Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT02780804
Collaborator
(none)
21
21
1
57.1
1
0

Study Details

Study Description

Brief Summary

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of entinostat administered as a single-agent, once weekly to children with recurrent or refractory solid tumors.

  2. To define and describe the toxicities of entinostat administered as a single agent, once weekly to children with recurrent or refractory solid tumors.

  3. To characterize the pharmacokinetics of entinostat in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:
  1. To preliminarily define the antitumor activity of entinostat within the confines of a phase 1 study.

  2. To assess change in histone H3 and H4 acetylation in peripheral blood mononuclear cells (PBMCs) as a marker of the biologic activity of entinostat.

OUTLINE: This is a dose escalation study.

Patients receive entinostat orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Study Design

Study Type:
Interventional
Actual Enrollment :
21 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Study of Entinostat, an Oral Histone Deacetylase Inhibitor, in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors and Lymphoma
Actual Study Start Date :
Dec 26, 2016
Actual Primary Completion Date :
Jun 30, 2021
Actual Study Completion Date :
Sep 30, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (entinostat)

Patients receive entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Drug: Entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Maximum tolerated dose [Up to 28 days]

      Will be defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity during cycle 1 of therapy. Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

    2. Incidence of adverse events [Up to 28 days]

      Will be described and graded using CTCAE version 5.0. A descriptive summary of all toxicities will be reported.

    3. Changes in pharmacokinetic (PK) parameters [Pre-dose on days 1, 8, and 22 and 1, 3 ,6, 24, 48 and 96 hours post-dose on day 1, and day 28]

      A descriptive analysis of PK parameters of entinostat will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

    4. Antitumor activity of entinostat [Up to 12 months]

    5. Change in histone H3 and H4 acetylation [Up to 12 months]

      Will be assessed in peripheral blood mononuclear cells.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Months to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 (within 7 days prior to enrollment)

    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (within 7 days prior to enrollment)

    • Hemoglobin >= 8.0 g/dl, with or without transfusion (within 7 days prior to enrollment)

    • 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 (within 7 days prior to enrollment)

    • Bilirubin (sum of conjugated + conjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)

    • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/l; for the purpose of this study, the ULN for SGPT is 45 U/l (within 7 days prior to enrollment)

    • Serum albumin >= 2 g/dl (within 7 days prior to enrollment)

    • 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 with a known history of corrected QT (QTc) prolongation (> 480 msec), or known history of ventricular tachycardia, ventricular fibrillation or Torsades de pointes 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 Children's Hospital Los Angeles Los Angeles California United States 90027
    3 Children's Hospital of Orange County Orange California United States 92868
    4 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    5 Children's Hospital Colorado Aurora Colorado United States 80045
    6 Children's National Medical Center Washington District of Columbia United States 20010
    7 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    8 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    9 Riley Hospital for Children Indianapolis Indiana United States 46202
    10 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    11 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    12 University of Minnesota/Masonic Cancer Center Minneapolis Minnesota United States 55455
    13 Washington University School of Medicine Saint Louis Missouri United States 63110
    14 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    15 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    16 Oregon Health and Science University Portland Oregon United States 97239
    17 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    18 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    19 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    20 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas United States 77030
    21 Seattle Children's Hospital Seattle Washington United States 98105

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Andrew Bukowinski, COG Phase I Consortium

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02780804
    Other Study ID Numbers:
    • NCI-2016-00708
    • NCI-2016-00708
    • ADVL1513
    • ADVL1513
    • ADVL1513
    • UM1CA097452
    First Posted:
    May 24, 2016
    Last Update Posted:
    Oct 7, 2021
    Last Verified:
    Oct 1, 2021

    Study Results

    No Results Posted as of Oct 7, 2021