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Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

Primary Purpose

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Promyelocytic Leukemia (M3), Myelodysplastic Syndromes

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
selumetinib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Chicago Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (selumetinib)

Arm Description

Patients receive selumetinib PO BID on days 1 -28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Proportion of Subjects With Baseline p-ERK Activation
Proportion of subjects with baseline p-ERK activation
Proportion of Subjects With NRAS Mutation
Proportion of Subjects With NRAS Mutation
Proportion of Subjects With KRAS Mutation
Proportion of subjects with KRAS mutation
Proportion of Subjects With FLT3 ITD Mutation
Proportion of subjects with FLT3 ITD mutation
Proportion of Subjects With KIT Mutation
Proportion of subjects with KIT mutation

Full Information

First Posted
December 21, 2007
Last Updated
July 6, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00588809
Brief Title
Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia
Official Title
A Phase 2 Study of AZD6244 in Relapsed or Refractory AML
Study Type
Interventional

2. Study Status

Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (selumetinib)
Arm Type
Experimental
Arm Description
Patients receive selumetinib PO BID on days 1 -28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
selumetinib
Other Intervention Name(s)
ARRY-142886, AZD6244
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Response Rate for Subjects Without FLT3 ITD Mutation
Description
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).
Time Frame
Up to 52 weeks
Secondary Outcome Measure Information:
Title
Proportion of Subjects With Baseline p-ERK Activation
Description
Proportion of subjects with baseline p-ERK activation
Time Frame
baseline (0 weeks)
Title
Proportion of Subjects With NRAS Mutation
Description
Proportion of Subjects With NRAS Mutation
Time Frame
baseline (0 weeks)
Title
Proportion of Subjects With KRAS Mutation
Description
Proportion of subjects with KRAS mutation
Time Frame
baseline (0 weeks)
Title
Proportion of Subjects With FLT3 ITD Mutation
Description
Proportion of subjects with FLT3 ITD mutation
Time Frame
baseline (0 weeks)
Title
Proportion of Subjects With KIT Mutation
Description
Proportion of subjects with KIT mutation
Time Frame
baseline (0 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olatoyosi Odenike
Organizational Affiliation
University of Chicago Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637-1470
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
14673054
Citation
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 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 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036. Erratum In: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco].
Results Reference
background
PubMed Identifier
24178622
Citation
Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, Poire X, Koval G, Shannon K, Reddy PL, Joseph L, Atallah EL, Dy P, Thomas SP, Smith SE, Doyle LA, Stadler WM, Larson RA, Stock W, Odenike O. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014 Jan 15;20(2):490-8. doi: 10.1158/1078-0432.CCR-13-1311. Epub 2013 Oct 31.
Results Reference
result

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Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

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