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

NCT02601950

Description:

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally in continuous 28 day cycles. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. Eligible subjects will be enrolled into one of fivecohorts based on tumor type: - Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, or 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 INI1 negative tumors or any solid tumor with an 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 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 8 weeks of treatment and then every 8 weeks thereafter while on study.

Related Conditions:
  • Malignant Solid Tumor
  • Rhabdoid Tumor
  • Synovial Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial 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

Clinical Trial IDs

  • ORG STUDY ID: EZH-202
  • NCT ID: NCT02601950

Conditions

  • 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

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438, E7438Open-label Tazemetostat

Purpose

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally in continuous 28 day cycles. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. Eligible subjects will be enrolled into one of fivecohorts based on tumor type: - Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, or 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 INI1 negative tumors or any solid tumor with an 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 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 8 weeks of treatment and then every 8 weeks thereafter while on study.

Trial Arms

NameTypeDescriptionInterventions
Open-label TazemetostatExperimentalAll Cohorts [Cohort 1 - MRT, RTK, ATRT, or 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 - Relapsed/refractory synovial sarcoma (SS18-SSX rea), Cohort 3 - Other INI1-negative tumors or any solid tumor with an EZH2 GOF mutation, Cohort 4 - Renal medullary carcinoma, Cohort 5 - Epithelioid sarcoma, Cohort 6 - Epithelioid sarcoma undergoing mandatory tumor biopsy and Cohort 7 - Poorly differentiated chordoma (or other chordoma with Sponsor approval)] will receive 800 mg oral Tazemetostat BID x 28 days
  • Tazemetostat

Eligibility 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 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 and Cohort 6 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, 5 and 7 (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 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 4.0.3 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, 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 (when this is in line with the preferred and usual
                  lifestyle of the subject,), 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 8.5.13.4.2, 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

        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 -
             NOTE: 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.

          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 30 days after last dose of tazemetostat.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects with objective response using disease appropriate standardized response criteria
Time Frame:Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
Safety Issue:
Description:The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment

Secondary Outcome Measures

Measure:Duration of response in subjects in Cohorts 1, 2, 3, 4, 5, 6 and 7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) and partial response (PR) following oral administration of tazemetostat 800 mg BID
Time Frame:Assess every 8 weeks for duration of study participation which is estimated to be 24 months
Safety Issue:
Description:
Measure:Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 5) and epithelioid sarcoma undergoing mandatory biopsy (Cohort 6) following oral administration of tazemetostat 800 mg BID
Time Frame:32 weeks of treatment
Safety Issue:
Description:The number of subjects with confirmed CR, PR or SD at 32 week assessment
Measure:Overall response rate ORR for Cohort 2 (relapsed/refractory synovial sarcoma) and Cohort 6 (epithelioid sarcoma undergoing mandatory biopsy)
Time Frame:Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
Safety Issue:
Description:ORR (confirmed CR+PR, RECIST 1.1)
Measure:PFS for each cohort
Time Frame:24, 32 and 56 weeks of treatment
Safety Issue:
Description: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
Measure:OS for each cohort
Time Frame:24, 32 and 56 weeks of treatment
Safety Issue:
Description:The time from the date of the first dose of study treatment to the date of death due to any cause
Measure:Incidence of treatment-emergent adverse events as a measure of safety and tolerability
Time Frame:Adverse events assessed from first dose through 30 days post last dose
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t)
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12)
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F
Time Frame:Days 1, 15, 29, 43, and 57
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F
Time Frame:Days 1, 15, 29, 43, and 57
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka
Time Frame:Days 1, 15, 29, 43, and 57
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough
Time Frame:Days 29, 43 and 57
Safety Issue:
Description:
Measure:Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue
Time Frame:At week 8
Safety Issue:
Description:IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Epizyme, Inc.

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