Selumetinib in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00588809
• Collaborator: (none)
• Enrollment: 47
• Location: 1
• Arm: 1
• Duration (Months): 60
• Patients Per Site Per Month: 0.8

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
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	Drug: selumetinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. To correlate the effects of AZD6244 with the presence (or absence) of mutated RAS or FLT-3 at baseline.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of AZD6244 in Relapsed or Refractory AML
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (selumetinib) 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; Given PO; Other Names: ARRY-142886 AZD6244

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Proportion of Subjects With Baseline p-ERK Activation [baseline (0 weeks)]

   Proportion of subjects with baseline p-ERK activation

2. Proportion of Subjects With NRAS Mutation [baseline (0 weeks)]

   Proportion of Subjects With NRAS Mutation

3. Proportion of Subjects With KRAS Mutation [baseline (0 weeks)]

   Proportion of subjects with KRAS mutation

4. Proportion of Subjects With FLT3 ITD Mutation [baseline (0 weeks)]

   Proportion of subjects with FLT3 ITD mutation

5. Proportion of Subjects With KIT Mutation [baseline (0 weeks)]

   Proportion of subjects with KIT mutation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Olatoyosi Odenike, University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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].

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00588809
• Other Study ID Numbers: NCI-2009-00250; 15455B; N01CM62209; N01CM62201
• First Posted: Jan 9, 2008
• Last Update Posted: Aug 5, 2015
• Last Verified: Feb 1, 2013

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Period Title: Overall Study
STARTED	47
COMPLETED	47
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Selumetinib
Arm/Group Description	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
Overall Participants	47
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	20 42.6%
Male	27 57.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis only includes subjects without FLT3 ITD mutation.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	36
Number [percentage of participants]	16.67 35.5%

2. Secondary Outcome

Title	Proportion of Subjects With Baseline p-ERK Activation
Description	Proportion of subjects with baseline p-ERK activation
Time Frame	baseline (0 weeks)

Outcome Measure Data

Analysis Population Description

The analysis includes the 20 patients with samples available for analysis.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	20
Number [percentage of participants]	85 180.9%

3. Secondary Outcome

Title	Proportion of Subjects With NRAS Mutation
Description	Proportion of Subjects With NRAS Mutation
Time Frame	baseline (0 weeks)

Outcome Measure Data

Analysis Population Description

The analysis includes the 41 patients with samples available for analysis.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	41
Number [percentage of participants]	7 14.9%

4. Secondary Outcome

Title	Proportion of Subjects With KRAS Mutation
Description	Proportion of subjects with KRAS mutation
Time Frame	baseline (0 weeks)

Outcome Measure Data

Analysis Population Description

The analysis includes the 41 patients with samples available for analysis.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	41
Number [percentage of participants]	2 4.3%

5. Secondary Outcome

Title	Proportion of Subjects With FLT3 ITD Mutation
Description	Proportion of subjects with FLT3 ITD mutation
Time Frame	baseline (0 weeks)

Outcome Measure Data

Analysis Population Description

FLT3 ITD mutation status was not available for one patient.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	46
Number [percentage of participants]	22 46.8%

6. Secondary Outcome

Title	Proportion of Subjects With KIT Mutation
Description	Proportion of subjects with KIT mutation
Time Frame	baseline (0 weeks)

Outcome Measure Data

Analysis Population Description

The analysis includes the 41 patients with samples available for analysis.

Arm/Group Title	Selumetinib
Arm/Group Description	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
Measure Participants	41
Number [percentage of participants]	0 0%

Adverse Events

Time Frame	1 year
Arm/Group Title	Selumetinib
Arm/Group Description	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
All Cause Mortality
	Selumetinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Selumetinib
	Affected / at Risk (%)	# Events
Total	38/47 (80.9%)
Blood and lymphatic system disorders
Anemia	2/47 (4.3%)
Febrile neutropenia	8/47 (17%)
Cardiac disorders
Ventricular tachycardia	1/47 (2.1%)
Gastrointestinal disorders
Diarrhea	2/47 (4.3%)
Dry mouth	1/47 (2.1%)
Mucositis oral	2/47 (4.3%)
Nausea	2/47 (4.3%)
Vomiting	3/47 (6.4%)
General disorders
Death NOS	10/47 (21.3%)
Fatigue	3/47 (6.4%)
Fever	2/47 (4.3%)
Infections and infestations
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Blood	4/47 (8.5%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Lung (pneumonia)	3/47 (6.4%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Rectum	1/47 (2.1%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Salivary gland	1/47 (2.1%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Skin (cellulitis)	1/47 (2.1%)
Infection with normal ANC or Grade 1 or 2 neutrophils: Blood	2/47 (4.3%)
Infections and infestations - Other	11/47 (23.4%)
Lung infection	3/47 (6.4%)
peritonsillar abscess	1/47 (2.1%)
Pharyngitis	1/47 (2.1%)
Sepsis	1/47 (2.1%)
Upper respiratory infection	1/47 (2.1%)
Urinary tract infection	1/47 (2.1%)
Investigations
Alanine aminotransferase increased	1/47 (2.1%)
Creatinine increased	1/47 (2.1%)
Neutrophil count decreased	1/47 (2.1%)
Platelet count decreased	3/47 (6.4%)
White blood cell decreased	1/47 (2.1%)
Metabolism and nutrition disorders
Acidosis	1/47 (2.1%)
Anorexia	1/47 (2.1%)
Dehydration	5/47 (10.6%)
Hyperuricemia	1/47 (2.1%)
Hypoalbuminemia	1/47 (2.1%)
Hypokalemia	1/47 (2.1%)
Hyponatremia	1/47 (2.1%)
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb	1/47 (2.1%)
Nervous system disorders
Dizziness	2/47 (4.3%)
Dysphasia	1/47 (2.1%)
Intracranial hemorrhage	4/47 (8.5%)
Psychiatric disorders
Psychosis	1/47 (2.1%)
Renal and urinary disorders
Urine discoloration	1/47 (2.1%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/47 (2.1%)
Dyspnea	2/47 (4.3%)
Epistaxis	1/47 (2.1%)
Hypoxia	1/47 (2.1%)
Pneumonitis	3/47 (6.4%)
Vascular disorders
Hypotension	3/47 (6.4%)
Other (Not Including Serious) Adverse Events
	Selumetinib
	Affected / at Risk (%)	# Events
Total	47/47 (100%)
Blood and lymphatic system disorders
Anemia	24/47 (51.1%)
Febrile neutropenia	3/47 (6.4%)
Cardiac disorders
Atrial fibrillation	3/47 (6.4%)
Paroxysmal atrial tachycardia	4/47 (8.5%)
Sinus tachycardia	13/47 (27.7%)
Gastrointestinal disorders
Abdominal distension	7/47 (14.9%)
Abdominal pain	13/47 (27.7%)
Constipation	4/47 (8.5%)
Diarrhea	29/47 (61.7%)
Dry mouth	6/47 (12.8%)
Dyspepsia	3/47 (6.4%)
Hemorrhoids	4/47 (8.5%)
Mucositis oral	9/47 (19.1%)
Nausea	24/47 (51.1%)
Oral hemorrhage	5/47 (10.6%)
Vomiting	15/47 (31.9%)
General disorders
Chills	16/47 (34%)
Edema limbs	21/47 (44.7%)
Fatigue	32/47 (68.1%)
Fever	21/47 (44.7%)
Non-cardiac chest pain	7/47 (14.9%)
Pain	6/47 (12.8%)
Immune system disorders
Allergic reaction	5/47 (10.6%)
Infections and infestations
Infections and infestations - Other	9/47 (19.1%)
Urinary tract infection	3/47 (6.4%)
Injury, poisoning and procedural complications
Bruising	3/47 (6.4%)
Investigations
Alanine aminotransferase increased	16/47 (34%)
Alkaline phosphatase increased	7/47 (14.9%)
Aspartate aminotransferase increased	19/47 (40.4%)
Blood bilirubin increased	5/47 (10.6%)
Creatinine increased	7/47 (14.9%)
Lymphocyte count decreased	8/47 (17%)
Neutrophil count decreased	20/47 (42.6%)
Platelet count decreased	24/47 (51.1%)
Weight loss	3/47 (6.4%)
White blood cell decreased	13/47 (27.7%)
Metabolism and nutrition disorders
Acidosis	5/47 (10.6%)
Anorexia	19/47 (40.4%)
Dehydration	4/47 (8.5%)
Hyperglycemia	17/47 (36.2%)
Hyperuricemia	3/47 (6.4%)
Hypoalbuminemia	20/47 (42.6%)
Hypocalcemia	13/47 (27.7%)
Hypoglycemia	3/47 (6.4%)
Hypokalemia	12/47 (25.5%)
Hypomagnesemia	9/47 (19.1%)
Hyponatremia	15/47 (31.9%)
Hypophosphatemia	5/47 (10.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/47 (6.4%)
Back pain	9/47 (19.1%)
Generalized muscle weakness	4/47 (8.5%)
Muscle weakness lower limb	4/47 (8.5%)
Nervous system disorders
Dizziness	10/47 (21.3%)
Headache	12/47 (25.5%)
Psychiatric disorders
Confusion	4/47 (8.5%)
Depression	4/47 (8.5%)
Renal and urinary disorders
Proteinuria	4/47 (8.5%)
Urinary retention	3/47 (6.4%)
Respiratory, thoracic and mediastinal disorders
Cough	18/47 (38.3%)
Dyspnea	19/47 (40.4%)
Epistaxis	9/47 (19.1%)
Hypoxia	5/47 (10.6%)
Pharyngolaryngeal pain	4/47 (8.5%)
Pleural effusion	5/47 (10.6%)
Pneumonitis	3/47 (6.4%)
Respiratory, thoracic and mediastinal disorders - Other, specify	3/47 (6.4%)
Skin and subcutaneous tissue disorders
Dry skin	3/47 (6.4%)
Hyperhidrosis	4/47 (8.5%)
Purpura	4/47 (8.5%)
Rash maculo-papular	10/47 (21.3%)
Skin and subcutaneous tissue disorders - Other	3/47 (6.4%)
Vascular disorders
Hypertension	9/47 (19.1%)
Hypotension	7/47 (14.9%)
Vascular disorders - Other	5/47 (10.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.