MEK Inhibitor AZD6244 in Treating Patients With Stage III or Stage IV Melanoma
Study Details
Study Description
Brief Summary
This phase II trial is studying how well MEK inhibitor AZD6244 works in treating patients with stage III or stage IV melanoma. MEK inhibitor AZD6244 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244.
SECONDARY OBJECTIVES:
- Identify other genetic predictors of sensitivity to MEK inhibition.
OUTLINE: Patients are stratified according to pAKT expression (low vs high).
Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Tumor tissue samples are collected for correlative laboratory studies. Samples are assessed for expression of pAKT, pPRAS40, and PTEN by IHC and mutations in BRAF, NRAS, KIT, and PIK3CAP by MALDI-TOF. PTEN is sequenced in tumors using whole genome amplification followed by high-throughput bidirectional dideoxynucleotide sequencing of PCR-amplified gene products.
After completion of study treatment, patients are followed for 4 weeks.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Arm I Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Selumetinib
Given orally
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST [Up to 4 weeks]
Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Histologically or cytologically confirmed melanoma
-
Stage IV or stage III disease not potentially curable with surgery
-
Documented tumor progression
-
Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61
-
Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan
-
Must have tumor tissue (block or unstained slides) available for IHC studies
-
No primary uveal or mucosal melanoma
-
No active or untreated brain metastases
-
Treated brain metastases allowed provided they have been stable for ≥ 3 months
-
ECOG performance status 0-1
-
Life expectancy > 3 months
-
WBC ≥ 3,000/mcL
-
Absolute neutrophil count ≥ 1,500/mcL
-
Platelet count ≥ 100,000/mcL
-
Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks)
-
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
-
AST/ALT ≤ 2.5 times ULN
-
Creatinine ≤ 1.5 mg/dL
-
Not pregnant or nursing
-
Negative pregnancy test
-
Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment
-
No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
-
No concurrent uncontrolled illness, including, but not limited to, any of the following:
-
Ongoing or active infection or bleeding
-
Symptomatic congestive heart failure
-
Unstable angina pectoris
-
Cardiac arrhythmia
-
Psychiatric illness/social situation that would limit compliance with study requirements
-
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244
-
Any number of prior therapies allowed
-
At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
-
At least 4 months since prior anti-CTLA4 monoclonal antibody therapy
-
At least 4 weeks since other prior systemic therapy
-
No other concurrent investigational agents
-
No concurrent antiretroviral therapy for HIV-positive patients
-
No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E
-
No concurrent anticancer chemotherapy or other systemic drugs
-
Concurrent palliative radiotherapy allowed
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Memorial Sloan-Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Paul Chapman, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2009-01164
- NCI-2009-01164
- MSKCC-09003
- CDR0000637669
- 09-003
- 8252
- N01CM62206
- P30CA008748
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | AZD6244 |
---|---|
Arm/Group Description | Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Period Title: Overall Study | |
STARTED | 167 |
COMPLETED | 15 |
NOT COMPLETED | 152 |
Baseline Characteristics
Arm/Group Title | AZD6244 |
---|---|
Arm/Group Description | Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Overall Participants | 167 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
107
64.1%
|
>=65 years |
60
35.9%
|
Sex: Female, Male (Count of Participants) | |
Female |
51
30.5%
|
Male |
116
69.5%
|
Region of Enrollment (participants) [Number] | |
United States |
167
100%
|
Outcome Measures
Title | Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST |
---|---|
Description | Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST |
Time Frame | Up to 4 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | AZD6244 |
---|---|
Arm/Group Description | Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Measure Participants | 15 |
Partial Response |
1
0.6%
|
Stable Disease |
8
4.8%
|
Progression of Disease |
6
3.6%
|
Adverse Events
Time Frame | ||
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | AZD6244 | |
Arm/Group Description | Patients receive oral MEK inhibitor AZD6244 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | |
All Cause Mortality |
||
AZD6244 | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
AZD6244 | ||
Affected / at Risk (%) | # Events | |
Total | 6/15 (40%) | |
Cardiac disorders | ||
Heart failure | 1/15 (6.7%) | 1 |
Left ventricular systolic dysfunction | 2/15 (13.3%) | 2 |
Right ventricular dysfunction | 1/15 (6.7%) | 1 |
Gastrointestinal disorders | ||
Diarrhea | 1/15 (6.7%) | 1 |
Vomiting | 1/15 (6.7%) | 1 |
General disorders | ||
Fatigue | 1/15 (6.7%) | 1 |
Fever | 1/15 (6.7%) | 2 |
Chest pain | 1/15 (6.7%) | 1 |
Rigors/chills | 1/15 (6.7%) | 1 |
Investigations | ||
Alanine aminotransferase increased | 2/15 (13.3%) | 2 |
Aspartate aminotransferase increased | 2/15 (13.3%) | 2 |
Alkaline phosphatase increased | 1/15 (6.7%) | 2 |
Blood Bilirubin increase | 1/15 (6.7%) | 2 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 2/15 (13.3%) | 2 |
Respiratory, thoracic and mediastinal disorders | ||
Dyspnea | 1/15 (6.7%) | 3 |
Pleural effusion | 1/15 (6.7%) | 1 |
Skin and subcutaneous tissue disorders | ||
Rash, acne | 1/15 (6.7%) | 1 |
Vascular disorders | ||
Thromboembolic event | 1/15 (6.7%) | 1 |
Vascular disorder | 2/15 (13.3%) | 2 |
Other (Not Including Serious) Adverse Events |
||
AZD6244 | ||
Affected / at Risk (%) | # Events | |
Total | 14/15 (93.3%) | |
Blood and lymphatic system disorders | ||
Anemia | 8/15 (53.3%) | 16 |
Cardiac disorders | ||
Cardiac disorder | 1/15 (6.7%) | 1 |
Heart failure | 1/15 (6.7%) | 1 |
Left ventricular systolic dysfunction | 2/15 (13.3%) | 2 |
Right ventricular dysfunction | 1/15 (6.7%) | 1 |
Gastrointestinal disorders | ||
Constipation | 1/15 (6.7%) | 1 |
Diarrhea | 3/15 (20%) | 3 |
Nausea | 2/15 (13.3%) | 2 |
Vomiting | 2/15 (13.3%) | 2 |
General disorders | ||
Edema-Limbs | 2/15 (13.3%) | 2 |
Fatigue | 5/15 (33.3%) | 6 |
Fever | 1/15 (6.7%) | 1 |
Investigations | ||
Alanine aminotransferase increased | 9/15 (60%) | 14 |
Alkaline phosphatase increased | 8/15 (53.3%) | 24 |
Aspartate aminotransferase increased | 10/15 (66.7%) | 30 |
Blood Bilirubin increased | 5/15 (33.3%) | 10 |
INR increase | 1/15 (6.7%) | 3 |
Lymphocyte count decrease | 3/15 (20%) | 3 |
Neutrophil count decrease | 1/15 (6.7%) | 1 |
Platelet count decrease | 3/15 (20%) | 10 |
White blood cell decrease | 4/15 (26.7%) | 6 |
Metabolism and nutrition disorders | ||
Hyperglycemia | 6/15 (40%) | 22 |
Hyperkalemia | 1/15 (6.7%) | 1 |
Hypoalbuminemia | 2/15 (13.3%) | 6 |
Hypocalcemia | 1/15 (6.7%) | 2 |
Hypokalemia | 2/15 (13.3%) | 2 |
Hypomagnesemia | 4/15 (26.7%) | 10 |
Hypophosphatemia | 1/15 (6.7%) | 2 |
Musculoskeletal and connective tissue disorders | ||
Chest wall pain | 1/15 (6.7%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Dyspnea | 4/15 (26.7%) | 5 |
Pleural effusion | 1/15 (6.7%) | 1 |
Skin and subcutaneous tissue disorders | ||
Alopecia | 1/15 (6.7%) | 1 |
Rash acneiform | 10/15 (66.7%) | 12 |
Rash maculo-papular | 2/15 (13.3%) | 2 |
Skin ulceration | 1/15 (6.7%) | 1 |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Dr. Paul Chapman |
---|---|
Organization | Memorial Sloan Kettering Cancer Center |
Phone | 646-888-4162 |
chapmanp@mskcc.org |
- NCI-2009-01164
- NCI-2009-01164
- MSKCC-09003
- CDR0000637669
- 09-003
- 8252
- N01CM62206
- P30CA008748