Prexasertib in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

Status: Recruiting
DFCI Protocol ID: 17-703

This phase I trial studies the side effects and best dose of prexasertib in treating pediatric patients with solid tumors that have come back after a period of time during which the tumor could not be detected or does not respond to treatment. Checkpoint kinase 1 inhibitor LY2606368 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Steven Dubois MD, Dana Farber Cancer Institute

Site-responsible Investigators:


Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP,

Eligibility Criteria

Inclusion Criteria:

  -  Patients with recurrent or refractory solid tumors, including central nervous system
     (CNS) tumors, 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 in 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

    -  >= 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 must have
  elapsed from last dose of agent; the duration of this interval must be discussed
  with the study chair and the study-assigned research coordinator prior to

       -  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 must have elapsed since 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 since 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 must have elapsed after infusion, and no evidence of
       graft-versus-host disease (GVHD)

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

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

       -  X ray (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)

       -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine
  metaiodobenzylguanidine [131I-MIBG]): >= 42 days must have elapsed since
  systemically administered radiopharmaceutical therapy

       -  Patients must not have received prior exposure to LY2606368

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

       -  Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

       -  Platelet count >= 75,000/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 packed red blood cell [PRBC]

  -  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; at least 5 of every cohort of 6 patients must
     be evaluable for hematologic toxicity for the dose-escalation part of the study; if
     dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must
     be evaluable for hematologic toxicity

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

       -  Age: maximum serum creatinine (mg/dL)

       -  1 to < 2 years: 0.6 (male and female)

       -  2 to < 6 years: 0.8 (male and female)

       -  6 to < 10 years: 1 (male and female)

       -  10 to < 13 years: 1.2 (male and female)

       -  13 to < 16 years: 1.5 (male), 1.4 (female)

       -  >= 16 years: 1.7 (male), 1.4 (female)

  -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for

  -  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

  -  Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
     gated radionuclide study

  -  Corrected QT (QTc) =< 480 msec

       -  Note: Patients should avoid concomitant medication known or suspected to prolong
  QTc interval or cause Torsades De Pointes; If possible, alternative agents
  should be considered

       -  Patients who are receiving drugs that prolong the QTc are eligible if the drug
  is necessary and no alternatives are available

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

  -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
     version [v]4) resulting from prior therapy must be =< grade 2

  -  For patients with CNS tumors, any baseline neurologic deficit, including seizures,
     must be stable for at least one week prior to initiating study treatment

  -  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

  -  Tissue blocks or slides must be sent if available; if tissue blocks or slides are
     unavailable, the study chair must be notified prior to study enrollment

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

  -  Corticosteroids: Patients receiving corticosteroids must have been on a stable or
     decreasing dose of corticosteroid for at least 7 days prior to enrollment; if used to
     modify immune adverse events related to prior therapy, >= 14 days must have elapsed
     since last dose of corticosteroid

  -  Investigational drugs: Patients who are currently receiving another investigational
     drug are not eligible

  -  Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are
     not eligible

  -  Anti-GVHD agents post-transplant: 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

  -  Strong CYP1A2 inhibitors: Patients must not have received strong CYP1A2 inhibitors
     (ciprofloxacin, fluvoxamine, zafirlukast) for at least 7 days prior to enrollment and
     must not receive them for the duration of the study

  -  Patients who have an uncontrolled infection are not eligible

  -  Patients who have received a prior solid organ transplantation are not eligible

  -  Patients with a history of allergic reactions attributed to compounds of similar
     chemical or biologic composition to LY2606368 or to its formulation 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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