Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

Myelodysplastic Syndromes Clinical Trial

Official title:

A Phase 2 Study of AZD6244 in Relapsed or Refractory AML

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00588809
• Other study ID #: NCI-2009-00250
• Secondary ID: 15455BN01CM62209
• Status: Completed
• Phase: Phase 2
• First received: December 21, 2007
• Last updated: July 6, 2015
• Start date: December 2007
• Est. completion date: December 2012

Study information

• Verified date: February 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Adult Acute Promyelocytic Leukemia (M3)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Promyelocytic, Acute
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasms
• Myeloproliferative Disorders
• Preleukemia
• Recurrent Adult Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia

Intervention

Drug:
• selumetinib
Given PO

Locations

Country	Name	City	State
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg 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. Erratum in: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco]. — View 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, Odenik — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	Up to 52 weeks	No
Secondary	Proportion of Subjects With Baseline p-ERK Activation	Proportion of subjects with baseline p-ERK activation	baseline (0 weeks)	No
Secondary	Proportion of Subjects With NRAS Mutation	Proportion of Subjects With NRAS Mutation	baseline (0 weeks)	No
Secondary	Proportion of Subjects With KRAS Mutation	Proportion of subjects with KRAS mutation	baseline (0 weeks)	No
Secondary	Proportion of Subjects With FLT3 ITD Mutation	Proportion of subjects with FLT3 ITD mutation	baseline (0 weeks)	No
Secondary	Proportion of Subjects With KIT Mutation	Proportion of subjects with KIT mutation	baseline (0 weeks)	No