Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II clinical trial is studying how well selumetinib works in treating patients with recurrent or refractory acute myeloid leukemia. Selumetinib may stop the growth of cancer by blocking some of the enzymes needed for cell growth

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate (includes complete response-CR, complete response with incomplete count recovery CRi, partial response-PR, and minor response-MR) to AZD6244 (selumetinib). SECONDARY OBJECTIVES: I. To determine the effects of AZD6244 in AML samples on p-ERK and evaluate the potential utility of p-ERK inhibition as a surrogate marker of biologic activity. II. To correlate the effects of AZD6244 with the presence (or absence) of mutated RAS or FLT-3 at baseline. III. To assess the safety profile of AZD6244 in patients with AML. OUTLINE: Patients receive selumetinib orally (PO) twice daily (BID) on days 1 -28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 52 weeks.

Official Title
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A Phase 2 Study of AZD6244 in Relapsed or Refractory AML

Conditions
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Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Promyelocytic Leukemia (M3), Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: selumetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of 1 of the following: Relapsed or refractory acute myeloid leukemia (AML) Secondary AML including AML arising from antecedent hematologic diseases (e.g., myelodysplastic syndrome, myeloproliferative disorders, or therapy-related AML) Elderly patients ≥ 60 years of age, previously untreated, and who are not candidates for or have refused standard chemotherapy are eligible for this trial Patients with relapsed acute promyelocytic leukemia (APL) who are FLT3+ and have failed both tretinoin and arsenic therapy are eligible for this trial No known active CNS disease ECOG performance status (PS) 0-2 or Karnofsky PS 60-100% Total bilirubin ≤ 2 mg/dL (unless due to disease, hemolysis, or Gilbert disease) In patients with associated hemolysis or Gilbert disease, a bilirubin of > 2 mg/dL is allowed as a result of predominantly unconjugated hyperbilirubinemia AST/ALT < 3 times upper limit of normal Creatinine < 2 mg/dL Baseline pulse oximetry > 92% Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to, during, and for 4 weeks (16 week for males) after completion of study treatment Recovered from prior therapy At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy Hydroxyurea may be administered for the first 7 days of therapy in patients with rapidly rising white count (WBC > 20 K/μL) At least 4 weeks since prior investigational agents No prior MEK inhibitors No concurrent medication that can prolong the QT interval No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients Exclusion Criteria: History of allergic reactions attributed to compounds of similar chemical or biological composition to AZD6244 or its excipient Captisol® QTc interval > 450 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, or family history of long QT interval syndrome), including New York Heart Association class III or IV heart failure Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness or social situations that would limit compliance with study requirements

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 (selumetinib)<br>Patients receive selumetinib PO BID on days 1 -28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: selumetinib<br>* Given PO<br>* Other names: AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate for Subjects Without FLT3 ITD Mutation | Responses were defined using standard criteria developed by an International Working Group. [Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-9.] In this primary outcome, we report the proportion of subjects without FLT3 ITD mutation that experienced a complete response (CR), partial response (PR), minor response (MR), or unconfirmed minor response (uMR). | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With Baseline p-ERK Activation | Proportion of subjects with baseline p-ERK activation | baseline (0 weeks) | 
| Proportion of Subjects With NRAS Mutation | Proportion of Subjects With NRAS Mutation | baseline (0 weeks) | 
| Proportion of Subjects With KRAS Mutation | Proportion of subjects with KRAS mutation | baseline (0 weeks) | 
| Proportion of Subjects With FLT3 ITD Mutation | Proportion of subjects with FLT3 ITD mutation | baseline (0 weeks) | 
| Proportion of Subjects With KIT Mutation | Proportion of subjects with KIT mutation | baseline (0 weeks) |