Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Cediranib in Treating Young Patients With Refractory or Recurrent Solid Tumors or Acute Myeloid Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Active 2 to 18 NCI, Pharmaceutical / Industry NCI-06-C-0152 NCI-P6571, NCT00354848, ZENECA-D8480C00016

Special Category: NCI Web site featured trial, NIH Clinical Center trial

Objectives

Primary

1. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of cediranib in pediatric patients with refractory or recurrent extracranial malignant solid tumors.
2. Determine the tolerability of this drug when given at the MTD or recommended dose in pediatric patients with relapsed or refractory acute myeloid leukemia (AML).
3. Determine the toxic effects of this drug in these patients.
4. Determine the pharmacokinetics of this drug in pediatric patients with refractory or recurrent extracranial malignant solid tumors or AML.

Secondary

1. Determine response to this drug in these patients.
2. Determine the effect of this drug on solid tumor vascularity and tumor blood flow using dynamic contrast-enhanced MRI.
3. Determine the number of endothelial cells in these patients prior to protocol therapy and on day 7 and day 27 or 28 of course 1.
4. Determine the plasma concentration of basic fibroblast growth factor, vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, thrombospondin-1, and matrix metalloproteinases in these patients prior to protocol therapy and on day 7 and day 27 or 28 of course 1.
5. Assess phospho-kinase domain-containing receptor (KDR) (VEGFR2) expression by immunohistochemistry in tumor specimens taken from these patients.
6. Analyze circulating leukemia blasts for the presence of phospho-KDR (VEGFR2) in AML patients treated with this drug.

Entry Criteria

Disease Characteristics:

• Histologically confirmed diagnosis of 1 of the following:
  • 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
  • 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



• Measurable or evaluable disease (for patients with solid tumors)



• 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



• No primary brain tumor, active CNS or spinal cord metastasis, or spinal cord compression

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
• At least 30 days since prior and no concurrent immunotherapy (i.e., antibody)
• At least 30 days since prior investigational cancer therapy
• At least 7 days since prior biologic cancer therapy
• 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 7 days since prior and no concurrent pegfilgrastim
• At least 72 hours since other prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or interleukin-11) except epoetin alfa
• No prior cediranib
• 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
• For patients with solid tumors, the following additional requirements apply:
  • 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
  • At least 21 days since prior and no concurrent cytotoxic chemotherapy
• For patients with AML, the following additional requirements apply:
  • At least 4 weeks since any prior and no concurrent radiotherapy
  • At least 14 days since prior and no concurrent cytotoxic chemotherapy
• No concurrent growth factors (e.g., GM-CSF or interleukin-11)
• No other concurrent investigational agents or therapies
• No concurrent intrathecal chemotherapy for prophylaxis of CNS leukemia
• No other concurrent anticancer therapy
• Concurrent thyroid replacement therapy (levothyroxine) allowed provided dose has been stable for ≥ 1 month
• No concurrent medications known to prolong QTc

Patient Characteristics:

• Karnofsky performance status (PS) 60-100% (for patients > 10 years of age) OR Lansky PS 60-100% (for patients ≤ 10 years of age)
• Must be able to swallow tablets intact
• PT and PTT ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• ALT ≤ 2.5 times ULN
• Proteinuria ≤ 1+ by dipstick OR total urinary protein ≤ 500 g by 24-hour urine collection
• Creatinine clearance ≥ 60 mL/min OR creatinine normal based on age as follows:
  • No greater than 0.8 mg/dL (for patients 5 years of age and under)
  • No greater than 1.0 mg/dL (for patients 6-10 years of age)
  • No greater than 1.2 mg/dL (for patients 11-15 years of age)
  • No greater than 1.5 mg/dL (for patients over 15 years of age)
• Absolute neutrophil count ≥ 1,500/mm³*
• Platelet count ≥ 100,000/mm³ (transfusion independent)*
• QTC ≤ 480 msec of ECG
• Left Ventricular Diastolic Function normal
• Ejection fraction ≥ 55% by echocardiogram or shortening fraction ≥ 27%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 weeks after completion of study treatment
• No hypertension requiring medical treatment
• No diastolic blood pressure 5 mm Hg above the 95^th percentile for gender and age confirmed by 3 repeated measurements with an appropriate size cuff
• No arterial or venous thrombosis within the past 3 months
• No significant hemorrhage (e.g., hemoptysis, melena, or hematemesis) within the past 2 weeks
• No clinically significant unrelated systemic illness (e.g., serious infection or hepatic, renal, gastrointestinal, or other organ dysfunction) that would preclude study participation
• No active graft-versus-host disease
• No known hepatitis B or C infection
• No known HIV infection
• No allergies to cediranib or its excipients (e.g., mannitol, sodium starch glycolate, and magnesium stearate)
• No history of prolonged QTc or other conduction abnormalities

 [Note: *Required for patients with solid tumors]

Expected Enrollment

A total of 40 patients will be accrued for this study.

Outcomes

Maximum tolerated dose of cediranib and dose-limiting toxicity in pediatric patients with relapsed or refractory solid tumors
Safety and tolerability of cediranib in pediatric patients with relapsed or refractory acute myeloid leukemia (AML)
Pharmacokinetics of cediranib in pediatric patients with relapsed or refractory solid tumors or AML

Pharmacodynamics of cediranib in pediatric patients with relapsed or refractory solid tumors or AML
Response to cediranib in pediatric patients with relapsed or refractory solid tumors or AML

Outline

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

• Stratum 1 (solid tumors): Patients receive oral cediranib once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

  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 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course of therapy. Up to 9 patients, preferably at least 3 patients < 12 years of age and at least 3 patients ≥ 12 years of age, are treated at the MTD.




• Stratum 2 (acute myeloid leukemia): Patients receive cediranib as in stratum 1 at one dose level below the solid tumor MTD OR at the solid tumor MTD.

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

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research-Medical Oncology

Elizabeth Fox, MD, Principal investigator		Ph: 301-402-6641 Email: foxb@mail.nih.gov

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Richard Aplenc, MD, MSCE	Ph:  267-426-7252

Related Information

Featured trial article

Registry Information
Official Title		Phase I Trial of AZD2171, An Orally Bioavailable Antiangiogenic Agent, in Children and Adolescents with Refractory or Recurrent Solid Tumors or Acute Myelogenous Leukemia
Trial Start Date		2005-12-01
Registered in ClinicalTrials.gov		NCT00354848
Date Submitted to PDQ		2006-05-04
Information Last Verified		2008-06-08