Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Promyelocytic Leukemia (M3), Myelodysplastic/Myeloproliferative Neoplasms, Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia
Conditions
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.
Interventions
DRUGselumetinib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate for Subjects Without FLT3 ITD Mutation | Up to 52 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Baseline p-ERK Activation | baseline (0 weeks) | Proportion of subjects with baseline p-ERK activation |
| Proportion of Subjects With NRAS Mutation | baseline (0 weeks) | Proportion of Subjects With NRAS Mutation |
| Proportion of Subjects With KRAS Mutation | baseline (0 weeks) | Proportion of subjects with KRAS mutation |
| Proportion of Subjects With FLT3 ITD Mutation | baseline (0 weeks) | Proportion of subjects with FLT3 ITD mutation |
| Proportion of Subjects With KIT Mutation | baseline (0 weeks) | Proportion of subjects with KIT mutation |
Countries
United States
Participant flow
Pre-assignment details
A Simon, optimal two-stage design was employed for subjects without FLT3 ITD mutations. The study also included a second cohort of subjects with FLT3 ITD mutations.
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib Patients receive selumetinib PO BID on days 1 -28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
selumetinib: Given PO | 47 |
| Total | 47 |
Baseline characteristics
| Characteristic | Selumetinib |
|---|---|
| Age, Continuous | 69 years |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 47 / 47 |
| serious Total, serious adverse events | 38 / 47 |
Outcome results
Primary
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).
Time frame: Up to 52 weeks
Population: Analysis only includes subjects without FLT3 ITD mutation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Response Rate for Subjects Without FLT3 ITD Mutation | 16.67 percentage of participants |
Secondary
Proportion of Subjects With Baseline p-ERK Activation
Proportion of subjects with baseline p-ERK activation
Time frame: baseline (0 weeks)
Population: The analysis includes the 20 patients with samples available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Proportion of Subjects With Baseline p-ERK Activation | 85 percentage of participants |
Secondary
Proportion of Subjects With FLT3 ITD Mutation
Proportion of subjects with FLT3 ITD mutation
Time frame: baseline (0 weeks)
Population: FLT3 ITD mutation status was not available for one patient.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Proportion of Subjects With FLT3 ITD Mutation | 22 percentage of participants |
Secondary
Proportion of Subjects With KIT Mutation
Proportion of subjects with KIT mutation
Time frame: baseline (0 weeks)
Population: The analysis includes the 41 patients with samples available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Proportion of Subjects With KIT Mutation | 0 percentage of participants |
Secondary
Proportion of Subjects With KRAS Mutation
Proportion of subjects with KRAS mutation
Time frame: baseline (0 weeks)
Population: The analysis includes the 41 patients with samples available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Proportion of Subjects With KRAS Mutation | 2 percentage of participants |
Secondary
Proportion of Subjects With NRAS Mutation
Proportion of Subjects With NRAS Mutation
Time frame: baseline (0 weeks)
Population: The analysis includes the 41 patients with samples available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib | Proportion of Subjects With NRAS Mutation | 7 percentage of participants |