Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. Evaluate the objective response rate in patients with relapsed, refractory, or untreated acute myeloid leukemia or high-risk myelodysplastic syndromes treated with AZD2171 (cediranib maleate).

SECONDARY OBJECTIVES:

I. Determine the toxicity of this drug in these patients. II. Determine the response duration, event-free survival, and overall survival of patients treated with this drug.

III. 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 cediranib maleate once daily (QD) 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.

Inclusion criteria

• Histologically or cytologically confirmed acute myeloid leukemia (AML) ormyelodysplastic syndromes meeting 1 of the following criteria:

• Relapsed AML meeting any of the following criteria:

• Good-risk cytogenetics (inv[16], t[8;21], or t[15;17]) in second orgreater relapse

• Patients with AML t(15;17) must have failed prior tretinoin and arsenic-containing regimens AND progressed orrelapsed within 12 months of therapy
• In first or greater relapse
• Resistant AML

• Unable to achieve first complete remission after at least 2 inductionregimens
• Untreated AML meeting any of the following criteria:

• At least 60 years of age
• Preceding MDS
• MDS

• International Prognosis Scoring System (IPSS) risk groupof intermediate-2 or higher
• Patients with relapsed disease after allogeneic hematopoietic stem cell transplantation (HSCT) must be off allimmunosuppressive medications for at least 30 days and have no symptoms orsigns of graft-vs-host disease
• No active CNS metastasis

• Patients with clinical signs of CNS disease or a history of CNS diseasewithin the past 6 months are required to undergo lumbar puncture to excludeCNS involvement
• No symptomatic leukostasis or requirement for leukapheresis
• Not eligible for allogeneic HSCTAND no suitable donor at the time of study entry

• Patients who areeligible for HSCT, informed of the option, and choose not to proceed to HSCTare 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 orbiological composition to AZD2171
• No concurrent uncontrolled illness, including, but not limited to, any of the following:

• Hypertension
• Thyroid disease
• Ongoing or active infection
• Symptomatic congestive heartfailure
• 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
• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks fornitrosoureas 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 aninvestigational trial
• No more than 3 prior courses of induction chemotherapy

• Induction chemotherapyis defined as that intended to induce complete remission and given at a time thatthe 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