Phase I Study of Cediranib in Pediatric Patients With Refractory or Recurrent Extracranial Malignant Solid Tumors or Acute Myeloid Leukemia (Acute Myeloid Leukemia Accrual Closed as of 02/19/10)
Cediranib in Treating Young Patients With Refractory or Recurrent Solid Tumors or Acute Myeloid Leukemia (Acute Myeloid Leukemia Accrual Closed as of 02/19/10)
Basic Trial Information
|Phase I||Biomarker/Laboratory analysis, Treatment||Closed||2 to 18||NCI, Pharmaceutical / Industry||NCI-06-C-0152|
NCI-P6571, NCT00354848, ZENECA-D8480C00016
Special Category: NCI Web site featured trial
- Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of cediranib in pediatric patients with refractory or recurrent extracranial malignant solid tumors.
- II. 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). (Closed to accrual as of 02/19/10)
- Determine the toxic effects of this drug in these patients.
- Determine the pharmacokinetics of this drug in pediatric patients with refractory or recurrent extracranial malignant solid tumors or AML (AML closed to accrual as of 02/19/10).
- Determine response to this drug in these patients.
- Determine the effect of this drug on solid tumor vascularity and tumor blood flow using dynamic contrast-enhanced MRI.
- 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.
- 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.
- Assess phospho-kinase domain-containing receptor (KDR) (VEGFR2) expression by immunohistochemistry in tumor specimens taken from these patients.
- Analyze circulating leukemia blasts for the presence of phospho-KDR (VEGFR2) in AML patients treated with this drug. (Closed to accrual as of 02/19/10)
- Assess growth plate volumes using non-contrast magnetic resonance imaging of the right knee prior to and during study treatment.
- 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
- Wilms' tumor
- Hepatic tumor
- Germ cell tumor
- Acute myeloid leukemia, meeting all of the following criteria (closed to accrual as of 02/19/10):
- 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
- Extracranial malignant solid tumors, including, but not limited to, any of the following:
- 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
- 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
- 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 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 95th 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]
A total of 40 patients will be accrued for this study.
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) (Closed to accrual as of 02/19/10)
Pharmacokinetics of cediranib in pediatric patients with relapsed or refractory solid tumors or AML (AML closed to accrual as of 02/19/10)
Pharmacodynamics of cediranib in pediatric patients with relapsed or refractory solid tumors or AML (AML closed to accrual as of 02/19/10)
Response to cediranib in pediatric patients with relapsed or refractory solid tumors or AML (AML closed to accrual as of 02/19/10)
Growth plate volumes using non-contrast magnetic resonance imaging of the right knee prior to and during study treatment
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 closed to accrual as of 02/19/10): 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. Patients also undergo non-contrast magnetic resonance imaging of the right knee for distal femor growth plate analysis prior to and during study.
Fox E, Aplenc R, Bagatell R, et al.: A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors. J Clin Oncol 28 (35): 5174-81, 2010.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
NCI - Center for Cancer Research
|Official Title||Phase I Trial of Cediranib (AZD2171), An Orally Bioavailable Antiangiogenic Agent, in Children and Adolescents with Refractory or Recurrent Solid Tumors or Acute Myeloid Leukemia (Acute Myeloid Leukemia Accrual Closed as of 02/19/10)|
|Trial Start Date||2005-12-01|
|Registered in ClinicalTrials.gov||NCT00354848|
|Date Submitted to PDQ||2006-05-04|
|Information Last Verified||2009-07-05|
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.