EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Registration Number
NCT02601937
Lead Sponsor
Epizyme, Inc.
Brief Summary

This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of the enhancer of zeste homolog-2 (EZH2) inhibitor, 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...

Detailed Description

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
...

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
109
Inclusion Criteria

  1. Age (at the time of consent/assent): ≥6 months to <18 years

    • Cohort 4 only: ≥10 years to <18 years

  2. Performance Status:

    • If <12 years of age: Lanksy Performance Status >50%
    • If ≥12 years of age: Karnofsky Performance Status >50% NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status.

  3. Has provided signed written informed consent/assent

  4. Has a life expectancy of >3 months

  5. Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion

  6. Is ineligible or inappropriate for other treatment regimens known to have effective potential

  7. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification

  8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment

  9. Has completed a prior therapy (ies) according to the criteria below:

    • Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat)
    • Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat)
    • Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat)
    • Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat)
    • Monoclonal antibody (ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)
    • Immunotherapy (e.g., tumor vaccine) At least 6 weeks since last dose of immunotherapy agent(s) prior to first dose of tazemetostat)
    • Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereotactic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥ 50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat)
    • Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat)
    • Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat)

  10. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below:

    • Hematologic (BM Function):

      • Hemoglobin ≥ 8 g/dL
      • Platelets ≥100,000/mm^3 (≥100 x 10^9/L)
      • ANC ≥1,000/mm^3 (≥1.0 x 10^9/L)

    • Hematologic (Coagulation Factors):

      • INR/ PTd ≤1.5 ULN
      • PTT ≤1.5 ULN
      • Fibrinogen ≥0.75 LLN

    • Renal Function (creatinine clearance or serum creatinine):

      • Calculated creatinine clearance ≥50 mL/min/1.73m^2
      • Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L)
      • Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L)
      • Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L)
      • Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L)
      • Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L)
      • Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L)
      • Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L)

    • Hepatic Function:

      • Total bilirubin <1.5 x ULN
      • ALT or AST <3 x ULN Eligibility can be determined by either total or conjugated bilirubin

  11. For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 7 days prior to enrollment NOTE: Subjects with leptomeningeal disease or brain tumors with positive cerebral spinal fluid cytology are eligible for this study. Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to enrollment.

  12. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram or multi-gated acquisition scan and New York Heart Association Class<2

  13. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec

  14. Is able to swallow and retain orally administered medication and does not have any uncontrolled gastrointestinal (GI) condition such as nausea, vomiting, or diarrhea, or any clinically significant GI abnormalities that may alter absorption such as malabsorption syndromes, hereditary fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltase insufficiency, or major resection of stomach and/or bowels NOTE: Nasogastric and gastrostomy tube administration of the oral suspension formulation of study drug is permitted.

  15. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of immunohistochemistry and/or cytogenetics/fluorescence in situ hybridization (FISH) and/or deoxyribonucleic acid mutation analysis (required for study entry but enrollment based on local results)

  16. Is willing and able to comply with all aspects of the protocol as judged by Investigator

  17. For female subjects of childbearing potential: Subject must:

    • Have a negative beta-human chorionic gonadotropin (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 8.6.11 start of Screening until 6 months following the last dose of study treatment and have a male partner who uses a condom, or
    • Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.6.11, or
    • Have a male partner who is vasectomized with confirmed azoospermia

  18. For male subjects with a female partner of childbearing potential: Subject must:

    • Be vasectomized or
    • Agree to use condoms as defined in Section 8.5.11 from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or
    • Have a female partner who is NOT of childbearing potential

For Dose Escalation Only:

To be eligible for enrollment in dose escalation, a subject must meet ALL of the following criteria in addition to the inclusion criteria listed above for all subjects:

  1. Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination and other lesions such as bone lesions, leptomeningeal disease, ascites, hepatosplenomegaly from disease.

  2. Has one of the following histologically confirmed tumors: (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available)

    • Rhabdoid tumor:

      • ATRT
      • MRT
      • RTK
      • Selected tumors with rhabdoid features

    • NI1-negative tumor:

      • Epithelioid sarcoma
      • Epithelioid malignant peripheral nerve sheath tumor
      • Extraskeletal myxoid chondrosarcoma
      • Myoepithelial carcinoma
      • Renal medullary carcinoma
      • Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval

    • Synovial sarcoma with SS18-SSX rearrangement (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) (Closed to enrollment)

  3. For subjects with ATRT, MRT, RTK, or selected tumors with rhabdoid features only: the following test results must be available: Morphology and immunophenotypic panel consistent with rhabdoid tumor and Loss of INI1 or SMARCA4 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

  4. For subjects with INI1 negative tumor only:

    the following test results must be available: Morphology and immunophenotypic panel consistent with INI1-negative tumors, and Loss of INI1 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable

  5. For subjects with synovial sarcoma only:

The following test results must be available:

Morphology consistent with synovial sarcoma, and Cytogenetics or FISH and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)

For Dose Expansion Only:

Note: To be eligible for enrollment in Dose Expansion, a subject must meet ALL of the following criteria in addition to the inclusion criteria for ALL subjects listed above

  1. Has measurable disease

  2. Has one of the following histologically confirmed tumors:

    • Cohort 1 - ATRT (Closed to enrollment)

    • Cohort 2 - MRT/RTK/selected tumors with rhabdoid features (Closed to enrollment)

    • Cohort 3 - INI-negative tumors (Closed to enrollment):

      • Epithelioid sarcoma
      • Epithelioid malignant peripheral nerve sheath tumor
      • Extraskeletal myxoid chondrosarcoma(EMC)
      • Myoepithelial carcinoma
      • Renal medullary carcinoma
      • Chordoma (poorly differentiated or de-differentiated)
      • Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval

    • Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Closed to enrollment) NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP or other Sponsor-approved certified laboratory must be available.

  3. For subjects with ATRT/MRT/RTK only - have the following test results available:

    • Morphology and immunophenotypic panel consistent with rhabdoid tumor, and
    • Loss of INI1 or SMARCA4 confirmed by IHC, or
    • Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

  4. For subjects with INI1-negative tumors only: The following test results must be available:

    • Morphology and immunophenotypic panel consistent with INI1-negative tumors, and
    • Loss of INI1 confirmed by IHC, or
    • Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable

  5. For subjects with synovial sarcoma with SS18-SSX rearrangement (in Cohort 4 ONLY - Closed to enrollment): The following test results must be available:

    • Morphology consistent with synovial sarcoma, and
    • Cytogenetics or FISH and/or molecular confirmation (e.g., deoxyribonucleic acid [DNA] sequencing) of SS18 rearrangement t(X;18)(p11;q11)

  6. For subjects to be enrolled in Cohort 4 (Closed to enrollment): Able to swallow and retain orally administered tablets

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Exclusion Criteria

  1. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2

  2. Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy

  3. Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat

  4. Has had major surgery within 2 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 2 weeks prior to enrollment.

  5. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.

    Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central lab at screening. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.

  6. Has a prior history of T-LBL/T-ALL.

  7. Has clinically active heart disease including prolonged corrected QTcF (>450 msec)

  8. Is currently taking any prohibited medication(s) as described in Section 7.3.

  9. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study

  10. Has an active infection requiring systemic treatment

  11. Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV)

  12. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)

  13. Has had a symptomatic venous thrombosis within the 14 days prior to study enrollment NOTE: Subjects with a history of a deep vein thrombosis 14 days prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study

  14. For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug,or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents 15.15. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben

  15. 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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Dose Expansion Cohort 2TazemetostatPediatric patients with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features who participated in the dose expansion portion of the study Patients whose disease was without central nervous system (CNS) involvement received 520 mg/m\^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Patients whose disease had CNS involvement received 1200 mg/m\^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
Dose Expansion Cohort 3TazemetostatPediatric patients with INI-negative tumors who participated in the dose expansion portion of the study. Patients whose disease was without central nervous system (CNS) involvement received 520 mg/m\^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Patients whose disease had CNS involvement received 1200 mg/m\^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
Dose Expansion Cohort 4TazemetostatPediatric patients with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement. Patients received 800 mg/m\^2 tazemetostat three times daily (TID) orally in continuous 28-day cycles.
Dose Escalation Level 1TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 240 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Escalation Level 2TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 300 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Escalation Level 3TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 400 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Escalation Level 4TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 520 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Escalation Level 5TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 700 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Escalation Level 6TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 900 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Dose Expansion Cohort 1TazemetostatPediatric patients with atypical teratoid rhabdoid tumor (ATRT) who participated in the dose expansion portion of the study. Patients received 1200 mg/m\^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
Dose Escalation Level 7TazemetostatPediatric patients with select R/R rhabdoid tumors, INI1- SMARCA4-negative tumors, or synovial sarcoma who participated in the dose escalation portion of the study. Participants received 1200 mg/m\^2, open-label, oral tazemetostat twice daily (BID) in continuous 28-day cycles
Primary Outcome Measures
NameTimeMethod
Recommended Phase 2 Dose (RP2D) (Dose Escalation Only)Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment

The incidence and severity of treatment-emergent adverse events qualifying as protocol-defined dose-limiting toxicities that occurred during the first month of treatment was used to determine the RP2D and/or maximum tolerated dose (MTD) in pediatric patients treated with tazemetostat.

Number of Dose-limiting Toxicities (Dose Escalation Only)Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment

The RP2D in pediatric patients treated with tazemetostat as determined by the incidence and severity of treatment-emergent adverse events qualifying as protocol-defined dose-limiting toxicities that occurred during the first month of treatment.

Overall Response Rate (ORR) (Dose Expansion Only)RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks

ORR is defined as the percentage of patients who achieved a confirmed complete response (CR) and/or partial response (PR) defined by response evaluation criteria in solid tumors (RECIST) or response assessment in neuro-oncology (RANO) criteria from the start of tazemetostat treatment until disease progression or the start of subsequent anticancer therapy, wh...

Secondary Outcome Measures
NameTimeMethod
ORR (Dose Escalation Only)RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks

ORR is defined as the percentage of patients who achieved a confirmed CR and/or PR defined by RECIST or RANO criteria from the start of tazemetostat treatment until disease progression or the start of subsequent anticancer therapy, whichever occurs first. CR is defined as disappearance of all target and non-target lesions (with all lymph nodes must be non-pa...

Progression Free Survival (PFS) (Dose Expansion Only)RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks

PFS was defined as the interval of time (in weeks) from the date of first dose of study drug and the earliest date of disease progression or death, from any cause defined by RECIST or RANO criteria. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including at ...

Overall Survival (Dose Expansion Only)RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks

Overall survival was defined as the time (in weeks) from the first dose of study drug to the date of death due to any cause.

Trial Locations

Locations (35)

The Hospital for Sick Children

🇨🇦

Toronto, Ontario, Canada

Dana Farber Cancer Institute

🇺🇸

Boston, Massachusetts, United States

Texas Children's Cancer and Hematology Center

🇺🇸

Houston, Texas, United States

Seattle Children's Hospital

🇺🇸

Seattle, Washington, United States

Children's Hospital of Los Angeles

🇺🇸

Los Angeles, California, United States

University of California San Francisco - Benioff Children's Hospital

🇺🇸

San Francisco, California, United States

John Hopkins Kimmel Cancer Center

🇺🇸

Baltimore, Maryland, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

🇺🇸

Chicago, Illinois, United States

Massachusetts General Hospital - Cancer Center

🇺🇸

Boston, Massachusetts, United States

Children's Hospital of Philadelphia

🇺🇸

Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital, Inc.

🇺🇸

Memphis, Tennessee, United States

Memorial Sloan Kettering

🇺🇸

New York, New York, United States

Oregon Health & Science University (OHSU)

🇺🇸

Portland, Oregon, United States

UT Southwestern Medical Center

🇺🇸

Dallas, Texas, United States

Sydney Children's Hospital

🇦🇺

Sydney, New South Wales, Australia

Lady Cilento/Queensland Children's Hospital

🇦🇺

South Brisbane, Queensland, Australia

The Royal Children's Hospital

🇦🇺

Melbourne, Victoria, Australia

The Childrens Hospital at Westmead Oncology Unit

🇦🇺

Westmead, Australia

Institut Gustave Roussy

🇫🇷

Villejuif, France

Institut Curie

🇫🇷

Paris, France

Rigshospitalet Department of Oncology Blegdamsvej

🇩🇰

Copenhagen, Denmark

Children's Hospital Augsburg Klinikum

🇩🇪

Augsburg, Germany

Charite - Universitatsmedizin Berlin

🇩🇪

Berlin, Germany

Universitaetsklinikum Heidelberg

🇩🇪

Heidelberg, Germany

Westfalische Wilhelms - Universitat Munster Padiatrische

🇩🇪

Munster, Germany

Fondazione IRCCS Istituto Nazionale dei Tumori

🇮🇹

Milano, Italy

Great Ormond Street Hospital for Children NHS Foundation Trust

🇬🇧

London, United Kingdom

Central Manchester University Hospital - Royal Manchester Children's Hospital

🇬🇧

Manchester, United Kingdom

Cincinnati Children's Hospital Medical Center

🇺🇸

Cincinnati, Ohio, United States

Children's Hospital Colorado

🇺🇸

Aurora, Colorado, United States

Istituto Giannina Gaslini- UOSD Centro di Neuro-Oncologia

🇮🇹

Genova, Italy

Children's Healthcare of Atlanta

🇺🇸

Atlanta, Georgia, United States

Children's National Medical Center

🇺🇸

Washington, District of Columbia, United States

Erasmus University Medical Center - Sophia Children's Hospital

🇳🇱

Rotterdam, Netherlands

Prinses Maxima Centrum voor Kinderoncologie

🇳🇱

Utrecht, Netherlands

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