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

• Register: EUCTR
• Last refreshed on: 4 May 2020
• Main ID: EUCTR2015-002469-41-GB
• Date of registration: 28/10/2015
• Prospective Registration: Yes
• Primary sponsor: Epizyme, Inc.
• Public title: A Study of the Effect of Tazemetostat (study drug) in Patients with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
• Scientific title: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
• Date of first enrolment: 18/04/2016
• Target sample size: 291
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002469-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: Single blind: Double blind: Parallel group: Cross over: Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, France, Germany, Italy, Taiwan, United Kingdom, United States

Contacts

• Name: Clinical Trials Information
• Affiliation: Epizyme, Inc.

• Name: Clinical Trials Information
• Affiliation: Epizyme, Inc.

Key inclusion & exclusion criteria

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 other solid tumour 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 optional tumor biopsy):•Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1) •If providing optional biopsy: 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 as 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: must have stable seizures, not increasing in freque
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 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.
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)
NOTE: HIV positive subjects who are taking antiretroviral therapy are ineligible due to potential PK interactions with tazemetostat.
13.Has known active infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
14.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 molec

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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 optional tumour biopsy Cohort 7: Poorly differentiated chordoma
MedDRA version: 20.0 Level: LLT Classification code 10007284 Term: Carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1 Level: LLT Classification code 10064886 Term: Renal medullary carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0 Level: PT Classification code 10073134 Term: Extraskeletal myxoid chondrosarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1 Level: LLT Classification code 10026667 Term: Malignant peripheral nerve sheath tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1 Level: LLT Classification code 10073335 Term: Rhabdoid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10042863 Term: Synovial sarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: HLT Classification code 10015100 Term: Epithelioid sarcomas System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: TAZVERIK [Trademark]
Product Name: tazemetostat
Product Code: EPZ-6438
Pharmaceutical Form: Tablet
INN or Proposed INN: TAZEMETOSTAT
CAS Number: 1403254-99-8
Current Sponsor code: EPZ-6438
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Primary end point(s): Cohorts 1,3,4,5,6 and 7 Overall response rate (ORR) (confirmed complete response (CR) and partial response (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 confirmed complete response (CR), partial response (PR) or stable disease (SD) at the week 16 assessment.
Cohort 8: Assessment of safety and tolerability of Tazemetostat following 1600 mg oral administration QD.

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), 6 [epithelioid sarcoma undergoing optional tumor biopsy and 7 - ORR: every 8 weeks for tumor response until disease progression;
Cohort 2 (synovial sarcoma) – PFS: every 8 weeks until disease progression
Cohort 8 assessment of AEs and Clinical Laboratory tests.

Secondary Objective: -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 administration 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 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

Main Objective: To assess the overall response rate (ORR) in subjects with rhabdoid tumors (Cohort 1) and other INI1-negative tumors or any other solid tumor with GOF mutation (Cohort 3), and renal medullary carcinoma (Cohort 4) and epithelioid sarcoma (Cohort 5), epithelioid sarcoma with optional tumor biopsy (Cohort 6) 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

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

Secondary Outcome(s)

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

Secondary end point(s): - Response duration for each cohort and Cohorts 1 ,3, 4, 5, 6 and 7 combined and Cohort 8. Response duration, for the subset of subjects with a confirmed CR or PR, is defined as the time from the first documented evidence of confirmed CR or PR to the time of first documented disease progression or death due to any cause, whichever comes first, 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 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 the 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 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 an 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

Secondary ID(s)

EZH-202

Source(s) of Monetary Support

Epizyme, Inc.

Ethics review

Status: Approved
Approval date: 18/04/2016
Contact: