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Imatinib Mesylate in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00470470
First received: May 3, 2007
Last updated: January 6, 2014
Last verified: January 2014
  Purpose

This phase II trial is studying how well imatinib mesylate works in treating patients with stage III or stage IV melanoma that cannot be removed by surgery. Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Acral Lentiginous Malignant Melanoma
Recurrent Melanoma
Stage IIIA Melanoma
Stage IIIB Melanoma
Stage IIIC Melanoma
Stage IV Melanoma
Drug: imatinib mesylate
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Imatinib Mesylate (STI571;NSC#716051:IND 61135) in Patients With Inoperable AJCC Stage III or IV Melanoma Harboring Somatic Alterations of C-KIT

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective response rate (complete response and partial response) [ Time Frame: Every 6 weeks for the first 3 courses and then every 12 weeks thereafter ] [ Designated as safety issue: No ]
    Response will be evaluated in this study using the new international criteria proposed by the RECIST Committee. A Simon two-stage minimax design will be employed.


Secondary Outcome Measures:
  • Time to progression [ Time Frame: Time from the treatment start to the date of disease progression ] [ Designated as safety issue: No ]
    Progression will be evaluated in this study using the new international criteria proposed by the RECIST Committee. Time to progression will be estimated using the Kaplan-Meier method.

  • Protein expression by IHC [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    IHC will be performed for expression of c-kit protein and possibly other targets of imatinib as possibly correlative predictors of outcome. IHC data will be summarized as both a continuous measure (percent cells positive) and also as a binary variable dichotomized as < 90% negative and >= 90% as positive. Correlations between each measure and response will be assessed.

  • Gene amplification by FISH [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    c-Kit sequencing and FISH will be performed to determine eligibility for the study. Correlations between each of measure and response will be assessed.

  • Gene amplification and gene copy number by comparative genomic hybridization [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    CGH will be performed on tumor samples from all eligible patients. Concordance between FISH and CGH will be assessed for eligible patients only. Correlations between each of these measures and response will be assessed.

  • c-KIT DNA sequencing [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    c-Kit sequencing and FISH will be performed to determine eligibility for the study. Correlations between each measure and response will be assessed.

  • Correlation of IHC criteria with sequencing or amplification results [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
  • Changes in levels of c-Kit, Ki-67, phospho-Akt, phospho-MEK, phosph-S6, phospho STAT3, cleaved caspase3, and IGF-1R [ Time Frame: Pre and post-treatment ] [ Designated as safety issue: No ]
    Compared by Wilcoxon signed-rank test or McNemar's test depending on the nature of the data. Exploratory plots over time will be utilized to assess any trends. Various exploratory comparisons will be made using Fisher's exact test.

  • Baseline and post-resistance blood samples for soluble cKIT levels, soluble VEGFR1, soluble VEGFR2, VEGF, PlGF, FGF, MIA levels, and circulating tumor cells. [ Time Frame: Baseline, 24 hours and after 8 days of first dose, beginning of subsequent courses, and at the time of progression or off-study ] [ Designated as safety issue: No ]
    Exploratory plots over time will be utilized to assess any trends. These analyses of the correlative endpoints would be exploratory and hypothesis-generating. Various exploratory comparisons will be made using Fisher's exact test.


Enrollment: 327
Study Start Date: April 2007
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (enzyme inhibitor therapy)
Patients receive oral imatinib mesylate twice daily for up to 12 weeks in the absence of disease progression or unacceptable toxicity.
Drug: imatinib mesylate
Given orally
Other Names:
  • CGP 57148
  • Gleevec
  • Glivec
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the overall objective response rate (complete response and partial response) in patients with inoperable stage III or IV melanoma harboring somatic alterations in c-KIT treated with imatinib mesylate.

SECONDARY OBJECTIVES:

I. Determine the time to progression in patients treated with this drug. II. Determine if c-KIT mutational status by DNA sequencing, DNA copy number status by fluorescent in situ hybridization (FISH) or comparative genomic hybridization, and/or protein expression by immunohistochemistry (IHC) can best predict clinical benefit from imatinib mesylate.

TERTIARY OBJECTIVES:

I. To evaluate tumors resistant to small molecule inhibitors of Kit for the development of secondary Kit mutations or for changes in Kit copy number.

II. To evaluate for changes in Ki-67, phospho-Akt, phospho-MEK, phospho-S6, phospho STAT3, cleaved caspase 3, IGF-1R, and Kit expression in paired tumor samples obtained from patients treated with a small molecule inhibitor of Kit.

III. To analyze baseline and post-resistance blood samples for soluble cKIT levels, soluble VEGFR1, soluble VEGFR2, VEGF, PlGF, FGF, and melanoma inhibitory activity (MIA) levels, and circulating tumor cells.

IV. To analyze concomitant samples of blood and tumor for imatinib levels in patients treated with imatinib.

OUTLINE: This is a multi-center study. Patients are stratified according to true amplification of c-KIT by FISH vs mutations by DNA sequencing.

Patients receive oral imatinib mesylate twice daily for up to 12 weeks in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples or unstained tissue slides/paraffin blocks may be collected. c-KIT is evaluated by IHC and comparative genomic hybridization.

After completion of study treatment, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed inoperable stage III or IV melanoma that began on acral skin or mucosa

    • Patients with cutaneous melanoma that began on sun exposed sites of the skin and whose pathology demonstrates signs of sun damage (solar elastosis) involving the skin surrounding their primary melanoma are eligible
  • Must have sufficient tumor tissue available for FISH and DNA sequencing

    • Patients must have either a true amplification of 4q12 or a detectable mutation of c-KIT
    • If no banked tumor tissue is available, or if the available banked tumor tissue is insufficient for the necessary testing, then a repeat biopsy procedure will be required to collect the necessary tumor sample
  • Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  • No known untreated brain or epidural metastases

    • Brain metastases that have been treated and deemed stable are allowed
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Life expectancy greater than 3 months
  • WBC ≥ 3,000/mm³
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)

    • Patients with unexplained hyperbilirubinemia that is clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert's syndrome) may be eligible
  • AST and ALT ≤ 2.5 times ULN (5 times ULN if hepatic metastases are present)
  • Creatinine ≤ 1.5 times ULN
  • PT and PTT ≤ 1.5 times ULN
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception before and during study participation
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to imatinib mesylate
  • No concurrent uncontrolled illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable anginapectoris
    • Cardiac arrhythmia resulting in hemodynamic instability
    • Intestinal malabsorption disorders
    • Psychiatric illness or social situations that would limit study compliance
  • Recovered to grade 1 from all prior therapies with the exception of alopecia
  • At least 2 weeks since prior radiotherapy (≤ 3,000 cGy to fields including substantial marrow)
  • At least 2 weeks since prior isolated limb infusion or perfusion (must have evidence of progression despite this therapy)
  • At least 2 weeks since prior chemotherapy
  • No more than 2 prior chemotherapy regimen for metastatic melanoma
  • Prior therapies with vaccines, targeted agents not believed to affect the kit proteins, cytokines, interferon-α, or intratumoral injections will NOT be considered prior therapy unless administered with a chemotherapy drug
  • No prior therapy with an inhibitor of the kit protein
  • No other concurrent investigational agents
  • No other concurrent anticancer agents or therapies
  • No concurrent antiretroviral therapy for HIV-positive patients
  • No concurrent inhibitors of CYP3A4, including any of the following:

    • Fluconazole, itraconazole, ketoconazole, macrolide antibiotics (azithromycin, clarithromycin, erythromycin, troleandomycin),midazolam, nifedipine, verapamil, diltiazem, terfenadine, cyclosporine and cisapride
    • Herbal extracts and tinctures with CYP3A4 inhibitory activity, including the following:

      • Hydrastis canadensis (goldenseal), Hypericum perforatum (St. John's wort),Uncaria tomentosa (cat's claw), Echinacea angustifolia roots, Trifolium pratense(wild cherry), Matricaria, chamomilla (chamomile), Glycyrrhiza glabra (licorice), dillapiol, hypericin, and naringenin
  • No concurrent inducers of CYP3A4, including any of the following:

    • Carbamazepine, phenobarbital, phenytoin, and rifampin
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00470470

Locations
United States, California
University of California at Los Angeles (UCLA )
Los Angeles, California, United States, 90095
United States, Florida
Mount Sinai Medical Center CCOP
Miami Beach, Florida, United States, 33140
Good Samaritan Medical Center
West Palm Beach, Florida, United States, 33401
Palm Beach Cancer Institute-Main Office
West Palm Beach, Florida, United States, 33401
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Mount Sinai Medical Center
New York, New York, United States, 10029
New York University Langone Medical Center
New York, New York, United States, 10016
Weill Medical College of Cornell University
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: Richard Carvajal Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00470470     History of Changes
Other Study ID Numbers: NCI-2009-00216, NCI-2009-00216, CDR0000543404, MSKCC-07014, 07-014, 7754, P30CA008748, N01CM62206, N01CM62204
Study First Received: May 3, 2007
Last Updated: January 6, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Imatinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014