MEK Inhibitor AZD6244 in Treating Patients With Stage III or Stage IV Melanoma

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT00866177
Collaborator
(none)
167
1
1
54
3.1

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:
  1. 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:
  1. 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

Study Type:
Interventional
Actual Enrollment :
167 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Trial of Hyd-sulfate AZD6244 [NSC 748727] in Patients With BRAF or NRAS Mutated Melanomas
Study Start Date :
Mar 1, 2009
Actual Primary Completion Date :
Sep 1, 2013
Actual Study Completion Date :
Sep 1, 2013

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:
  • ARRY-142886
  • AZD6244
  • MEK Inhibitor AZD6244
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00866177
    Other Study ID Numbers:
    • NCI-2009-01164
    • NCI-2009-01164
    • MSKCC-09003
    • CDR0000637669
    • 09-003
    • 8252
    • N01CM62206
    • P30CA008748
    First Posted:
    Mar 20, 2009
    Last Update Posted:
    Aug 11, 2015
    Last Verified:
    Jun 1, 2013
    Additional relevant MeSH terms:

    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

    1. Primary Outcome
    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

    [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.

    Results Point of Contact

    Name/Title Dr. Paul Chapman
    Organization Memorial Sloan Kettering Cancer Center
    Phone 646-888-4162
    Email chapmanp@mskcc.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00866177
    Other Study ID Numbers:
    • NCI-2009-01164
    • NCI-2009-01164
    • MSKCC-09003
    • CDR0000637669
    • 09-003
    • 8252
    • N01CM62206
    • P30CA008748
    First Posted:
    Mar 20, 2009
    Last Update Posted:
    Aug 11, 2015
    Last Verified:
    Jun 1, 2013