Clinical Trials Register

Summary
EudraCT Number:	2015-002468-18
Sponsor's Protocol Code Number:	EZH-102
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2015-002468-18

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study on the Effect of Tazemetostat (study drug) in Pediatric Subjects with relapsed or refractory Tumors or Synovial Sarcoma

A.4.1

Sponsor's protocol code number

EZH-102

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Epizyme, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Epizyme, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Epizyme, Inc.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	400 Technology Square, 4th Floor
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02139
B.5.3.4	Country	United States
B.5.4	Telephone number	001855500-1011
B.5.6	E-mail	clinicaltrials@epizyme.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	tazemetostat
D.3.2	Product code	EPZ-6438 (E7438)
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TAZEMETOSTAT
D.3.9.2	Current sponsor code	EPZ-6438
D.3.9.3	Other descriptive name	ESQR
D.3.9.4	EV Substance Code	SUB178719
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	tazemetostat
D.3.2	Product code	EPZ-6438 (E7438)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TAZEMETOSTAT
D.3.9.2	Current sponsor code	EPZ-6438
D.3.9.3	Other descriptive name	ESQR
D.3.9.4	EV Substance Code	SUB178719
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Atypical teratoid rhabdoid tumor (ATRT), Malignant rhabdoid tumor (MRT), Rhabdoid tumor of kidney (RTK), selected tumors with rhabdoid features.
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

E.1.1.1

Medical condition in easily understood language

Relapsed/refractory rhabdoid tumors and central nervous system (CNS) tumors.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10064886
E.1.2	Term	Renal medullary carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10065870
E.1.2	Term	Atypical teratoid/rhabdoid tumor of CNS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10073134
E.1.2	Term	Extraskeletal myxoid chondrosarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10073335
E.1.2	Term	Rhabdoid tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10074121
E.1.2	Term	Rhabdoid tumor of the kidney
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10042863
E.1.2	Term	Synovial sarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10015100
E.1.2	Term	Epithelioid sarcomas
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Dose Escalation:
To determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) of tazemetostat when administered as an oral suspension twice daily (BID) in pediatric subjects with relapsed/refractory rhabdoid tumors, integrase interactor 1 (INI1)-negative tumors or synovial sarcoma

Dose Expansion:
To evaluate the antitumor activity of tazemetostat as assessed by overall response rate (ORR) in pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1-closed to enrollment), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3)and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX
rearrangement (Cohort 4-closed to enrollment) using disease appropriate standardized response criteria.

E.2.2

Secondary objectives of the trial

Dose Escalation:
To evaluate the preliminary antitumor activity of tazemetostat as assessed by ORR using disease appropriate standardized response criteria
Dose Expansion:
To determine the progression-free survival (PFS) and overall survival (OS) at 24 and 56 weeks and overall pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1-closed to enrollment), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4-closed to enrollment) using disease-appropriate standardized response criteria.
ALL subjects:
-To assess the safety and tolerability &pharmakokinetic (PK) parameters of tazemetostat administered as an oral suspension BID and/or tablets
three times daily (TID), in pediatric subjects
-To evaluate the duration of response in subjects achieving a PR or CR according to a disease appropriate standardized response criteria

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age (at the time of consent/assent): ≥6 months to <18 years of age
Cohort 4 only: ≥10 y to <18 y
2.Performance Status: If <12 y: Lansky Performance Status >50% ,If ≥12 y of age: Karnofsky Performance Status >50%
3.Has provided signed written ICF 4. Has a life expectancy of >3 months. 5.Has relapsed or refractory disease and no standard treatment options.
6.Is ineligible for other treatment regimens. 7.Has a documented local diagnostic pathology of original biopsy. 8.Has all prior treatment related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable& not clinically significant. 9.Prior therapies must be completed according to the protocol. 10.Has adequate hemat. BM & coagulation factors, renal&hepatic function as defined by criteria in the protocol
11.Specific requirements for subjects with CNS involvement eg: stable deficits within certain timeframe, stable seizure, treated brain metastases without evidence of progression. 12. Has a LV fractional shortening of >27% or an LV ejection fraction of ≥50% by ECHO or MUGA scan & NYHAC ≤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 GI condition that may alter absorption. 15.Has sufficient tumor tissue for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis. 16.Is willing and able to comply with all aspects of the protocol. 17.18. For female subjects of childbearing potential and for male subjects with a female partner of childbearing potential Subject must adhere to contraception methods described in the protocol.
For Dose Escalation Only:
ALL criteria above and the following:
1.Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination or and other lesions such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis or hepatosplenomegaly from disease
2.Has one of the following histologically confirmed tumors: Rhabdoid tumor: ATRT (closed to enrollment), MRT, RTK, selected tumors with rhabdoid features, INI1-negative tumor: (Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, EMC, Myoepithelial carcinoma, Renal medullary carcinoma), other INI1-negative malignant tumors, Synovial sarcoma with SS18-SSX rearrangement (closed to enrollment).
3. For subjects with ATRT, MRT, and RTK or 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 SMARCA 4 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 or SMARCA 4 loss or 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 or mutation when INI1 IHC is equivocal or unavailable
5.For subjects with synovial sarcoma with SS18-SSX rearangement 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
ALL listed above for All subjects and in addition:
1.Has measurable disease
2.Has one of the following tumors: Cohort 1: ATRT-(enrollment closed), Cohort 2: MRT, RTK, Selected tumors with rhabdoid features, Cohort 3:INI1-negative tumors or synovial sarcoma: ES, Epithelioid malignant peripheral nerve sheath tumor, EMC, Myoepithelial carcinoma, Renal medullary carcinoma, Chordoma (poorly differentiated or de-differentiated), other INI1-negative malignant tumors, Cohort 4 (enrollment closed):one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement.
3.For subjects with ATRT/MRT/RTK only -have 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.
4. For subjects with INI1-negative tumors only – test results 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.
5.For subjects with synovial sarcoma with SS18-SSX rearrangement (in Cohort 4 only- closed to enrollment): Morphology consistent with synovial sarcoma & Cytogenetics or FISH &/or molecular confirmation of SS18 rearrangement t(X;18)(p11;q11)
6.For subjects Cohort 4-(closed to enrollment): Able to swallow&retain orally taken tablets

E.4

Principal exclusion criteria

1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homolog2 (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 five 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.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 at Screening.
Cytogenetic testing and DNA sequencing will be conducted by a central laboratory following an abnormal result of bone marrow aspirate/biopsy.
6.Has a prior history of T-LBL/T-ALL.
7.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
8.Has clinically active heart disease including prolonged QTcF QTcF
(>450 msec).
9.Is currently taking any prohibited medication(s) as described in
section 7.3.
10.Has an active infection requiring systemic treatment.
11.Is immunocompromised (ie congenital immunodeficiency), including subjects with a 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 14 days prior to study enrollment.
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 antiplatelet or anti-thrombotic agents.
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 3 months after last dose of

E.5 End points

E.5.1

Primary end point(s)

Dose Escalation:
•Incidence and severity of treatment -emergent AEs (TEAEs) qualifying as protocol-defined dose-limiting toxicities (DLTs), and establishment of the protocol-defined RP2D and/or MTD.
Dose Expansion:
•Overall response rate CR + PR to tazemetostat for each cohort in pediatric subjects with relapsed or refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3) ), and tumor types eligible for Cohorts 1
through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4),
using disease- appropriate standardized response criteria .

E.5.1.1

Timepoint(s) of evaluation of this end point

Dose Escalation: All DLTs occurring during the first 28 days of exposure summarized.
Dose Expansion: Data sets for each cohort will be reviewed as completed.
timepoint for every 8 weeks until documented disease progression or new anti-cancer therapy started.

E.5.2

Secondary end point(s)

Dose Escalation:
•Overall response rate (CR+PR) to tazemetostat in pediatric subjects with relapsed or refractory CNS and solid tumors, using disease-appropriate standardized response criteria;
Dose Expansion:
•Progression-free survival (PFS) and overall survival (OS) at 24 and 56 weeks and overall following receipt of tazemetostat for subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort
3)and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4) using disease-appropriate standardized response;
All Parts and Cohorts:
•Safety and tolerability parameters including treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, and other safety measures
•PK parameters including Cmax, Tmax, t1/2, AUC(0-t), AUC(0-12hr), CL/F, Vd/F, Ka (if data permit)
•Response duration, for the subset of subjects with a confirmed CR or PR, defined as the time from the first documented evidence of CR or PR to time of first documented disease progression or death due to any cause, using disease appropriate standardized response criteria.
Exploratory Endpoints:
•To assess the PK and pharmacodynamic (PD) relationship for tazemetostat in pediatric subjects
•Tumor target gene expression and phenotypic markers including those for differentiation, apoptosis, inflammation, and cell proliferation and
their correlation with activity
•H3K27 methylation in PBMC population
•Somatic mutation analysis of tumor tissue and blood derived circulating DNA

E.5.2.1

Timepoint(s) of evaluation of this end point

1.Dose Escalation
ORR: every 8 weeks for tumor response until disease progression
2.Dose Expansion
PFS: every 8 weeks until disease progression or death
OS: throughout the treatment period and then every 16 weeks until death, withdrawal of consent or they are lost to follow up
3.All Groups
•Safety: At each visit or required timepoint during treatment and until for 30 days after last dose of tazemetostat or until new anti-cancer therapy
•PK parameters: Cycle 1 (Days 1 and 15) and Cycles 2, 3 and 4 (Day 1).

•Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose Escalation and Dose Expansion

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open