- Evaluate the objective response rate in patients with relapsed, refractory, or untreated acute myeloid leukemia or high-risk myelodysplastic syndromes treated with AZD2171.
- Determine the toxicity of this drug in these patients.
- Determine the response duration, event-free survival, and overall survival of patients treated with this drug.
- Determine the hematological response rate in patients treated with this drug.
OUTLINE: This is a multicenter study. Patients are stratified according to disease (acute myeloid leukemia vs myelodysplastic syndromes).
Patients receive oral AZD2171 once daily on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow biopsy at baseline and on day 28 for correlative studies. Samples are analyzed for circulating endothelial cells, VEGF receptor expression, and leukemic blasts via flow cytometry and microvessel density via histopathological techniques.
After completion of study treatment, patients are followed up at 3 months and then every 6 months for up to 2 years.
PROJECTED ACCRUAL: A total of 73 patients will be accrued for this study.
- Histologically or cytologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndromes meeting 1 of the following criteria:
- Relapsed AML meeting any of the following criteria:
- Good-risk cytogenetics (inv, t[8;21], or t[15;17]) in second or greater relapse
- Patients with AML t(15;17) must have failed prior tretinoin and arsenic-containing regimens AND progressed or relapsed within 12 months of therapy
- In first or greater relapse
- Resistant AML
- Unable to achieve first complete remission after at least 2 induction regimens
- Untreated AML meeting any of the following criteria:
- At least 60 years of age
- Preceding MDS
- International Prognosis Scoring System (IPSS) risk group of intermediate-2 or higher
- Patients with relapsed disease after allogeneic hematopoietic stem cell transplantation (HSCT) must be off all immunosuppressive medications for at least 30 days and have no symptoms or signs of graft-vs-host disease
- No active CNS metastasis
- Patients with clinical signs of CNS disease or a history of CNS disease within the past 6 months are required to undergo lumbar puncture to exclude CNS involvement
- No symptomatic leukostasis or requirement for leukapheresis
- Not eligible for allogeneic HSCT AND no suitable donor at the time of study entry
- Patients who are eligible for HSCT, informed of the option, and choose not to proceed to HSCT are allowed
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Bilirubin normal
- AST and/or ALT ≤ 2.5 times upper limit of normal
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- No proteinuria ≥ 1+ on 2 consecutive urinalysis taken ≥ 1 week apart
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No HIV positivity
- LVEF ≥ 45% by echocardiography
- Mean QTc ≤ 500 msec (with Bazett's correction)
- No other significant ECG abnormality
- No history of familial long QT syndrome
- No disseminated intravascular coagulation
- No history of allergic reactions attributed to compounds of similar chemical or biological composition to AZD2171
- No concurrent uncontrolled illness, including, but not limited to, any of the following:
- Thyroid disease
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- NYHA class III-IV heart disease
- NYHA class II heart disease controlled with treatment allowed
- Psychiatric illness or social situations that would limit study compliance
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, or major surgery and recovered
- Hydroxyurea allowed to control peripheral blast count > 20,000/mcL prior to study entry and during the first 3 days of study therapy
- More than 4 weeks since prior and no concurrent growth factor or other cytokine support
- At least 30 days since prior investigational agents or participation in an investigational trial
- No more than 3 prior courses of induction chemotherapy
- Induction chemotherapy is defined as that intended to induce complete remission and given at a time that the patient has active disease
- No concurrent CYP interactive medications
- No other concurrent investigational agents
- No concurrent drugs or biologics with proarrhythmic potential
- Prior and concurrent hydroxyurea allowed to control peripheral blast count > 20,000/mcL during the first 3 days of study therapy
Last updated: 05/18/2012
NCT ID: NCT00475150