Adult Solid Neoplasm
Conditions
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.
Interventions
DRUGSelumetinib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Selumetinib) 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 | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up | being followed for long-term survival | 1 |
| Treatment With Study Drug | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Selumetinib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 11 Participants |
| Type of cancer Colon cancer | 10 participants |
| Type of cancer Non small-cell lung cancer | 14 participants |
| Type of cancer Other cancer | 4 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 17 / 28 |
Outcome results
Primary
Objective Response Rate in Patients With Cancers Other Than Melanoma
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Selumetinib) | Objective Response Rate in Patients With Cancers Other Than Melanoma | 0 percentage of participants |
Secondary
AKT Pathway Activity
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
Population: Samples and data were not collected for this outcome.
Secondary
Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Selumetinib) | Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers | 0 percentage of participants |
Secondary
Progression-free Survival
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Selumetinib) | Progression-free Survival | 21.4 percentage of participants |
Secondary
Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip
Time frame: Up to 4 years
Population: Samples and data were not collected for this outcome.