Clinical Trials Register

Summary
EudraCT Number:	2015-002469-41
Sponsor's Protocol Code Number:	EZH-202
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-12
Trial 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

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-002469-41

A.3

Full title of the trial

A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

A.3.1

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

A Study of the Effect of Tazemetostat (study drug) in Patients with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

A.4.1

Sponsor's protocol code number

EZH-202

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	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 milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

Cohort 1: Rhabdoid tumors (malignant rhabdoid tumors, rhabdoid tumors of the kidney, atypical teratoid rhabdoid tumors, and selected tumors
Cohort 2: Relapsed/refractory synovial sarcoma with SS18-SSX rearrangement
Cohort 3: Other INI1-negative tumors or any solid tumor with EZH2 GOF (gain of function) mutation
Cohort 4: Renal medullary carcinoma
Cohort 5 and 8: Epithelioid sarcoma
Cohort 6: Epithelioid sarcoma undergoing mandatory tumor biopsy
Cohort 7: Poorly differentiated chordoma

E.1.1.1

Medical condition in easily understood language

INI1-negative tumors and synovial sarcoma

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007284
E.1.2	Term	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	21.1
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	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	10026667
E.1.2	Term	Malignant peripheral nerve sheath 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	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	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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10008747
E.1.2	Term	Chordoma
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

To assess the Overall Response Rate (ORR) in subjects with rhabdoid tumors (Cohort 1), other INI1-negative tumors or any solid tumor with EZH2 GOF mutation (Cohort 3), renal medullary carcinoma (Cohort 4), epithelioid sarcoma (Cohort 5), and chordoma (Cohort 7) following oral administration of tazemetostat 800 mg twice daily (BID);

To determine the progression-free survival (PFS) rate after 16 weeks of treatment with tazemetostat in subjects with relapsed/refractory synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg BID

Cohort 6 (epithelioid sarcoma undergoing mandatory tumor biopsy):
To assess the effects of tazemetostat on tumor immune priming (e.g., PD-L1 and CD8 IHC)

To assess the safety and tolerability of tazemetostat 1600 mg QD (Cohort 8)

E.2.2

Secondary objectives of the trial

- To evaluate duration of response in subjects from Cohorts 1-7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) or partial response (PR) after oral admin of tazemetostat 800 mg BID and in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD;
- To assess: disease control rate (DCR) in subjects in Cohort 5 and 6 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
- To assess the ORR in subjects in Cohort 2 and 6 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
- To determine PFS and OS at Week 24, 32 & 56 & overall in subjects in Cohort 1-7 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
- To assess safety and tolerability of IMP (Cohort 1-7);
- To assess PK of IMP;
- To investigate the PD effects of IMP in tumor tissue

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age(at the time of consent/assent): ≥18 years of age
2.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1, or 2
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
4.Has a life expectancy of >3 months
5.Has a malignancy:
•For which there are no standard therapies available (Cohorts 1, 3, 4&5)
•That is relapsed or refractory, defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies), if therapy(ies) exists (Cohort 2)
•That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion,Cohort 6 and 8 ONLY)
6.Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or other Sponsor-approved laboratory certification
7.For Cohort 1 (subjects with rhabdoid tumors only): The following test results must be available by local laboratory:
•Morphology and immunophenotypic panel consistent with rhabdoid tumors, and
•Loss of INI1 or SMARCA4 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable
8.For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only): The following test results must be available by local laboratory:
•Morphology consistent with synovial sarcoma, and
•Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)
9.For Cohort 3,4, 5, 7 and 8 (subjects with INI1-negative tumor or any solid tumor with EZH2 GOF mutation only): The following test results must be available by local laboratory:
•Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), 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, or
•Molecular evidence of EZH2 GOF mutation
10.For Cohort 6 (subjects with epithelioid sarcoma undergoing mandatory tumor biopsy):
•Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)
•Tumor that is accessible for mandatory biopsy
Note: Subjects who are unable to undergo pre-dose (screening biopsy) will not be eligible
•Willingness to provide informed consent to undergo pre- and post-dose biopsy
11. 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
12.Prior anti-cancer therapy(ies) according to the criteria described in the protocol.
13.Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results).
14.Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors as defined in the protocol.
15.Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria in the protocol.
16.For subjects with CNS tumors only: Subject must have seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 21 days prior to the planned first dose of tazemetostat
17.Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan and New York Heart Association (NYHA) Class less than or equal to 2
18.Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
19.Female subjects of childbearing potential must:
•Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of Screening and within 14 days 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 the protocol, from start of screening until 30 days following the last dose of tazemetostat and have a male partner who uses a condom, or
•Practice true abstinence, or
•Have a male partner who is vasectomized
20.Male subjects with a female partner of childbearing potential must:
•Be vasectomized, or
•Agree to use condoms, from first dose of tazemetostat until 30 days following the last dose of tazemetostat, or
•Have a female partner who is NOT of childbearing potential
21.For French subjects only: Is either affiliated with or a beneficiary of a social security category

E.4

Principal exclusion criteria

1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)
2.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
3. Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug.
NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a radiation therapy or neurosurgical consultant.
4.Has had a prior malignancy other than the malignancies under study
Exception: Subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible.
5.Has had major surgery within 3 weeks prior to enrollment
NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
6.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 laboratory. Cytogenetic testing and DNA sequencing will be
conducted following an abnormal result of bone marrow aspirate/biopsy.
7.Has a prior history of T-LBL/T-ALL.
8.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.
9.Has cardiovascular impairment, history of congestive heart failure
greater than NYHA Class II, uncontrolled arterial hypertension, unstable
angina, myocardial infarction, or stroke within 6 months prior to the
planned first dose of tazemetostat; or ventricular cardiac arrhythmia
requiring medical treatment
10.Is currently taking any prohibited medication(s) as described in the protocol.
NOTE: Subjects with a history of hepatitis B or C with normal ALT and
undetectable HBV DNA or HCV RNA are eligible for this study;
11.Has an active infection requiring systemic treatment
12.Is immunocompromised (ie has a congential immunodeficiency),
including subjects known history of infection with human
immunodeficiency virus (HIV)
13.Has known active infection with hepatitis B virus or hepatitis C virus
•Note - Subjects with a history of hepatitis B or C with normal ALT and
undetectable HBV DNA or HCV RNA are eligible for this study
14.Has had a symptomatic venous thrombosis within the 2 weeks prior
to study enrollment.
NOTE: Subjects with a history of a deep vein thrombosis > 2 weeks prior
to study enrollment who are on anticoagulation therapy with low
molecular weight heparin are eligible for this study.
15. 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
16.Has known hypersensitivity to any of the components of tazemetostat
or other inhibitor(s) of EZH2
17.Is unable to take oral medications, malabsorption syndrome or any
other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or
vomiting) that might impair the bioavailability of tazemetostat
18.Has an uncontrolled intercurrent illness including, but not limited to,
uncontrolled infection, or psychiatric illness/social situations that would
limit compliance with study requirements.
19.For female subjects of childbearing potential: Is pregnant or nursing
20.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.

E.5 End points

E.5.1

Primary end point(s)

- Cohorts 1 , 3, 4, 5 and 7 ORR (confirmed CR+PR) for tazemetostat in subjects with INI1-negative tumors using disease-appropriate standardized response criteria (primary CNS tumors: Response Assessment for Neuro-Oncology [RANO] and all others: RECIST 1.1).
-Cohort 2: PFS rate after 16 weeks of treatment with tazemetostat. This is the number of subjects with CR, PR, or stable disease (SD) at the Week 16 assessment.
- Cohort 6: Assessment of pre- and post-dose biopsies for immune priming (e.g., PD-L1 and CD8 IHC);
- Cohort 8: Assessment of safety and tolerability of tazemetostat following 1600 mg oral administration QD.

E.5.1.1

Timepoint(s) of evaluation of this end point

- Cohorts 1 (rhabdoid tumors), 3 (other INI1-negative tumors), 4 (renal medullary carcinoma) and 5 (epithelioid sarcoma) and 7- ORR: every 8 weeks for tumor response until disease progression;
- Cohort 2 (synovial sarcoma) – PFS: every 8 weeks until disease progression
- Cohort 6 pre-and post-dose biopsies;
- Cohort 8 assessment of AEs and clinical laboratory tests.

E.5.2

Secondary end point(s)

- Duration of response for each cohort and for Cohorts 1, 3, 4, 5, 6, and 7 combined. Duration of response, for the subset of subjects with a confirmed CR or PR, is defined as the time from the first documented evidence of CR or PR to the time of first documented disease progression or death due to any cause, using disease-appropriate standardized response criteria;
- Cohorts 5, 6 and 8: Disease control rate (DCR) for tazemetostat. This is defined as the number of subjects who achieve confirmed response (CR+PR) or who have SD lasting at least 32 weeks;
- Cohorts 2, 6 and 8: ORR (confirmed CR+PR, RECIST 1.1) for tazemetostat;
- PFS at Weeks 24, 32, and 56 and overall for each cohort. PFS is defined as the time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause;
- OS at Weeks 24, 32, and 56 and overall for each cohort. OS is defined as the time from the date of the first dose of study treatment to the date of death due to any cause;
Cohorts 1-7: Safety and tolerability of of orally administered tazemetostat 800 mg BID;
- Population PK parameters for tazemetostat including, but not limited to: oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka), AUC and CMAX, and apparent half-life;
- PD effects of tazemetostat in tumor tissue in IHC assessments of changes in the level of H3K27me3 following tazemetostat dosing.

E.5.2.1

Timepoint(s) of evaluation of this end point

Cohort 2 (synovial sarcoma) – ORR: every 8 weeks until disease progression
All Cohorts -
•PFS: every 8 weeks until disease progression and analyzed at 24 and 56 weeks. OS: continuously throughout the treatment period and then every 16 weeks until death or study completion
•Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death.
•Safety: At each visit or required timepoint during treatment and until for 30 days after last treatment or until new anti-cancer therapy
•PK: Days 1, 15, 29, 43 and 57
•PD: Any time after week 8

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

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

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