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Investigator(s):
Elizabeth Fox, M.D. Principal Investigator Phone: 301-402-6641 foxb@mail.nih.gov
Referral Contact(s):
Pediatric Oncology  Phone: 1-877-624-4878 (Toll free)

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Primary Eligibility:

• Histologically confirmed diagnosis of extracranial malignant solid tumors, including, but not limited to, any of the following:
• Rhabdomyosarcoma or other soft tissue sarcomas, Ewing’s sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms’ tumor, hepatic tumor, germ cell tumor
• At least 4 months since prior total-body irradiation or radiotherapy to the craniospinal area or to > 50% of the pelvis
• At least 4 weeks since prior and no concurrent radiotherapy and at least 21 days since prior and no concurrent cytotoxic chemotherapy
• Absolute neutrophil count ≥ 1,500/mm³, platelet count ≥ 100,000/mm³ (transfusion independent)
• Measurable or evaluable disease
• Acute myeloid leukemia, meeting all of the following criteria:
• M3 bone marrow (i.e., > 25% leukemic blasts)
• At least 1,000/mm³ circulating leukemic blasts in the peripheral blood
• No CNS leukemia, as evidenced by both of the following:
• Less than 5 nucleated cells/mm³
• Negative cerebrospinal fluid cytology
• At least 4 weeks since any prior and no concurrent radiotherapy and at least 14 days since prior and no concurrent cytotoxic chemotherapy
• No minimal ANC or platelet count requirements
• Relapsed or refractory disease after frontline standard therapy (e.g., surgery, radiotherapy, chemotherapy, or any combination of these modalities) AND no other standard curative treatment available
• > 2 years and < 19 years of age
• No primary brain tumor, active CNS or spinal cord metastasis, or spinal cord compression
• At least 3 months since prior allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) (≥ 2 months since autologous BMT or SCT)
• At least 3 months since prior major surgery (≥ 2 weeks for minor surgery [e.g., central line placement])
• At least 3 months since prior and no concurrent full-dose anticoagulants (e.g., systemic thrombolytics, heparin, warfarin, low-molecular weight heparin, or any other anticoagulants) for treatment of active thrombosis
• Concurrent prophylactic anticoagulation for thrombosis allowed provided thrombotic episode occurred > 3 months prior to study entry
• Concurrent anticoagulants or thrombotics for care and maintenance of central venous catheters (e.g., intraluminal tissue plasminogen activator [TPA]) allowed)
• No concurrent growth factors (e.g., GM-CSF or interleukin-11), investigational agents or therapies, intrathecal chemotherapy for prophylaxis of CNS leukemia, or anticancer therapy
• Concurrent thyroid replacement therapy (levothyroxine) allowed provided dose has been stable for ≥ 1 month
• Karnofsky performance status (PS) 60–100% (for patients > 10 years of age) or Lansky PS 60–100% (for patients ≤ 10 years of age)
• PT and PTT ≤ 1.5 x upper limit of normal (ULN)
• Bilirubin ≤ 1.5 x ULN; ALT ≤ 2.5 x ULN
• Proteinuria ≤ 1 + on dipstick when urine specific gravity is ≤ 1.015 OR total urinary protein ≤ 500 g by 24-hour urine collection
• Creatinine clearance ≥ 60 mL/min OR creatinine normal based on age
• QTC ≤ 480 msec of ECG
• Normal left ventricular diastolic function: echocardiogram with ejection fraction ≥ 55% or shortening fraction ≥ 27%
• Patients receiving a medication that has a known risk of QTc prolongation within the last 2 weeks are excluded
• No medical condition that would preclude study participation
• No active graft-versus-host disease
• No known hepatitis B, hepatitis C, or HIV infection
• No allergies to cediranib or its excipients (e.g., mannitol, sodium starch glycolate, and magnesium stearate)
• Not pregnant or nursing; fertile patients must use effective contraception during and for 2 weeks after completion of study treatment

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Treatment Plan:

This is an open-label, dose-escalation study. Patients are stratified according to diagnosis (solid tumor vs. acute myeloid leukemia).

Stratum I (solid tumors):

• Patients receive oral cediranib once daily on Days 1–28
• Treatment may be repeated immediately after completion of a 28-day cycle
• Cohorts of 3–6 patients receive escalating doses of cediranib until the maximum tolerated dose (MTD) is determined
• The MTD is defined as the dose preceding that at which two of three—or two of six—patients experience dose-limiting toxicity during the first course of therapy
• Up to nine patients, preferably at least three patients < 12 years of age and at least three patients ≥ 12 years of age, are treated at the MTD

Stratum II (acute myeloid leukemia):

• The MTD in AML patients is the dose level below the dose level at which two or more patients (in a cohort [dose level] of 2–6 patients) experienced a DLT
• The MTD in children with AML will not exceed the solid tumor MTD
• Enrollment to stratum II will not begin until enrollment to stratum I (solid tumors) is complete

Patients undergo blood collection periodically during study for pharmacologic and pharmacodynamic correlative studies

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• FAQs about this study - provides information for patients about the trial such as frequency and duration of visits, costs, how to enroll, treatment plan.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 11/26/08
Updated: 12/8/08