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About
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.
Full description
PRIMARY OBJECTIVES:
I. 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.
II. To define and describe the toxicities of LY2606368 administered on this schedule.
III. To characterize the pharmacokinetics of LY2606368 in children with recurrent or refractory cancer.
SECONDARY OBJECTIVES:
I. To preliminarily define the antitumor activity of LY2606368 within the confines of a phase 1 study.
II. To examine checkpoint kinase (CHK)1/2 expression status in archival tumor tissue from solid tumor pediatric patients using immunohistochemistry.
III. To evaluate tumor tissue for deletion and/or mutation of tumor protein 53 (TP53) as a potential biomarker of Chk1 inhibition.
IV. 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.
OUTLINE: This is a dose-escalation study.
Patients receive prexasertib IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Enrollment
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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
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
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 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
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]):
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) radiation
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:
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:
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 (3x ULN); 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
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) 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
Primary purpose
Allocation
Interventional model
Masking
30 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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