Selumetinib in Cancers With BRAF Mutations

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00888134
• Collaborator: (none)
• Enrollment: 28
• Locations: 5
• Arm: 1
• Duration (Months): 66
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine if selumetinib is safe and effective in treating patients with cancers with a mutated BRAF gene. Selumetinib is an investigational drug that works by blocking a protein called MEK, which is known to play a role in the growth of cancer cells lines and tumors that have a mutated BRAF gene. There are multiple types of cancers that have mutations in the BRAF gene and depend on the activity of this gene for their growth and survival.

Condition or Disease	Intervention/Treatment	Phase
Adult Solid Neoplasm	Drug: Selumetinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the objective response rate to AZD6244 (selumetinib) in patients with cancers other than melanoma in which BRAF mutations have been identified prospectively.

SECONDARY OBJECTIVES:

1. To evaluate progression-free survival in subjects treated with AZD6244. II. To obtain a preliminary estimate of the objective response rate in non-small cell lung cancers and colon cancers with BRAF mutations.

2. To explore biologic correlates of responsiveness to AZD6244, and specifically to correlate AKT pathway activity with sensitivity to MEK inhibition in the BRAF mutant class of tumors.

3. To estimate the sensitivity and specificity of detection of the BRAF V600E mutation in circulating tumor cells (CTC) using a microfluidic platform (the 'CTC-chip').

OUTLINE:

Patients receive selumetinib orally (PO) twice daily (BID) for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Trial of the MEK 1/2 Inhibitor AZD6244 in Cancers With BRAF Mutations Identified by Prospective Genotypic Analysis
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (selumetinib) Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Selumetinib; Given PO; Other Names: ARRY-142886 AZD6244 MEK Inhibitor AZD6244

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate in Patients With Cancers Other Than Melanoma [4 years]

   Percentage of participants achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans (which are done every 6 weeks).

Secondary Outcome Measures

1. AKT Pathway Activity [Up to 4 years]

   Correlation between response to AZD6244 and mutational analysis of AKT pathway (an intracellular signaling pathway important in regulating the cell cycle)

2. Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers [Up to 4 years]

   Percentage of participants with either colon cancer or non-small cell lung cancer achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans.

3. Progression-free Survival [4 months]

   Reported as percentage of participants alive and progression free at 4-months. Will be estimated using Kaplan-Meier survival curves. Confidence intervals will be calculated and reported.

4. Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip [Up to 4 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability to understand and willingness to sign a written informed consent document

• Histologically confirmed metastatic or unresectable solid tumor

• Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping

• Patients may have received any number of prior systemic treatments for their cancer

• At least one measurable site of disease by CT, according to standard RECIST criteria 1.0

• ECOG performance status 0-1

• Absolute neutrophil count > 1500 per cubic mm

• Platelet count > 100,000 per cubic mm

• Hemoglobin > 9 g/dl

• Serum bilirubin < 1.5 x upper limit of normal

• Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases)

• Serum creatinine < 1.5 x upper limit of normal

• For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study

Exclusion Criteria:

• Estimated life expectancy > 12 weeks

• Patients with melanoma

• Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study

• Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline)

• Currently receiving other investigational agents

• Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244

• Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed)

• Uncontrolled intercurrent illness, including but not limited to:

• Clinically significant active infection

• Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation

• Psychiatric illness/social situations that would limit compliance with study requirements

• Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication

• Pregnant and/or breast-feeding women

• Previous or concurrent malignancy, except for the following circumstances:

• Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy

• Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin)

• History of solid organ transplantation or other condition requiring the use of immunosuppressive medications

• Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications)

• A mean left ventricular ejection fraction (LVEF) less than 45%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
4	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129
5	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Donald Lawrence, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00888134
• Other Study ID Numbers: NCI-2013-00576; NCI-2013-00576; P30CA006516; U01CA062490; CDR642346; N01CM62206; 09-005; 8281
• First Posted: Apr 27, 2009
• Last Update Posted: Jan 15, 2016
• Last Verified: Jul 1, 2015

Study Results

Participant Flow

Pre-assignment Detail	Participants 'complete' the treatment period if they ended their treatment for disease progression, unacceptable toxicity, withdrawal of consent, or intercurrent illness. Those participants who completed treatment then enter a follow-up period when they are followed until death or lost-to-follow-up.

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Period Title: Treatment With Study Drug
STARTED	28
COMPLETED	27
NOT COMPLETED	1
Period Title: Treatment With Study Drug
STARTED	27
COMPLETED	26
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Overall Participants	28
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 67.9%
>=65 years	9 32.1%
Sex: Female, Male (Count of Participants)
Female	17 60.7%
Male	11 39.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	27 96.4%
Unknown or Not Reported	1 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.6%
White	27 96.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	28 100%
Type of cancer (participants) [Number]
Non small-cell lung cancer	14 50%
Colon cancer	10 35.7%
Other cancer	4 14.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate in Patients With Cancers Other Than Melanoma
Description	Percentage of participants achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans (which are done every 6 weeks).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	28
Number [percentage of participants]	0 0%

2. Secondary Outcome

Title	AKT Pathway Activity
Description	Correlation between response to AZD6244 and mutational analysis of AKT pathway (an intracellular signaling pathway important in regulating the cell cycle)
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

Samples and data were not collected for this outcome.

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	0

3. Secondary Outcome

Title	Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers
Description	Percentage of participants with either colon cancer or non-small cell lung cancer achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	24
Number [percentage of participants]	0 0%

4. Secondary Outcome

Title	Progression-free Survival
Description	Reported as percentage of participants alive and progression free at 4-months. Will be estimated using Kaplan-Meier survival curves. Confidence intervals will be calculated and reported.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Selumetinib: Given PO
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	21.4 76.4%

5. Secondary Outcome

Title	Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

Samples and data were not collected for this outcome.

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	0

Adverse Events

Time Frame	Adverse events experienced by participants will be followed for 30 days after participant stops treatment. (if ongoing beyond 30 days, they were contacted by the study team until the event resolved)
Adverse Event Reporting Description	Participants were seen every 3 weeks during study treatment for physical exam, vital signs and laboratory assessments.
Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
All Cause Mortality
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	17/28 (60.7%)
Endocrine disorders
hypothyroidism	1/28 (3.6%)
Eye disorders
increased intraocular pressure	1/28 (3.6%)
blurry vision	2/28 (7.1%)
retinopathy	1/28 (3.6%)
Gastrointestinal disorders
Fistula	1/28 (3.6%)
Abdominal Pain	1/28 (3.6%)
malignant ascites	1/28 (3.6%)
ileus	1/28 (3.6%)
General disorders
fatigue	1/28 (3.6%)
Infections and infestations
pulmonary / URT infection	1/28 (3.6%)
Metabolism and nutrition disorders
SGPT	3/28 (10.7%)
SGOT	1/28 (3.6%)
hypoalbuminemia	1/28 (3.6%)
Musculoskeletal and connective tissue disorders
joint pain	1/28 (3.6%)
muscle pain	1/28 (3.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
fatal progressive disease	3/28 (10.7%)
Nervous system disorders
dizziness	1/28 (3.6%)
Psychiatric disorders
confusion	1/28 (3.6%)
mental status changes	1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
dyspnea	2/28 (7.1%)
Skin and subcutaneous tissue disorders
dry skin	1/28 (3.6%)
skin infection	2/28 (7.1%)
Other (Not Including Serious) Adverse Events
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Blood and lymphatic system disorders
hemoglobin - low	19/28 (67.9%)
leukocytes	2/28 (7.1%)
lymphopenia	8/28 (28.6%)
platelets	6/28 (21.4%)
edema - head and neck	5/28 (17.9%)
edema - limb	14/28 (50%)
edema - trunk	2/28 (7.1%)
Cardiac disorders
hypertension	3/28 (10.7%)
Ear and labyrinth disorders
tinnitus	2/28 (7.1%)
Eye disorders
tearing	2/28 (7.1%)
other	3/28 (10.7%)
Gastrointestinal disorders
anorexia	5/28 (17.9%)
constipation	8/28 (28.6%)
diarrhea	14/28 (50%)
dry mouth	3/28 (10.7%)
fistula	2/28 (7.1%)
mucositis	4/28 (14.3%)
nausea	15/28 (53.6%)
taste disturbance	2/28 (7.1%)
vomiting	13/28 (46.4%)
hemorrhage - anus	2/28 (7.1%)
abdominal pain	8/28 (28.6%)
other	3/28 (10.7%)
General disorders
fatigue	19/28 (67.9%)
fever (without neutropenia)	2/28 (7.1%)
Infections and infestations
infection	5/28 (17.9%)
Investigations
INR	3/28 (10.7%)
PTT	3/28 (10.7%)
Metabolism and nutrition disorders
hypoalbuminemia	16/28 (57.1%)
alkaline phosphatase	17/28 (60.7%)
SGPT	10/28 (35.7%)
SGOT	21/28 (75%)
bicarbonate	4/28 (14.3%)
bilirubin	3/28 (10.7%)
hypocalcemia	7/28 (25%)
hypercholesterolemia	2/28 (7.1%)
creatinine	3/28 (10.7%)
hyperglycemia	20/28 (71.4%)
hypoglycemia	2/28 (7.1%)
hypermagnesemia	3/28 (10.7%)
hypomagnesemia	8/28 (28.6%)
hypophosphatemia	3/28 (10.7%)
hyperkalemia	6/28 (21.4%)
hypokalemia	7/28 (25%)
hyponatremia	8/28 (28.6%)
other	5/28 (17.9%)
Musculoskeletal and connective tissue disorders
back pain	7/28 (25%)
extremity - limb pain	3/28 (10.7%)
joint pain	2/28 (7.1%)
Nervous system disorders
dizziness	6/28 (21.4%)
neuropathy - sensory	7/28 (25%)
headache	3/28 (10.7%)
Psychiatric disorders
insomnia	5/28 (17.9%)
depression	4/28 (14.3%)
Respiratory, thoracic and mediastinal disorders
allergic rhinitis	2/28 (7.1%)
hemorrhage - nose	2/28 (7.1%)
cough	13/28 (46.4%)
dyspnea	10/28 (35.7%)
voice changes/ dysarthria	4/28 (14.3%)
other	4/28 (14.3%)
Skin and subcutaneous tissue disorders
dry skin	3/28 (10.7%)
nail changes	3/28 (10.7%)
pruritis	4/28 (14.3%)
rash/desquamation	6/28 (21.4%)
rash: acneiform	19/28 (67.9%)
rash: erythema multiforme	2/28 (7.1%)
skin - other	4/28 (14.3%)
other	4/28 (14.3%)

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.