Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)

Registration Number
NCT03213665
Lead Sponsor
National Cancer Institute (NCI)
Brief Summary

This phase II Pediatric MATCH trial studies how well tazemetostat works in treating patients with brain tumors, solid tumors, non-Hodgkin lymphoma, or histiocytic disorders that have come back (relapsed) or do not respond to treatment (refractory) and have EZH2, SMARCB1, or SMARCA4 gene mutations. Tazemetostat may stop the growth of tumor cells by blocking E...

Detailed Description

PRIMARY OBJECTIVE:
...

Recruitment & Eligibility

Status
ACTIVE_NOT_RECRUITING
Sex
All
Target Recruitment
20
Inclusion Criteria
  • Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621C based on the presence of an actionable mutation

  • Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice; Note: The following do not qualify as measurable disease:

    • Malignant fluid collections (e.g., ascites, pleural effusions)
    • Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
    • Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
    • Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
    • Previously radiated lesions that have not demonstrated clear progression post radiation
    • Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

      • >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent

    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1

    • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid

    • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator

    • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)

    • Stem cell Infusions (with or without total body irradiation [TBI]):

      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
      • Autologous stem cell infusion including boost infusion: >= 42 days
    • Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)

    • Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation; Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment

    • Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy

    • Patients must not have had prior exposure to tazemetostat or other inhibitor(s) of EZH2

  • For patients with solid tumors without known bone marrow involvement:

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
    • Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity

  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • Age 1 to < 2 years: male: 0.6 mg/dL; female: 0.6 mg/dL
    • Age 2 to < 6 years: male: 0.8 mg/dL; female: 0.8 mg/dL
    • Age 6 to < 10 years: male: 1 mg/dL; female: 1 mg/dL
    • Age 10 to < 13 years: male: 1.2 mg/dL; female: 1.2 mg/dL
    • Age 13 to < 16 years: male: 1.5 mg/dL; female: 1.4 mg/dL
    • Age >= 16 years: male: 1.7 mg/dL; female: 1.4 mg/dL
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)

  • Serum albumin >= 2 g/dL

  • Corrected QT (QTc) interval =< 480 milliseconds

  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled

  • Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [V] 4.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible

  • International normalized ratio (INR) =< 1.5

  • For subjects with CNS involvement (primary tumor or metastatic disease): Subjects must not have any active bleeding, or new intratumoral hemorrhage of more than punctate size on screening MRI or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents

  • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

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Exclusion Criteria
  • Pregnant or breast-feeding women will not be entered on this study because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment; female subjects of childbearing potential should agree to remain abstinent or use adequate contraceptive methods for 30 days after the last dose of tazemetostat; male subjects should agree to remain abstinent or use adequate contraceptive methods, and agree to refrain from donating sperm, and for 90 days after the last dose of tazemetostat
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
  • Patients who are currently receiving drugs that are strong inducers or strong inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 are prohibited from 14 days prior to the first dose of tazemetostat to the end of the study; Note: Dexamethasone for CNS tumors or metastases, on a stable dose, is allowed
  • Patients who have an uncontrolled infection are not eligible
  • On complete blood count (CBC) differential, patients must not have any significant morphologic abnormalities concerning for myeloproliferative neoplasm (MPN)/myelodysplastic syndrome (MDS) or T- acute lymphoblastic leukemia (ALL)
  • Patients must not have thrombocytopenia, neutropenia, or anemia of grade >= 3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)
  • Patients with a history of prior history of T-lymphoblastic lymphoma (LBL)/T-ALL
  • Patients with any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
  • Patients who have received prior solid organ transplantation are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Treatment (tazemetostat)TazemetostatPatients receive tazemetostat PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Primary Outcome Measures
NameTimeMethod
Objective Response Rate (ORR)From enrollment to the end of treatment, up to 2 years

ORR will be defined as complete response + partial response and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.

Secondary Outcome Measures
NameTimeMethod
Percentage of Patients Experiencing Grade 3 or 4 Adverse EventsFrom initiation of treatment to disease progression, disease recurrence, or death from any cause assessed up to 2 years

Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Any eligible patient who receives at least one dose of protocol therapy will be considered in the evaluation of toxicity. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.

Progression-free Survival (PFS)From start of subprotocol treatment to time of progression or death, whichever occurs first, assessed for up to 2 years

Progression free survival will be defined as time from the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause. PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

Trial Locations

Locations (117)

Children's Healthcare of Atlanta - Arthur M Blank Hospital

🇺🇸

Atlanta, Georgia, United States

Children's Hospital of Alabama

🇺🇸

Birmingham, Alabama, United States

Providence Alaska Medical Center

🇺🇸

Anchorage, Alaska, United States

Banner Children's at Desert

🇺🇸

Mesa, Arizona, United States

Phoenix Childrens Hospital

🇺🇸

Phoenix, Arizona, United States

Banner University Medical Center - Tucson

🇺🇸

Tucson, Arizona, United States

Arkansas Children's Hospital

🇺🇸

Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center

🇺🇸

Downey, California, United States

Loma Linda University Medical Center

🇺🇸

Loma Linda, California, United States

Miller Children's and Women's Hospital Long Beach

🇺🇸

Long Beach, California, United States

Children's Hospital Los Angeles

🇺🇸

Los Angeles, California, United States

Mattel Children's Hospital UCLA

🇺🇸

Los Angeles, California, United States

Valley Children's Hospital

🇺🇸

Madera, California, United States

UCSF Benioff Children's Hospital Oakland

🇺🇸

Oakland, California, United States

Kaiser Permanente-Oakland

🇺🇸

Oakland, California, United States

Lucile Packard Children's Hospital Stanford University

🇺🇸

Palo Alto, California, United States

Rady Children's Hospital - San Diego

🇺🇸

San Diego, California, United States

UCSF Medical Center-Mission Bay

🇺🇸

San Francisco, California, United States

Children's Hospital Colorado

🇺🇸

Aurora, Colorado, United States

Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center

🇺🇸

Denver, Colorado, United States

Yale University

🇺🇸

New Haven, Connecticut, United States

Alfred I duPont Hospital for Children

🇺🇸

Wilmington, Delaware, United States

Children's National Medical Center

🇺🇸

Washington, District of Columbia, United States

University of Florida Health Science Center - Gainesville

🇺🇸

Gainesville, Florida, United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

🇺🇸

Hollywood, Florida, United States

Nemours Children's Clinic-Jacksonville

🇺🇸

Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

🇺🇸

Miami, Florida, United States

Nicklaus Children's Hospital

🇺🇸

Miami, Florida, United States

AdventHealth Orlando

🇺🇸

Orlando, Florida, United States

Arnold Palmer Hospital for Children

🇺🇸

Orlando, Florida, United States

Nemours Children's Hospital

🇺🇸

Orlando, Florida, United States

Nemours Children's Clinic - Pensacola

🇺🇸

Pensacola, Florida, United States

Johns Hopkins All Children's Hospital

🇺🇸

Saint Petersburg, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa

🇺🇸

Tampa, Florida, United States

Saint Mary's Hospital

🇺🇸

West Palm Beach, Florida, United States

Kapiolani Medical Center for Women and Children

🇺🇸

Honolulu, Hawaii, United States

Saint Luke's Cancer Institute - Boise

🇺🇸

Boise, Idaho, United States

University of Chicago Comprehensive Cancer Center

🇺🇸

Chicago, Illinois, United States

Saint Jude Midwest Affiliate

🇺🇸

Peoria, Illinois, United States

Southern Illinois University School of Medicine

🇺🇸

Springfield, Illinois, United States

Riley Hospital for Children

🇺🇸

Indianapolis, Indiana, United States

Ascension Saint Vincent Indianapolis Hospital

🇺🇸

Indianapolis, Indiana, United States

Blank Children's Hospital

🇺🇸

Des Moines, Iowa, United States

University of Iowa/Holden Comprehensive Cancer Center

🇺🇸

Iowa City, Iowa, United States

Norton Children's Hospital

🇺🇸

Louisville, Kentucky, United States

Children's Hospital New Orleans

🇺🇸

New Orleans, Louisiana, United States

Ochsner Medical Center Jefferson

🇺🇸

New Orleans, Louisiana, United States

Maine Children's Cancer Program

🇺🇸

Scarborough, Maine, United States

Sinai Hospital of Baltimore

🇺🇸

Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

🇺🇸

Baltimore, Maryland, United States

C S Mott Children's Hospital

🇺🇸

Ann Arbor, Michigan, United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

🇺🇸

Grand Rapids, Michigan, United States

Bronson Methodist Hospital

🇺🇸

Kalamazoo, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

🇺🇸

Minneapolis, Minnesota, United States

University of Minnesota/Masonic Cancer Center

🇺🇸

Minneapolis, Minnesota, United States

University of Mississippi Medical Center

🇺🇸

Jackson, Mississippi, United States

Children's Mercy Hospitals and Clinics

🇺🇸

Kansas City, Missouri, United States

Cardinal Glennon Children's Medical Center

🇺🇸

Saint Louis, Missouri, United States

Washington University School of Medicine

🇺🇸

Saint Louis, Missouri, United States

Mercy Hospital Saint Louis

🇺🇸

Saint Louis, Missouri, United States

Children's Hospital and Medical Center of Omaha

🇺🇸

Omaha, Nebraska, United States

University of Nebraska Medical Center

🇺🇸

Omaha, Nebraska, United States

University Medical Center of Southern Nevada

🇺🇸

Las Vegas, Nevada, United States

Alliance for Childhood Diseases/Cure 4 the Kids Foundation

🇺🇸

Las Vegas, Nevada, United States

Hackensack University Medical Center

🇺🇸

Hackensack, New Jersey, United States

Morristown Medical Center

🇺🇸

Morristown, New Jersey, United States

Albany Medical Center

🇺🇸

Albany, New York, United States

Roswell Park Cancer Institute

🇺🇸

Buffalo, New York, United States

The Steven and Alexandra Cohen Children's Medical Center of New York

🇺🇸

New Hyde Park, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

🇺🇸

New York, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

🇺🇸

New York, New York, United States

Memorial Sloan Kettering Cancer Center

🇺🇸

New York, New York, United States

NYP/Weill Cornell Medical Center

🇺🇸

New York, New York, United States

University of Rochester

🇺🇸

Rochester, New York, United States

State University of New York Upstate Medical University

🇺🇸

Syracuse, New York, United States

New York Medical College

🇺🇸

Valhalla, New York, United States

Mission Hospital

🇺🇸

Asheville, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute

🇺🇸

Charlotte, North Carolina, United States

Duke University Medical Center

🇺🇸

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

🇺🇸

Cincinnati, Ohio, United States

Cleveland Clinic Foundation

🇺🇸

Cleveland, Ohio, United States

Nationwide Children's Hospital

🇺🇸

Columbus, Ohio, United States

Dayton Children's Hospital

🇺🇸

Dayton, Ohio, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital

🇺🇸

Toledo, Ohio, United States

University of Oklahoma Health Sciences Center

🇺🇸

Oklahoma City, Oklahoma, United States

Legacy Emanuel Children's Hospital

🇺🇸

Portland, Oregon, United States

Oregon Health and Science University

🇺🇸

Portland, Oregon, United States

Geisinger Medical Center

🇺🇸

Danville, Pennsylvania, United States

Children's Hospital of Philadelphia

🇺🇸

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

🇺🇸

Pittsburgh, Pennsylvania, United States

BI-LO Charities Children's Cancer Center

🇺🇸

Greenville, South Carolina, United States

Sanford USD Medical Center - Sioux Falls

🇺🇸

Sioux Falls, South Dakota, United States

East Tennessee Childrens Hospital

🇺🇸

Knoxville, Tennessee, United States

Saint Jude Children's Research Hospital

🇺🇸

Memphis, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

🇺🇸

Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas

🇺🇸

Austin, Texas, United States

Medical City Dallas Hospital

🇺🇸

Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas

🇺🇸

Dallas, Texas, United States

Cook Children's Medical Center

🇺🇸

Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

🇺🇸

Houston, Texas, United States

M D Anderson Cancer Center

🇺🇸

Houston, Texas, United States

Children's Hospital of San Antonio

🇺🇸

San Antonio, Texas, United States

Methodist Children's Hospital of South Texas

🇺🇸

San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio

🇺🇸

San Antonio, Texas, United States

Scott and White Memorial Hospital

🇺🇸

Temple, Texas, United States

Primary Children's Hospital

🇺🇸

Salt Lake City, Utah, United States

University of Vermont and State Agricultural College

🇺🇸

Burlington, Vermont, United States

Children's Hospital of The King's Daughters

🇺🇸

Norfolk, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center

🇺🇸

Richmond, Virginia, United States

Seattle Children's Hospital

🇺🇸

Seattle, Washington, United States

Providence Sacred Heart Medical Center and Children's Hospital

🇺🇸

Spokane, Washington, United States

Madigan Army Medical Center

🇺🇸

Tacoma, Washington, United States

West Virginia University Healthcare

🇺🇸

Morgantown, West Virginia, United States

University of Wisconsin Carbone Cancer Center - University Hospital

🇺🇸

Madison, Wisconsin, United States

Children's Hospital of Wisconsin

🇺🇸

Milwaukee, Wisconsin, United States

San Jorge Children's Hospital

🇵🇷

San Juan, Puerto Rico

University Pediatric Hospital

🇵🇷

San Juan, Puerto Rico

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