Clinical Trials /

A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

NCT02601937

Description:

This is a Phase I, open-label, dose escalation and dose expansion study with a BID 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 Expansion at the MTD or the RP2D - Cohort 1 -(closed to enrollment) ATRT - Cohort 2 - MRT/RTK/selected tumors with rhabdoid features - 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 -(closed to enrollment) Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
  • Official Title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: EZH-102
  • NCT ID: NCT02601937

Conditions

  • Rhabdoid Tumors
  • INI1-negative Tumors
  • Synovial Sarcoma
  • Malignant Rhabdoid Tumor of Ovary

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438, E7438Open-label Tazemetostat

Purpose

This is a Phase I, open-label, dose escalation and dose expansion study with a BID 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 Expansion at the MTD or the RP2D - Cohort 1 -(closed to enrollment) ATRT - Cohort 2 - MRT/RTK/selected tumors with rhabdoid features - 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 -(closed to enrollment) Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Trial Arms

NameTypeDescriptionInterventions
Open-label TazemetostatExperimentalLevel 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
  • Tazemetostat

Eligibility Criteria

        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 written informed consent

          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 brian 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 (β-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 8.5.11 start of
                  Screening until 30 days 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 8.5.11, 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 30 days 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)

          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)

        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

               -  Cohort 2 - MRT/RTK/selected tumors with rhabdoid features

               -  Cohort 3 - INI-negative tumors:

                    -  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 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.

             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 only: 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: Able to swallow and retain orally
             administered tablets

        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. 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)

          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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:6 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the MTD or the RP2D (Dose Escalation)
Time Frame:1 cycle/28 days
Safety Issue:
Description:The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 will guide establishment of the protocol defined RP2D and/or MTD

Secondary Outcome Measures

Measure:Dose escalation: 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:
Measure:Dose Expansion: Progression-free survival (PFS)
Time Frame:At 24 and 56 weeks post treatment using Kaplan-Meier method
Safety Issue:
Description:
Measure:Dose Expansion: Overall Survival (OS)
Time Frame:At 24 and 56 weeks post treatment using Kaplan-Meier method
Safety Issue:
Description:
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 tazemetostat and its metabolite (plasma): Cmax
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Tmax
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-t)
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): AUC(0-12)
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): t1/2
Time Frame:Days 1 and 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): CL/F
Time Frame:Day 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Vd/F
Time Frame:Day 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ka
Time Frame:Day 15
Safety Issue:
Description:
Measure:Pharmacokinetics profile of tazemetostat and its metabolite (plasma): Ctrough
Time Frame:Day 1 of cycles 2, 3 and 4
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Epizyme, Inc.

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