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A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma

Primary Purpose

Malignant Rhabdoid Tumors (MRT), Rhabdoid Tumors of the Kidney (RTK), Atypical Teratoid Rhabdoid Tumors (ATRT)

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tazemetostat
Sponsored by
Epizyme, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Rhabdoid Tumors (MRT)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 and 5)
    • That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2)

      • That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 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 equivalent laboratory certification
  7. For Cohort 1 (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 tests must be available by local laboratory: Morphology consistent with synovial sarcomas, 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/aberrant tumors 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 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 4.0.3 or are clinically stable and not clinically significant, at time of enrollment.
  12. Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below:

    • 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 42 days 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 stereostatic 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)
    • High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion 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)
  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
  15. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria below:

    • Hematologic (BM Function):

      • Hemoglobin ≥9 mg/dL
      • Platelets ≥100,000/mm^3 (≥100x10^9/L)
      • ANC ≥1,000/mm^3 (≥1.0x10^9/L)
    • Hematologic (Coagulation Factors):

      • INR/PT₫ <1.5 ULN
      • PTT>1.5 ULN
    • Renal Function:

      - Serum creatinine ≤1.5 x ULN

    • Hepatic Function:

      • Total bilirubin <1.5 x ULN(Eligibility can be determined by conjugated or total bilirubin)
      • AST and ALT <3 x ULN NOTE: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the Investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility.
  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 NOTE: 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 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 ≤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 Section 8.6.1, from a minimum of 7 days prior to first dose until 6 months following the last dose of tazemetostat 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 8.6.1), 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 as defined in Section 8.6.2, 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

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: A 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 re-vision) is permitted 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)
  11. Has an active infection requiring systemic treatment
  12. Is immunocompromised (i.e. has congenital 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 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 punctuate size of screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents
  16. Has known hypersensitivity to any of the component of tazemetostat or other inhibitor(s)of EZH2
  17. Is unable to take oral medications, or has a malabsorption syndrome or any uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that would limit compliance with study requirements.
  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 the study to at least 3 months after last dose of tazemetostat.

Sites / Locations

  • University of California San Francisco
  • University of Colorado Denver
  • Mayo Clinic - Jacksonville
  • Northwestern Memorial Hospital
  • Massachusetts General Hospital - Cancer Center
  • Dana Farber Cancer Institute
  • University of Michigan
  • Washington University
  • Memorial Sloan Kettering Cancer Center
  • Cincinnati Children's Hospital Medical Center
  • Oregon Health Sciences University
  • MD Anderson Cancer Center
  • Seattle Children's Hospital
  • Fred Hutchinson Cancer Research Center
  • Chris O'Brien Lifehouse
  • Metro South Hospital and Health Service via Princess Alexandra Hospital
  • Institut Jules Bordet Medical Oncology Clinic
  • University Hospital Leuven
  • Alberta Health Services
  • Princess Margaret Hospital
  • McGill University Health Centre - Royal Victoria Hospital
  • Institut Bergonie
  • Centre Leon Berard
  • Hospital Pitie Salpetriere
  • Institut Curie
  • Institut Gustave Roussy
  • Children's Hospital Augsburg Klinikum
  • Sarcoma Center HELIOS Klinikum Berlin
  • Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian
  • National Taiwan University Hospital
  • University College London Hospital
  • Royal Marsden Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-label Tazemetostat

Arm Description

All cohorts will receive 800 mg oral Tazemetostat twice a day in continuous 28-day cycles.

Outcomes

Primary Outcome Measures

Objective response rate (ORR) in Cohorts 1,3,4,5,6 and 7
Defined as the percentage of participants achieving a confirmed response (CR) or partial Response (PR) from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RANO criteria for primary brain tumors or RECIST 1.1 criteria for all other solid tumors. Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.
Progression-free survival (PFS) rate in Cohort 2
Defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause
Number of participants with adverse events (AEs) in Cohort 8
Severity of AEs experienced by all participants will be evaluated by the Investigator based on the Common Terminology Criteria for Adverse Events (CTCAE) CTCAE, version 5.0.
Percentage of Participants with Clinically Significant changes in Laboratory Parameters (blood chemistry, hematology and coagulation)
Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be evaluated by the investigator

Secondary Outcome Measures

Duration of response (DOR) in all Cohorts
Defined as the time from the first documented evidence of a response of at least partial remission (including partial remission and complete remission) to the time of first documented disease progression or death due to any cause, whichever comes first, using disease-appropriate standardized response criteria.
Disease control rate (DCR) in Cohort 5, 6 and 8
Defined as the percentage of participants who achieve a CR or PR (as per RECIST 1.1 criteria) or who have stable disease (SD) lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy
Objective Response Rate (ORR) in Cohort 2
Defined as the percentage of participants achieving a CR and PR from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RECIST 1.1 criteria for all other solid tumors (Appendix 5). Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.
Overall survival (OS) in all cohorts
Defined as the interval of time between the date of the first dose of study drug and the date of death due to any cause.
Overall survival for each cohort
The time from the date of the first dose of study treatment to the date of death due to any cause

Full Information

First Posted
October 21, 2015
Last Updated
September 21, 2023
Sponsor
Epizyme, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02601950
Brief Title
A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma
Official Title
A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 22, 2015 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Epizyme, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will include participants with various types of cancer known as soft-tissue sarcomas. Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep skin tissues, tendons and ligaments. Soft tissue cancers are rare and can occur almost anywhere in the body. Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front line treatment) can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for the next part of the study. Part 2 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy treatment).
Detailed Description
This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts: Cohort using tazemetostat 800 mg BID Cohort 1 (Closed for enrollment): malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type (SCCOHT), also known as malignant rhaboid tumor of the ovary (MRTO) Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement Cohort 3 (Closed for enrollment): Other integrase interactor 1 (INI1) negative tumors or any solid tumor with an enhancer of zeste homologue-2 (EZH2) gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC) Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES) Cohort 6 (Closed for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy Cohort 7 (Closed for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Closed for enrollment): Epitheliod sarcoma Participants will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Rhabdoid Tumors (MRT), Rhabdoid Tumors of the Kidney (RTK), Atypical Teratoid Rhabdoid Tumors (ATRT), Selected Tumors With Rhabdoid Features, Synovial Sarcoma, INI1-negative Tumors, Malignant Rhabdoid Tumor of Ovary, Renal Medullary Carcinoma, Epithelioid Sarcoma, Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval), Any Solid Tumor With an EZH2 GOF Mutation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
267 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open-label Tazemetostat
Arm Type
Experimental
Arm Description
All cohorts will receive 800 mg oral Tazemetostat twice a day in continuous 28-day cycles.
Intervention Type
Drug
Intervention Name(s)
Tazemetostat
Other Intervention Name(s)
EPZ-6438, E7438, IPN60200
Intervention Description
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Primary Outcome Measure Information:
Title
Objective response rate (ORR) in Cohorts 1,3,4,5,6 and 7
Description
Defined as the percentage of participants achieving a confirmed response (CR) or partial Response (PR) from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RANO criteria for primary brain tumors or RECIST 1.1 criteria for all other solid tumors. Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.
Time Frame
Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years
Title
Progression-free survival (PFS) rate in Cohort 2
Description
Defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause
Time Frame
16 weeks of treatment
Title
Number of participants with adverse events (AEs) in Cohort 8
Description
Severity of AEs experienced by all participants will be evaluated by the Investigator based on the Common Terminology Criteria for Adverse Events (CTCAE) CTCAE, version 5.0.
Time Frame
Through study completion, an average of 2 years
Title
Percentage of Participants with Clinically Significant changes in Laboratory Parameters (blood chemistry, hematology and coagulation)
Description
Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be evaluated by the investigator
Time Frame
Up to 2 years.
Secondary Outcome Measure Information:
Title
Duration of response (DOR) in all Cohorts
Description
Defined as the time from the first documented evidence of a response of at least partial remission (including partial remission and complete remission) to the time of first documented disease progression or death due to any cause, whichever comes first, using disease-appropriate standardized response criteria.
Time Frame
Assess every 8 weeks for duration of study participation which is estimated to be 2 years.
Title
Disease control rate (DCR) in Cohort 5, 6 and 8
Description
Defined as the percentage of participants who achieve a CR or PR (as per RECIST 1.1 criteria) or who have stable disease (SD) lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy
Time Frame
32 weeks of treatment
Title
Objective Response Rate (ORR) in Cohort 2
Description
Defined as the percentage of participants achieving a CR and PR from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RECIST 1.1 criteria for all other solid tumors (Appendix 5). Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.
Time Frame
Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years
Title
Overall survival (OS) in all cohorts
Description
Defined as the interval of time between the date of the first dose of study drug and the date of death due to any cause.
Time Frame
24, 32 and 56 weeks of treatment
Title
Overall survival for each cohort
Description
The time from the date of the first dose of study treatment to the date of death due to any cause
Time Frame
Weeks 24, 32, 56, and at end of study, an average of 2 years.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age (at the time of consent/assent): ≥18 years of age Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Has provided signed written informed consent Has a life expectancy of >3 months Has a malignancy: For which there are no standard therapies available (Cohorts 1, 3, 4 and 5) That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2) That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 8 ONLY) 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 For Cohort 1 (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 For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only), the following tests must be available by local laboratory: Morphology consistent with synovial sarcomas, and cytogenetics or fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) For Cohort 3, 4, 5, 7 and 8 (subjects with INI1-negative/aberrant tumors 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 For Cohort 6 (subjects with ES undergoing optional tumor biopsy) only: Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA, Keratin, and INI1) Has all prior treatment (i.e. chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are clinically stable and not clinically significant, at time of enrollment. Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below: 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 42 days 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 stereostatic 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) High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion 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) Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function. 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 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 ≤2 Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 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 and Agree to use effective contraception from a minimum of 7 days prior to first dose until 6 months 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 Male subjects with a female partner of childbearing potential must: Be vasectomized, or Agree to use condoms as defined in Section 8.6.2, 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 Exclusion Criteria: Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2) 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 Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor. Has had a prior malignancy other than the malignancies under study - EXCEPTION: A 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 Has had major surgery within 3 weeks prior to enrollment 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. Has a prior history of T-LBL /T-ALL Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet 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 Is currently taking any prohibited medication(s) Has an active infection requiring systemic treatment Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV) Has known active infection with hepatitis B virus or hepatitis C virus Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment - For subjects with CNS involvement (primary tumor or metastatic disease), have any active bleeding or new intratumoral hemorrhage of more than punctuate size of screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents Has known hypersensitivity to any of the component of tazemetostat or other inhibitor(s)of EZH2 Is unable to take oral medications, or has a malabsorption syndrome or any uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that would limit compliance with study requirements. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. 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 the study to at least 3 months after last dose of tazemetostat.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ipsen Medical Director
Organizational Affiliation
Ipsen
Official's Role
Study Director
Facility Information:
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
University of Colorado Denver
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Mayo Clinic - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Massachusetts General Hospital - Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Chris O'Brien Lifehouse
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
Metro South Hospital and Health Service via Princess Alexandra Hospital
City
Woolloongabba
ZIP/Postal Code
QLD 4102
Country
Australia
Facility Name
Institut Jules Bordet Medical Oncology Clinic
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
University Hospital Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Alberta Health Services
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
McGill University Health Centre - Royal Victoria Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Facility Name
Institut Bergonie
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Centre Leon Berard
City
Lyon
ZIP/Postal Code
69008
Country
France
Facility Name
Hospital Pitie Salpetriere
City
Paris Cedex 13
ZIP/Postal Code
75651
Country
France
Facility Name
Institut Curie
City
Paris
ZIP/Postal Code
75248
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Children's Hospital Augsburg Klinikum
City
Augsburg
ZIP/Postal Code
86156
Country
Germany
Facility Name
Sarcoma Center HELIOS Klinikum Berlin
City
Berlin
ZIP/Postal Code
13125
Country
Germany
Facility Name
Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian
City
Milano
ZIP/Postal Code
20133
Country
Italy
Facility Name
National Taiwan University Hospital
City
Taipei City
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
University College London Hospital
City
London
ZIP/Postal Code
NW1 2PG
Country
United Kingdom
Facility Name
Royal Marsden Foundation Trust
City
London
ZIP/Postal Code
SW3 6JJ
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33035459
Citation
Gounder M, Schoffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, Attia S, Chugh R, Chen TW, Jahan T, Loggers ET, Gupta A, Italiano A, Demetri GD, Ratan R, Davis LE, Mir O, Dileo P, Van Tine BA, Pressey JG, Lingaraj T, Rajarethinam A, Sierra L, Agarwal S, Stacchiotti S. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020 Nov;21(11):1423-1432. doi: 10.1016/S1470-2045(20)30451-4. Epub 2020 Oct 6.
Results Reference
derived

Learn more about this trial

A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma

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