Rhabdoid TumorsPhase 1NCT02601937
EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
A Phase 1 study testing Tazemetostat in people with Rhabdoid Tumors and INI1-negative Tumors, run by Epizyme, Inc. at 35 sites in 9 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 months to 17 years
- Conditions the study is for
- Rhabdoid Tumors, INI1-negative Tumors, Synovial Sarcoma
- What is being tested?
- Tazemetostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 109 participants
- Where
- 35 sitesin 9 countries
- Study dates
- 7 Jan 2016to 22 Oct 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Age (at the time of consent/assent): ≥6 months to <18 years
- Cohort 4 only: ≥10 years to <18 years
- 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.
- Has provided signed written informed consent/assent
Show all 107Show fewer
- Has a life expectancy of >3 months
- 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
- Is ineligible or inappropriate for other treatment regimens known to have effective potential
- 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
- 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
- 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)
- 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
- 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.
- 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
- Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec
- 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.
- 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)
- Is willing and able to comply with all aspects of the protocol as judged by Investigator
- 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
- 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:
- 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.
- 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)
- 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
- 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
- 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
- Has measurable disease
- 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.
- 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
- 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
- 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)
- For subjects to be enrolled in Cohort 4 (Closed to enrollment): Able to swallow and retain orally administered tablets
Who cannot join
- Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2
- Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy
- 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 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.
- 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.
Show all 16Show fewer
- Has a prior history of T-LBL/T-ALL.
- Has clinically active heart disease including prolonged corrected QTcF (>450 msec)
- Is currently taking any prohibited medication(s) as described in Section 7.3.
- 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
- Has an active infection requiring systemic treatment
- Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV)
- Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
- 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
- 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.
Trial locations and contacts
35 sites in 9 countries.
35 sites in 9 countries
United States17 sites
Children's Healthcare of Atlanta
Atlanta, Georgia, 30322
Children's Hospital Colorado
Aurora, Colorado, 80045
John Hopkins Kimmel Cancer Center
Baltimore, Maryland, 21287
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Massachusetts General Hospital - Cancer Center
Boston, Massachusetts, 02215
Ann and Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
UT Southwestern Medical Center
Dallas, Texas, 75235
Texas Children's Cancer and Hematology Center
Houston, Texas, 77098
Children's Hospital of Los Angeles
Los Angeles, California, 90027
St. Jude Children's Research Hospital, Inc.
Memphis, Tennessee, 38105
Memorial Sloan Kettering
New York, New York, 10065
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Oregon Health & Science University (OHSU)
Portland, Oregon, 97239
University of California San Francisco - Benioff Children's Hospital
San Francisco, California, 94158
Seattle Children's Hospital
Seattle, Washington, 98105
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Australia4 sites
The Royal Children's Hospital
Melbourne, Victoria, 3052
Lady Cilento/Queensland Children's Hospital
South Brisbane, Queensland, 4101
Sydney Children's Hospital
Sydney, New South Wales, 2031
The Childrens Hospital at Westmead Oncology Unit
Westmead, 2145
Germany4 sites
Children's Hospital Augsburg Klinikum
Augsburg, 86156
Charite - Universitatsmedizin Berlin
Berlin, 13353
Universitaetsklinikum Heidelberg
Heidelberg
Westfalische Wilhelms - Universitat Munster Padiatrische
Münster, 48149
France2 sites
Institut Curie
Paris, 75248
Institut Gustave Roussy
Villejuif, 94800
Italy2 sites
Istituto Giannina Gaslini- UOSD Centro di Neuro-Oncologia
Genova, 16147
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, 20133
Netherlands2 sites
Erasmus University Medical Center - Sophia Children's Hospital
Rotterdam
Prinses Maxima Centrum voor Kinderoncologie
Utrecht, 3584 EA
United Kingdom2 sites
Great Ormond Street Hospital for Children NHS Foundation Trust
London, WC1N 3JH
Central Manchester University Hospital - Royal Manchester Children's Hospital
Manchester, M13 9WL
Denmark1 site
Rigshospitalet Department of Oncology Blegdamsvej
Copenhagen, 2100
About this study
Official title: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
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 after 8 weeks of treatment and subsequently every 8 weeks while on study.
Read the 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
- Integrase interactor 1 (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)
- Synovial Sarcoma with a SS18-SSX rearrangement Dose Escalation cohorts are closed to enrollment.
Dose Expansion at the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D)
- 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
- Myoepithelial carcinoma
- Renal medullary carcinoma
- Chordoma (poorly differentiated or de-differentiated)
- Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma)
- Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement
- Conditions
- Rhabdoid Tumors, INI1-negative Tumors, Synovial Sarcoma, Malignant Rhabdoid Tumor of Ovary
- Being tested
- Tazemetostat
- Medical subject headings
- Rhabdoid Tumor, Sarcoma, Synovial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TazemetostatDrug
Also called IPN60200, EPZ-6438, E7438
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.
| Study group | Role | What they receive |
|---|---|---|
| Dose Escalation Level 1 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 2 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 3 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 4 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 5 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 6 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Escalation Level 7 | Experimental | Pediatric 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 Receives: Drug: Tazemetostat |
| Dose Expansion Cohort 1 | Experimental | Pediatric 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. Receives: Drug: Tazemetostat |
| Dose Expansion Cohort 2 | Experimental | Pediatric 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. Receives: Drug: Tazemetostat |
| Dose Expansion Cohort 3 | Experimental | Pediatric 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. Receives: Drug: Tazemetostat |
| Dose Expansion Cohort 4 | Experimental | Pediatric 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. Receives: Drug: Tazemetostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended Phase 2 Dose (RP2D) (Dose Escalation Only)
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.
Measured: Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment
Number of Dose-limiting Toxicities (Dose Escalation Only)
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.
Measured: Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment
Overall Response Rate (ORR) (Dose Expansion Only)
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, whichever occurs first. CR is defined as disappearance of all target and non-target lesions (with all lymph nodes must be non-pathological in size or under 10 millimeters [mm] in short axis) and PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR= CR+PR.
Measured: 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
Secondary outcomes (3)
ORR (Dose Escalation Only)
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-pathological in size or under 10 mm in short axis) and PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR= CR+PR.
Measured: 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
Progression Free Survival (PFS) (Dose Expansion Only)
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 least a 5 mm absolute increase). The presence of new lesions also constitutes to disease progression.
Measured: 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 (Dose Expansion Only)
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2015 (estimated)
- Study start7 Jan 2016
- Primary completion19 Jun 2021
- Study completion22 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Rhabdoid TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Participants were enrolled either to the dose escalation or the dose expansion portion of the study. Participants in the dose expansion portion of the study were separated into cohorts based on their disease-type.
- Masking
- None (open label)
- Enrolment
- 109 participants (actual)
Sponsor and investigators
- Lead sponsor
- Epizyme, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ipsen Medical, Study director, Ipsen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02601937
- Sponsor's protocol ID
- EZH-102
- Other IDs
- 2015-002468-18, 2015
- Status last verified
- Jun 2024
- First submitted
- 21 Oct 2015
- Last updated
- 3 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
- ClinicalTrials.gov ID
- NCT02601937
- Acronym / sponsor ID
- EZH-102
- Conditions
- Rhabdoid Tumors, INI1-negative Tumors, Synovial Sarcoma, Malignant Rhabdoid Tumor of Ovary
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 109 participants (actual)
- Lead sponsor
- Epizyme, Inc.Industry (pharma, biotech, devices)
- Study start
- 7 Jan 2016 (actual)
- Primary completion
- 19 Jun 2021 (actual)
- Study completion
- 22 Oct 2021 (actual)
- First posted
- 11 Nov 2015 (estimated)
- Results
- Posted 3 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 after 8 weeks of treatment and subsequently every 8 weeks while on study.
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
- Integrase interactor 1 (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)
- Synovial Sarcoma with a SS18-SSX rearrangement Dose Escalation cohorts are closed to enrollment.
Dose Expansion at the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D)
- 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
- Myoepithelial carcinoma
- Renal medullary carcinoma
- Chordoma (poorly differentiated or de-differentiated)
- Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma)
- Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 11
- Model description
- Participants were enrolled either to the dose escalation or the dose expansion portion of the study. Participants in the dose expansion portion of the study were separated into cohorts based on their disease-type.
| Arm | Type | Receives |
|---|---|---|
| Dose Escalation Level 1 | Experimental | Drug: TazemetostatPediatric 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 2 | Experimental | Drug: TazemetostatPediatric 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 3 | Experimental | Drug: TazemetostatPediatric 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 4 | Experimental | Drug: TazemetostatPediatric 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 5 | Experimental | Drug: TazemetostatPediatric 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 6 | Experimental | Drug: TazemetostatPediatric 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 Escalation Level 7 | Experimental | Drug: TazemetostatPediatric 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 |
| Dose Expansion Cohort 1 | Experimental | Drug: TazemetostatPediatric 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 Expansion Cohort 2 | Experimental | Drug: TazemetostatPediatric 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 3 | Experimental | Drug: TazemetostatPediatric 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 4 | Experimental | Drug: TazemetostatPediatric 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. |
Who may qualify
- Ages
- 6 months to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (107 listed)
- Age (at the time of consent/assent): ≥6 months to <18 years
- Performance Status:
- Has provided signed written informed consent/assent
- Has a life expectancy of >3 months
- 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
Key exclusion criteria (16 listed)
- Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2
- Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy
- 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 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TazemetostatAlso: IPN60200, EPZ-6438, E7438Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene. | Drug | Dose Escalation Level 1, Dose Escalation Level 2, Dose Escalation Level 3, Dose Escalation Level 4, Dose Escalation Level 5, Dose Escalation Level 6, Dose Escalation Level 7, Dose Expansion Cohort 1, Dose Expansion Cohort 2, Dose Expansion Cohort 3, Dose Expansion Cohort 4 |
Primary outcome
Recommended Phase 2 Dose (RP2D) (Dose Escalation Only)
Time frame: 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)
Time frame: 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)
Time frame: 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, whichever occurs first. CR is defined as disappearance of all target and non-target lesions (with all lymph nodes must be non-pathological in size or under 10 millimeters [mm] in short axis) and PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR= CR+PR.
3 secondary outcomes
ORR (Dose Escalation Only)
Time frame: 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
Progression Free Survival (PFS) (Dose Expansion Only)
Time frame: 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 (Dose Expansion Only)
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Rhabdoid Tumors
RecruitingEarly Phase 1
Pilot Study of IT Topotecan and Maintenance Chemotherapy for HR-EBTs in Children < 6 Years, Post Consolidation
CNS Embryonal Tumor, CNS, Medulloblastoma
Active, not recruitingPhase 2
Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
Advanced Malignant Solid Neoplasm, Malignant Solid Neoplasm
RecruitingPhase 2
Study of Novel Therapies for Young People With Recurrent/Progressive Atypical Teratoid Rhabdoid Tumor (ATRT)
Recurrent Atypical Teratoid/Rhabdoid Tumor, Atypical Teratoid/Rhabdoid Tumor (ATRT) of the CNS
Active, not recruitingPhase 3
Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
Clear Cell Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Bone
RecruitingPhase 2
A Study of Selinexor in People With Wilms Tumors and Other Solid Tumors
Wilms Tumor, Rhabdoid Tumor
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ipsen Medical study director
Ipsen
35 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tazemetostat in people with Rhabdoid Tumors and INI1-negative Tumors, run by Epizyme, Inc. at 35 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 107 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 sites in United States, Australia, Germany, France, Italy and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recommended Phase 2 Dose (RP2D) (Dose Escalation Only) (time frame: Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2024.