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

  • STATUS
    Recruiting
  • End date
    Nov 13, 2022
  • participants needed
    82
  • sponsor
    Epizyme, Inc.
Updated on 13 May 2020
Investigator
Harry Miao, MD, PhD
Primary Contact
Children's National Medical Center (5.4 mi away) Contact
+35 other location

Summary

This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) 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

Details
Treatment Tazemetostat
Clinical Study IdentifierNCT02601937
SponsorEpizyme, Inc.
Last Modified on13 May 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 1 yrs and 17 yrs?
Gender: Male or Female
Do you have any of these conditions: Rhabdoid Tumor or INI1-negative Tumors or synovial sarcoma or Malignant Rhabdoid Tumor of Ovary?
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
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 mol/L) female 0.5 mg/dL (44 mol/L)
Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 mol/L) female 0.6 mg/dL (53 mol/L)
Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 mol/L) female 0.8 mg/dL (71 mol/L)
Serum creatinine 6 to <10 years: male 1 mg/dL (88 mol/L) female 1 mg/dL (88 mol/L)
Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 mol/L) female 1.2 mg/dL (106 mol/L)
Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 mol/L) female 1.4 mg/dL (125 mol/L)
Serum creatinine 16 years: male 1.7 mg/dL (150 mol/L) female 1.4 mg/dL (125 mol/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 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
\. 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 (-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
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 (Closed to enrollment)
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
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 (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

Exclusion Criteria

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
\. 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
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. Has known hypersensitivity to any of the components of tazemetostat or
other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben
\. 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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