Selumetinib in Cancers With BRAF Mutations

Phase 2

Completed

Conditions: Adult Solid Neoplasm

Interventions: Drug: Selumetinib

Registration Number: NCT00888134

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: PRIMARY OBJECTIVES:

I. 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:

I. 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.

III. 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.

IV. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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%

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (selumetinib)	Selumetinib	Patients receive selumetinib PO BID for 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)
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.
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.
Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip	Up to 4 years

Trial Locations

Locations (5): Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸
Charlestown, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States