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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)

NCT03213665

Description:

This phase II Pediatric MATCH trial studies how well tazemetostat works in treating patients with solid tumors, non-hodgkin lymphoma, or histiocytic disorders that have spread to other places in the body and have come back or do not respond to treatment and have EZH2, SMARCB1, or SMARCA4 gene mutations. Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Histiocytic and Dendritic Cell Neoplasm
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pediatric MATCH: Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations
  • Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tazemetostat in Patients With Tumors Harboring Alterations in EZH2 or Members of the SWI/SNF Complex

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01245
  • SECONDARY ID: NCI-2017-01245
  • SECONDARY ID: APEC1621C
  • SECONDARY ID: APEC1621C
  • SECONDARY ID: APEC1621C
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03213665

Conditions

  • Advanced Malignant Solid Neoplasm
  • Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • EZH2 Gene Mutation
  • Histiocytosis
  • Loss of BRG1 Protein Expression
  • Loss of INI 1 Protein Expression
  • Low Grade Glioma
  • Malignant Glioma
  • Recurrent Childhood Central Nervous System Neoplasm
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma
  • Recurrent Germ Cell Tumor
  • Recurrent Glioma
  • Recurrent Hepatoblastoma
  • Recurrent Hodgkin Lymphoma
  • Recurrent Langerhans Cell Histiocytosis
  • Recurrent Malignant Solid Neoplasm
  • Recurrent Medulloblastoma
  • Recurrent Neuroblastoma
  • Recurrent Non-Hodgkin Lymphoma
  • Recurrent Osteosarcoma
  • Recurrent Peripheral Primitive Neuroectodermal Tumor
  • Recurrent Rhabdomyosarcoma
  • Refractory Central Nervous System Neoplasm
  • Refractory Hodgkin Lymphoma
  • Refractory Langerhans Cell Histiocytosis
  • Refractory Malignant Germ Cell Tumor
  • Refractory Neuroblastoma
  • Refractory Non-Hodgkin Lymphoma
  • Rhabdoid Tumor
  • Stage III Childhood Hodgkin Lymphoma
  • Stage III Childhood Non-Hodgkin Lymphoma
  • Stage III Soft Tissue Sarcoma AJCC v7
  • Stage IV Childhood Hodgkin Lymphoma
  • Stage IV Childhood Non-Hodgkin Lymphoma
  • Stage IV Soft Tissue Sarcoma AJCC v7
  • Wilms Tumor

Interventions

DrugSynonymsArms
TazemetostatE7438, EPZ-6438, EPZ6438Treatment (tazemetostat)

Purpose

This phase II trial studies how well tazemetostat works in treating patients with solid tumors, non-hodgkin lymphoma, or histiocytic disorders that have spread to other places in the body and have come back or do not respond to treatment and have EZH2, SMARCB1, or SMARCA4 gene mutations. Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the objective response rate (ORR; complete response + partial response) in
      pediatric patients treated with tazemetostat with advanced solid tumors (including central
      nervous system [CNS] tumors), lymphomas or histiocytic disorders that harbor gain of function
      mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or
      SMARCA4.

      SECONDARY OBJECTIVES:

      I. To estimate the progression-free survival in pediatric patients treated with tazemetostat
      that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF
      complex subunits SMARCB1 or SMARCA4.

      II. To obtain information about the tolerability of tazemetostat in children with relapsed or
      refractory cancer.

      TERTIARY OBJECTIVES:

      I. To evaluate other biomarkers as predictors of response to tazemetostat and specifically,
      whether tumors that harbor different missense mutations or fusions will demonstrate
      differential response to tazemetostat treatment.

      II. To explore approaches to profiling changes in tumor genomics over time through evaluation
      of circulating tumor deoxyribonucleic acid (DNA).

      OUTLINE:

      Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Courses repeat
      every 28 days for up to 2 years in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tazemetostat)ExperimentalPatients receive tazemetostat PO BID on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Tazemetostat

Eligibility Criteria

        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)

          -  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

          -  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

        Exclusion Criteria:

          -  Pregnant or breast-feeding women will not be entered on this study; 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

          -  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; Note: Dexamethasone for CNS tumors or
             metastases, on a stable dose, is allowed

          -  Patients who have an uncontrolled infection are not eligible

          -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) defined as complete response + partial response and assessed by Response Evaluation Criteria in Solid Tumors (RECIST)
Time Frame:Up to 2 years
Safety Issue:
Description: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

Measure:Progression-free survival (PFS)
Time Frame:From start of subprotocol treatment to time of progression or death, whichever occurs first, assessed for up to 2 years
Safety Issue:
Description:PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 4, 2017