ADVL1515: A Phase 1 Study of LY2606368, a CHK1/2 Inhibitor, in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors

Why are we doing this research?

PURPOSE:

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.


DETAILED DESCRIPTION:

PRIMARY OBJECTIVES:

  • To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of prexasertib (LY2606368) administered as an intravenous (IV) infusion over 60 minutes, every 14 days of a 28-day cycle to children with recurrent or refractory solid tumors.
  • To define and describe the toxicities of LY2606368 administered on this schedule.
  • To characterize the pharmacokinetics of LY2606368 in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

  • To preliminarily define the antitumor activity of LY2606368 within the confines of a phase 1 study.
  • To examine checkpoint kinase (CHK) 1/2 expression status in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.
  • To evaluate tumor tissue for deletion and/or mutation of tumor protein 53 (Trp53) as a potential biomarker of Chk1 inhibition.
  • To evaluate autophosphorylation of Chk1 and H2A histone family, member x (H2AX) in peripheral blood mononuclear cells as a potential pharmacodynamic marker of LY2606368 activity.

Study Type: Interventional

Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 12 Months to 21 Years

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

Conditions

  • Brain Spinal Tumors Medulloblastoma Relapse
  • Brain Spinal Tumor Low Grade Glioma Relapse
  • Brain Spinal Tumor DIPG Relapse
  • Brain and Spinal Tumor Ependymoma Relapse
  • Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Brain Spinal Neurofibromatosis OPG
  • Brain Spinal Other ATRT
  • Brain Spinal Other Craniopharyngioma
  • Brain Spinal Other Germ Cell Tumor
  • Brain Spinal Other Choroid Plexus Tumor
  • Brain Spinal Other All Other
  • Sarcoma Ewing Relapse
  • Sarcoma Osteosarcoma Relapse
  • Sarcoma Rhabdomyosarcoma Relapse
  • Neuroblastoma Relapse - Refractory
  • Liver Relapse - Refractory
  • Kidney Relapse - Refractory
  • Solid Tumors - All Other
  • Solid Tumor Retinoblastoma Relapse - Refractory
  • Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Solid Tumor Melanoma Relapse - Refractory
  • Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Adult - Brain Spinal Tumors Medulloblastoma Relapse
  • Adult - Brain Spinal Tumor Low Grade Glioma Relapse
  • Adult - Brain Spinal Tumor DIPG Relapse
  • Adult - Brain and Spinal Tumor Ependymoma Relapse
  • Adult - Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Adult - Brain Spinal Neurofibromatosis OPG
  • Adult - Brain Spinal Other All Other
  • Adult - Brain Spinal Other ATRT
  • Adult - Brain Spinal Other Choroid Plexus Tumor
  • Adult - Brain Spinal Other Craniopharyngioma
  • Adult - Brain Spinal Other Germ Cell Tumor
  • Adult - Sarcoma Ewing Relapse
  • Adult - Sarcoma Osteosarcoma Relapse
  • Adult - Sarcoma Rhabdomyosarcoma Relapse
  • Adult - Neuroblastoma Relapse - Refractory
  • Adult - Liver Relapse - Refractory
  • Adult - Kidney Relapse - Refractory
  • Adult - Solid Tumor Melanoma Relapse - Refractory
  • Adult - Solid Tumor Retinoblastoma Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Adult - Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Adult - Solid Tumors - All Other

Contact

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799