Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

This phase I trial studies the side effects and best dose of entinostat in treating pediatric patients with solid tumors that have come back or have not responded to treatment. Entinostat may block some of the enzymes needed for cell division and it may help to kill tumor cells.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility Criteria

Inclusion Criteria:

  -  Patients must have a body surface area (BSA) of >= 1.17 m^2 at time of study
     enrollment

  -  Patients must be able to swallow intact tablets

  -  Patients with recurrent or refractory solid tumors, including central nervous system
     (CNS) tumors or lymphoma, are eligible; patients must have had histologic
     verification of malignancy at original diagnosis or relapse except in patients with
     intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors
     and elevations of cerebrospinal fluid (CSF) or serum tumor markers including
     alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

  -  Patients must have either measurable or evaluable disease

  -  Patient's current disease state must be one for which there is no known curative
     therapy or therapy proven to prolong survival with an acceptable quality of life

  -  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
     relatively 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 defined 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;
  the duration of this interval must be discussed with the study chair and the
  study-assigned research coordinator prior to enrollment

    -  Solid tumor patients: >= 21 days after the last dose of cytotoxic or
       myelosuppressive chemotherapy (42 days if prior nitrosourea)

    -  Lymphoma patients: a waiting period prior to enrollment is not required for
       patients receiving standard cytotoxic maintenance chemotherapy (i.e.
       corticosteroid, vincristine, thioguanine[6MP], and/or methotrexate)

    -  >=14 days must have elapsed after the completion of other cytotoxic
       therapy, with the exception of hydroxyurea, for patients not receiving
       standard maintenance therapy; additionally, patients must have fully
       recovered from all acute toxic effects of prior therapy; Note:
       cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to
       the start of protocol therapy

       -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
  reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days must have
  elapsed from the last dose of agent; the duration of this interval must be
  discussed with the study chair and the study-assigned research coordinator prior
  to enrollment

       -  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

       -  Hematopoietic growth factors: >= 14 days must have elapsed from the last dose of
  a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting
  growth factor; for agents 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 must have elapsed from the last dose of interleukins,
  interferon or cytokines (other than hematopoietic growth factors)

       -  Stem cell infusions (with or without traumatic brain injury [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 must have elapsed from infusion and no evidence of
       graft versus host disease (GVHD)

    -  Autologous stem cell infusion including boost infusion: >= 42 days must
       have elapsed from infusion

       -  Cellular therapy: >= 42 days must have elapsed from last dose of any type of
  cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic
  cells, etc.)

       -  External beam radiation (XRT)/External beam irradiation including protons: >= 14
  days must have elapsed 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

       -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, iobenguane I-131
  [131I-MIBG]): >= 42 days must have elapsed from the last dose of systemically
  administered radiopharmaceutical therapy

       -  Histone deacetylase (HDAC) inhibitors: Patients must not have received prior
  therapy with entinostat; patients who have received therapy with other HDAC
  inhibitors are eligible

  -  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, with or without transfusion

  -  Patients with known bone marrow metastatic disease will not be eligible

  -  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:

       -  1 to < 2 years: 0.6 mg/dL for males and females

       -  2 to < 6 years: 0.8 mg/dL for males and females

       -  6 to < 10 years: 1.0 mg/dL for males and females

       -  10 to < 13 years: 1.2 mg/dL for males and females

       -  13 to < 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females

       -  > = 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females

  -  Bilirubin =< 1.5 x upper limit of normal (ULN) for age

  -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
     U/l; for the purpose of this study, the ULN for SGPT is 45 U/l

  -  Serum albumin >= 2 g/dl

  -  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 both during and for 3 months after participation in this study;
     abstinence is an acceptable method of contraception; those who become pregnant while
     on treatment with entinostat must discontinue immediately and consult their treating
     physician

  -  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 requiring concurrent administration of valproic acid are not eligible for
     this trial

  -  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 with a BSA ˂ 1.17 m^2 at time of study enrollment are not eligible

  -  Patients who are not able to swallow intact tablets are not eligible

  -  Patients who have an uncontrolled infection are not eligible

  -  Patients who have received a 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

  -  Patients with a history of allergy to medications that have a benzamide structure
     (e.g., metoclopramide, procarbazine, domperidone, cisapride etc.) are not eligible