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

NCT02601937 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: EZH-1022015-002468-18
• Study Type: interventional
• Target: 109
• Locations: 9 countries
• Sites: 35

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 after 8 weeks of treatment and subsequently every 8 weeks while on study.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  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)

  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)

  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)

  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

Study Arms (11)

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

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

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

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

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

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

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

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.

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.

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.

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.

Drug: Tazemetostat

Interventions

Tazemetostat DRUG

Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.

Also known as: IPN60200, EPZ-6438, E7438

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

Eligibility Criteria

• Age: 6 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Epizyme, Inc.: lead

Study Sites (35)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

University of California San Francisco - Benioff Children's Hospital

San Francisco, California, 94158, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

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

Chicago, Illinois, 60611, United States

Location

John Hopkins Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital - Cancer Center

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Oregon Health & Science University (OHSU)

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude Children's Research Hospital, Inc.

Memphis, Tennessee, 38105, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

Texas Children's Cancer and Hematology Center

Houston, Texas, 77098, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Sydney Children's Hospital

Sydney, New South Wales, 2031, Australia

Location

Lady Cilento/Queensland Children's Hospital

South Brisbane, Queensland, 4101, Australia

Location

The Royal Children's Hospital

Melbourne, Victoria, 3052, Australia

Location

The Childrens Hospital at Westmead Oncology Unit

Westmead, 2145, Australia

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Rigshospitalet Department of Oncology Blegdamsvej

Copenhagen, 2100, Denmark

Location

Institut Curie

Paris, 75248, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Children's Hospital Augsburg Klinikum

Augsburg, 86156, Germany

Location

Charite - Universitatsmedizin Berlin

Berlin, 13353, Germany

Location

Universitaetsklinikum Heidelberg

Heidelberg, Germany

Location

Westfalische Wilhelms - Universitat Munster Padiatrische

Münster, 48149, Germany

Location

Istituto Giannina Gaslini- UOSD Centro di Neuro-Oncologia

Genova, 16147, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

Erasmus University Medical Center - Sophia Children's Hospital

Rotterdam, Netherlands

Location

Prinses Maxima Centrum voor Kinderoncologie

Utrecht, 3584 EA, Netherlands

Location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Location

Central Manchester University Hospital - Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

Location

MeSH Terms

Conditions

Rhabdoid Tumor; Sarcoma, Synovial

Interventions

tazemetostat

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma

Results Point of Contact

• Title: Medical Lead or Designee
• Organization: Epizyme, Inc.

clinicaltrials@epizyme.com

(855) 500-1011

Study Officials

• Ipsen Medical

  Ipsen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 21, 2015
• First Posted: November 11, 2015
• Study Start: January 7, 2016
• Primary Completion: June 19, 2021
• Study Completion: October 22, 2021
• Last Updated: October 3, 2024
• Results First Posted: October 3, 2024

Record last verified: 2024-06

Locations

AU (4); FR (2); GB (2); DK (1); IT (2); NL (2); CA (1); DE (4); US (17)