-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rhabdoid Tumors 0 0
INI1-negative Tumors 0 0
Synovial Sarcoma 0 0
Malignant Rhabdoid Tumor of Ovary 0 0
Condition category
Condition code
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 0 0 0 0
Bone
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Children's - Other
Cancer 0 0 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tazemetostat

Experimental: Open-label Tazemetostat - 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)


Treatment: Drugs: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
To determine the MTD or the RP2D (Dose Escalation)
Timepoint [1] 0 0
1 cycle/28 days
Primary outcome [2] 0 0
Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria
Timepoint [2] 0 0
Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
Secondary outcome [1] 0 0
Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria
Timepoint [1] 0 0
Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
Secondary outcome [2] 0 0
Dose Expansion: Progression-free survival (PFS)
Timepoint [2] 0 0
At 24 and 56 weeks post treatment using Kaplan-Meier method
Secondary outcome [3] 0 0
Dose Expansion: Overall Survival (OS)
Timepoint [3] 0 0
At 24 and 56 weeks post treatment using Kaplan-Meier method
Secondary outcome [4] 0 0
Incidence of treatment-emergent adverse events as a measure of safety and tolerability
Timepoint [4] 0 0
Adverse events assessed from first dose through 30 days post last dose
Secondary outcome [5] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax
Timepoint [5] 0 0
Days 1 and 15
Secondary outcome [6] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax
Timepoint [6] 0 0
Days 1 and 15
Secondary outcome [7] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)
Timepoint [7] 0 0
Days 1 and 15
Secondary outcome [8] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)
Timepoint [8] 0 0
Days 1 and 15
Secondary outcome [9] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2
Timepoint [9] 0 0
Days 1 and 15
Secondary outcome [10] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F
Timepoint [10] 0 0
Day 15
Secondary outcome [11] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F
Timepoint [11] 0 0
Day 15
Secondary outcome [12] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka
Timepoint [12] 0 0
Day 15
Secondary outcome [13] 0 0
Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough
Timepoint [13] 0 0
Day 1 of cycles 2, 3 and 4

Eligibility
Key inclusion criteria
1. Age (at the time of consent/assent): =6 months to <18 years

- Cohort 4 only: =10 years to <18 years
2. 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.
3. Has provided signed written informed consent/assent
4. Has a life expectancy of >3 months
5. 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
6. Is ineligible or inappropriate for other treatment regimens known to have effective potential
7. 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
8. 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
9. 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)
10. 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
11. 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.
12. 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
13. Has a QT interval corrected by Fridericia's formula (QTcF) =450 msec
14. 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.
15. 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)
16. Is willing and able to comply with all aspects of the protocol as judged by Investigator
17. For female subjects of childbearing potential: Subject must:

* Have a negative beta-human chorionic gonadotropin (ß-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
18. 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:

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 (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) (Closed to enrollment)
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)

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

1. Has measurable disease
2. 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.
3. 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
4. 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
5. 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)
6. For subjects to be enrolled in Cohort 4 (Closed to enrollment): Able to swallow and retain orally administered tablets
Minimum age
6 Months
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 2 weeks prior to enrollment.
5. 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.
6. Has a prior history of T-LBL/T-ALL.
7. Has clinically active heart disease including prolonged corrected QTcF (>450 msec)
8. Is currently taking any prohibited medication(s) as described in Section 7.3.
9. 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
10. Has an active infection requiring systemic treatment
11. Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV)
12. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
13. 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
14. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/01/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
22/10/2021
Sample size
Target
Accrual to date
Final
109
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Sydney
Recruitment hospital [2] 0 0
Lady Cilento/Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
The Royal Children's Hospital - Melbourne
Recruitment hospital [4] 0 0
The Childrens Hospital at Westmead Oncology Unit - Westmead
Recruitment postcode(s) [1] 0 0
2031 - Sydney
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
3052 - Melbourne
Recruitment postcode(s) [4] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Maryland
Country [7] 0 0
United States of America
State/province [7] 0 0
Massachusetts
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Pennsylvania
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Washington
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Denmark
State/province [16] 0 0
Copenhagen
Country [17] 0 0
France
State/province [17] 0 0
Paris
Country [18] 0 0
France
State/province [18] 0 0
Villejuif
Country [19] 0 0
Germany
State/province [19] 0 0
Augsburg
Country [20] 0 0
Germany
State/province [20] 0 0
Berlin
Country [21] 0 0
Germany
State/province [21] 0 0
Heidelberg
Country [22] 0 0
Germany
State/province [22] 0 0
Munster
Country [23] 0 0
Italy
State/province [23] 0 0
Genova
Country [24] 0 0
Italy
State/province [24] 0 0
Milano
Country [25] 0 0
Netherlands
State/province [25] 0 0
Rotterdam
Country [26] 0 0
Netherlands
State/province [26] 0 0
Utrecht
Country [27] 0 0
United Kingdom
State/province [27] 0 0
London
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Epizyme, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT02601937