AZD2171 to Treat Children and Adolescents With Solid Tumors or Acute Myelogenous Leukemia

Background:

- Cediranib is a potent orally bioavailable inhibitor of VEGFR1, VEGFR2, VEGFR3 tyrosine
kinase activity, but also inhibits c-kit and PDGFR-Beta in vitro.

- Phase I trials of Cediranib are ongoing in adults and the drug is well tolerated at
doses up to 45 mg/d. The toxicity profile includes hypertension, hypoglycemia, elevated
LFTs, fatigue, dysphonia, diarrhea, nausea and vomiting.

Objectives:

- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of orally
administered Cediranib on a daily for 28 consecutive days schedule in children and
adolescents with refractory childhood solid tumors.

- To define the toxicity spectrum of oral Cediranib in children and adolescents.

- To assess the pharmacokinetics and pharmacodynamics of oral Cediranib in children and
adolescents.

- Assess growth plate volume in the right knee using non-contrast MRI scans prior to and
during administration of cediranib.

Eligibility:

-Children and adolescents (greater than 2 yrs and less than 19 years of age) with
histologically confirmed relapsed or refractory extracranial solid tumors that are measurable
or evaluable.

Design:

- Cediranib will be administered orally, daily. Treatment cycles are 28 days with no break
in treatment between cycles. The starting dose level is 12 mg/m(2)/d with escalations to
17, 25, 35, and 50 mg/ m(2)/d, due to dose limiting toxicity in the initial 2 subjects
enrolled at 12 mg/m(2)/d the protocol was amended to restart dose escalation at 8
mg/m(2)/d.

- Detailed pharmacokinetic and pharmacodynamic studies will be performed during the first
28 day treatment cycle.

- The trial follows a standard phase I design with 3 to 6 patients per dose level and
standard definitions of MTD and DLT. Up to 28 patients will be entered on this trial.

- INCLUSION CRITERIA:

AGE: Patients must be greater than 2 years and less than 19 years of age.

DIAGNOSIS: Solid Tumors (dose escalation component of the trial): Histologically confirmed
extracranial malignant solid tumors, which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, and germ cell tumors.

DISEASE STATUS: Patients with solid tumors must have measurable or evaluable disease.

- Patients must be able to swallow tablets intact.

PRIOR THERAPY: The patient's cancer must have relapsed after or failed to respond to
frontline standard therapy and no other standard curative treatment options are available.
Standard therapy may include surgery, radiation therapy, chemotherapy, or any combination
of these modalities.

Patients must have had their last fraction of radiation therapy:

- at least 4 months prior to study entry for large ports (greater than 50% pelvis, TBI,
or craniospinal) for solid tumor patients.

- at least 4 weeks prior to study entry for other radiation in solid tumor patients or
for any type of radiation in leukemia patients.

Patients must have had their last dose of:

Cytotoxic chemotherapy:

-Patients with solid tumors, the last dose of cytotoxic therapy must be at least 21 days
prior to study entry.

Biological therapy that was administered for the treatment of cancer at least 7 days prior
to study entry.

Immunotherapy (antibody) at least 30 days prior to study entry.

Any investigational cancer therapy at least 30 days prior to study entry.

Patients who have received an allogeneic BM or SC transplant must be at least 3 months
post-transplant; and patients who have received an autologous BM or SC transplant must be
at least 2-months post-transplant.

Patients must have recovered from the acute toxic effects of prior therapy before entry
onto this trial.

Patients should be off colony stimulating factors such as filgrastim (G-CSF), sargramostim
(GM-CSF), and IL-11 (with the exception of erythropoietin) for at least 72 hours prior to
study entry. Patients receiving PEG-filgrastim (Neulasta ) must be at least 7 days from the
last dose.

CONCOMITANT MEDICATIONS:

- Patients requiring systemic full dose anticoagulation with systemic thrombolytics,
heparin, coumadin, low molecular weight heparin, or other anticoagulants for therapy
of active thrombosis within the prior 3 months are excluded.

- Patients receiving prophylactic anticoagulation for thrombosis are eligible if they
meet criteria for adequate hemostatic function (PT and PTT less than or equal to 1.5 x
ULN) and the thrombotic episode occurred greater than 3 months prior to enrollment.
Use of anticoagulants or thrombolytics for care and maintenance of central venous
catheters (e.g., intralumenal TPA) is acceptable.

- Patients on thyroid replacement (levothyroxine, synthroid ) must be on a stable dose
for at least 1 month.

- Patient receiving a medication that has a known risk of QTc prolongation with in the
last 2 weeks are excluded.

- Patient receiving corticosteroids must be on a stable or tapering dose for 14 days
prior to study enrollment.

PERFORMANCE STATUS: Patients greater than 10 years old must have a Karnofsky performance
level greater than 50, and children less than or equal to 10 years old must have a Lansky
performance level greater than 50.

HEMATOLOGICAL FUNCTION:

-Patients with solid tumors must have adequate bone marrow function, defined as a
peripheral absolute neutrophil count of greater than or equal to 1,500/microL, and a
platelet count greater than or equal to 100,000/microL (transfusion independent).

Coagulation: Patients must have adequate hemostatic function defined as PT and PTT less
than or equal to 1.5 x ULN. It is recommended that PT and PTT be drawn by peripheral
venipuncture rather than from an indwelling central venous catheter.

CARDIAC: Patients must have:

- QTc (Bazett's Correction) less than or equal to 480 msec on ECG.

- Normal Left Ventricular Diastolic Function: Echocardiogram with ejection fraction
greater than or equal to 55 percent or shortening fraction greater than or equal to 27
percent.

HEPATIC FUNCTION: Patients must have adequate liver function, defined as bilirubin less
than or equal to 1.5 x ULN, SGPT (ALT) less than or equal to 2.5 x ULN.

RENAL FUNCTION:

- Proteinuria less than or equal to 1 + on dipstick when urine specific gravity is less
than or equal to 1.015 or 24 hr urine total protein is less than or equal to 500
grams/24hr.

- Patients must have an age-adjusted normal serum creatinine (See Table Below) OR a
creatinine clearance is greater than or equal to 60 mL/min/1.73 m(2).

2 to less than 6 years of age equals a maximum serum creatinine of 0.8 mg/dl.

6 to less than 10 years of age equals a maximum serum creatinine of 1 mg/dl.

10 to less than 13 years of age equals a maximum serum creatinine of 1.2 mg/dl.

13 years to less than 16 years of age equals a maximum serum creatinine of 1.5 mg/dl
(male) and 1.4 mg/dl (female).

Greater than or equal to 16 years of age equals a maximum serum creatine of 1.7 mg/dl
(male) and 1.4 mg/dl (female).

INFORMED CONSENT: All patients or their legal guardians (if the patient is less than 18
years old) must sign a document of informed consent (Pediatric Oncology Branch, NCI
screening protocol for NIH patients) prior to performing studies to determine patient
eligibility. After confirmation of patient eligibility all patients or their legal
guardians must voluntarily sign the IRB approved protocol specific informed consent to
document their understanding of the investigational nature and the risks of this study
before any protocol related studies are performed (other than the studies which were
performed to determine patient eligibility).

DURABLE POWER OF ATTORNEY (DPA): Patients who are 18 years of age will be offered the
opportunity to assign a DPA so that another person can make decisions about their medical
care if they become incapacitated or cognitively impaired.

BIRTH CONTROL: Patients of childbearing or child-fathering potential must be willing to use
a medically acceptable form of birth control, which includes abstinence, while they are
receiving protocol therapy and for 2 weeks after the last dose of Cediranib.

EXCLUSION CRITERIA:

Patients with primary brain tumors.

Patients with a history of congenitally prolonged QTc, or history of arrhythmia (multifocal
premature ventricular contractions, bigeminy,trigeminy, ventricular tachycardia,
uncontrolled atrial fibrillation, left bundle block) that is symptomatic or requires
treatment (except for controlled atrial fibrillation).

- Patients receiving medication for treatment of hypertension or patients with a
diastolic blood pressure 5mmHg greater than the 95% for gender and age on 3
measurements using an appropriate size cuff are excluded.

- Patients who have had major surgery within the past 3 months. Patients having minor
surgery (e.g., central line placement) within the past 2 weeks.

- Patients with history of arterial or venous thrombosis within the prior 3 months.

- Patients requiring systemic full dose anticoagulation with systemic thrombolytics,
heparin, coumadin, or low molecular weight heparin or other anticoagulants for therapy
of active thrombosis within the prior 3 months.

- Patients experiencing significant hemorrhage (hemoptysis, melena, or hematemesis)
within the past 2 weeks.

- Clinically significant unrelated systemic illness, such as serious infections,
hepatic, renal, gastrointestinal or other organ dysfunction, which in the judgment of
the principal investigator, protocol chairperson or associate investigator would
compromise the patient's ability to tolerate the investigational agent or are likely
to interfere with the study procedures or endpoints.

- Patients with active GVHD are excluded.

- Pregnant or breastfeeding females are excluded because Cediranib may be harmful to the
developing fetus or nursing child.

- Patients currently receiving other investigational agents.

- Patients previously known to be Hepatitis B, Hepatitis C, or HIV infected because of
the unknown interaction of Cediranib with antiviral therapy.

- Patients or first degree relatives of persons that are involved in the planning and
conduct of this trial are excluded.

- Patients who have previously received Cediranib.

- Patients who are allergic to Cediranib or its excipients (mannitol, sodium starch
glycollate and magnesium stearate).