Clinical trial NCT00888134: Selumetinib in Cancers With BRAF Mutations
Official title: Phase II Clinical Trial of the MEK 1/2 Inhibitor AZD6244 in Cancers With BRAF Mutations Identified by Prospective Genotypic Analysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Solid Neoplasm
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-04-27
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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%

Primary outcomes:
measure: Objective Response Rate in Patients With Cancers Other Than Melanoma
timeFrame: 4 years
Secondary outcomes:
measure: AKT Pathway Activity
timeFrame: Up to 4 years
measure: Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers
timeFrame: Up to 4 years
measure: Progression-free Survival
timeFrame: 4 months
measure: Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip
timeFrame: Up to 4 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Charlestown
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Massachusetts General Hospital
name: Donald Lawrence
role: PRINCIPAL_INVESTIGATOR
References: