Prexasertib in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

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 (Trp53) 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.

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
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]):

- 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)
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:

- 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

- 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
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

- 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
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:

- 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