ANZCTR - Registration

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]

EZH-102

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Rhabdoid Tumors

INI1-negative Tumors

Synovial Sarcoma

Malignant Rhabdoid Tumor of Ovary

Condition category

Condition code

Cancer

Sarcoma (also see 'Bone') - soft tissue

Cancer

Bone

Cancer

Kidney

Cancer

Children's - Other

Cancer

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]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

To determine the MTD or the RP2D (Dose Escalation)

Timepoint [1]

1 cycle/28 days

Primary outcome [2]

Dose expansion: Number of subjects with objective response using disease appropriate standardized response criteria

Timepoint [2]

Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Secondary outcome [1]

Dose escalation: Number of subjects with objective response using disease appropriate standardized response criteria

Timepoint [1]

Assessed every 8 weeks for duration of study participation which is estimated to be 24 months

Secondary outcome [2]

Dose Expansion: Progression-free survival (PFS)

Timepoint [2]

At 24 and 56 weeks post treatment using Kaplan-Meier method

Secondary outcome [3]

Dose Expansion: Overall Survival (OS)

Timepoint [3]

At 24 and 56 weeks post treatment using Kaplan-Meier method

Secondary outcome [4]

Incidence of treatment-emergent adverse events as a measure of safety and tolerability

Timepoint [4]

Adverse events assessed from first dose through 30 days post last dose

Secondary outcome [5]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Cmax

Timepoint [5]

Days 1 and 15

Secondary outcome [6]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax

Timepoint [6]

Days 1 and 15

Secondary outcome [7]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)

Timepoint [7]

Days 1 and 15

Secondary outcome [8]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)

Timepoint [8]

Days 1 and 15

Secondary outcome [9]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2

Timepoint [9]

Days 1 and 15

Secondary outcome [10]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F

Timepoint [10]

Day 15

Secondary outcome [11]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F

Timepoint [11]

Day 15

Secondary outcome [12]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka

Timepoint [12]

Day 15

Secondary outcome [13]

Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough

Timepoint [13]

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

Statistical methods / analysis

Recruitment

Recruitment status

Completed

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]

Sydney Children's Hospital - Sydney

Recruitment hospital [2]

Lady Cilento/Queensland Children's Hospital - South Brisbane

Recruitment hospital [3]

The Royal Children's Hospital - Melbourne

Recruitment hospital [4]

The Childrens Hospital at Westmead Oncology Unit - Westmead

Recruitment postcode(s) [1]

2031 - Sydney

Recruitment postcode(s) [2]

4101 - South Brisbane

Recruitment postcode(s) [3]

3052 - Melbourne

Recruitment postcode(s) [4]

2145 - Westmead

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

United States of America

State/province [2]

Colorado

Country [3]

United States of America

State/province [3]

District of Columbia

Country [4]

United States of America

State/province [4]

Georgia

Country [5]

United States of America

State/province [5]

Illinois

Country [6]

United States of America

State/province [6]

Maryland

Country [7]

United States of America

State/province [7]

Massachusetts

Country [8]

United States of America

State/province [8]

New York

Country [9]

United States of America

State/province [9]

Ohio

Country [10]

United States of America

State/province [10]

Oregon

Country [11]

United States of America

State/province [11]

Pennsylvania

Country [12]

United States of America

State/province [12]

Tennessee

Country [13]

United States of America

State/province [13]

Texas

Country [14]

United States of America

State/province [14]

Washington

Country [15]

Canada

State/province [15]

Ontario

Country [16]

Denmark

State/province [16]

Copenhagen

Country [17]

France

State/province [17]

Paris

Country [18]

France

State/province [18]

Villejuif

Country [19]

Germany

State/province [19]

Augsburg

Country [20]

Germany

State/province [20]

Berlin

Country [21]

Germany

State/province [21]

Heidelberg

Country [22]

Germany

State/province [22]

Munster

Country [23]

Italy

State/province [23]

Genova

Country [24]

Italy

State/province [24]

Milano

Country [25]

Netherlands

State/province [25]

Rotterdam

Country [26]

Netherlands

State/province [26]

Utrecht

Country [27]

United Kingdom

State/province [27]

London

Country [28]

United Kingdom

State/province [28]

Manchester

Funding & Sponsors

Primary sponsor type

Commercial sector/Industry

Name

Epizyme, Inc.

Country

Ethics approval

Ethics application status

Summary

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)

Trial website

https://clinicaltrials.gov/ct2/show/NCT02601937

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Email

Contact person for public queries

Name

Address

Country

Phone

Email

Contact person for scientific queries

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02601937