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

Study Overview
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Brief Summary
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This phase II trial is studying how well cediranib maleate works in treating patients with relapsed, refractory, or untreated acute myeloid leukemia or high-risk myelodysplastic syndrome. Cediranib maleate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Detailed Description
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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.

Official Title
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A Phase II Study of AZD2171 in the Treatment of Patients With Acute Leukemia and Myelodysplastic Syndrome.

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: cediranib maleate
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>Patients receive oral cediranib maleate QD on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. | Drug: cediranib maleate<br>* Given orally<br>* Other names: Recentin;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Confirmed Disease Response: Complete Response (CR), Partial Response (PR), and Hematologic Improvement (HI). A Confirmed Response is Defined to be an Objective Status of CR, PR, or HI Noted on 2 Consecutive Evaluations. | Complete Response (CR) requires a repeat bone marrow with < 5% myeloblasts, hemoglobin ≥ 11 g/dl, neutrophils ≥ 1000/mm3, platelets ≥ 100,000/mm3, and no circulating blasts. Partial Response (PR) requires a bone marrow blast reduction of 50% or more, hemoglobin ≥ 11 g/dl, neutrophils ≥ 1000/mm3, platelets ≥ 100,000/mm3, and no circulating blasts. Hematologic Improvement (HI) requires one of the following: RBC transfusion independent participants are required to have >1.5 g/dL increase in hemoglobin, RBC transfusion-dependent participants are required to be transfusion independent, A 100% increase, and an absolute increase over 500mm^3 in Absolute Neutrophil Count, Participants with a pretreatment platelet count over 20,000/mm3 require an absolute increase of 30,000/mm^3 or more, Participants with platelet count below 20,000/mm3 require an increase over 20,000/mm^3 and by at least 100%. | At the end of cycles 1 and 3 and every 3 cycles thereafter up to 26 cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Defined as the time from date of registration to date of death due to any cause or date last known alive. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Every cycle during treatment and every 6 months for up to 2 years after completion of study treatment | 
| Progression-free Survival | Defined as the time from date of registration to date that disease progression was documented, death, or last date that progression-free status was documented, whichever comes first. Estimated using the method of Kaplan-Meier. Disease progression is defined as one of the following: A ≥ 50% increase in bone marrow blasts from the best response, or A 50% or greater decrement from maximum remission/response levels in neutrophils or platelets, or A reduction in hemoglobin concentration by at least 1.5 g/dl, or Transfusion dependence (without alternative explanation and sustained for at least 2 weeks). | Every 3 courses during treatment and then at 3 months and every 6 months for up to 2 years after completion of study treatment | 
| Duration of Response | Measured from the time criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Estimated using the method of Kaplan-Meier. | Every 3 courses up to 26 courses | 
| The Number of Patients That Report Adverse Events Possibly, Probably, or Definitely Related to AZD2171. | Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. All adverse events determined to be possibly, probably, or definately related to AZD2171 are included in this analysis. | Continuously during treatment up to 26 courses |