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

Brief Title

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

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

Brief Summary

      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.
    

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective Response Rate

Secondary Outcome

 Time to Progression

Condition

Acral Lentiginous Malignant Melanoma

Intervention

imatinib mesylate

Study Arms / Comparison Groups

 Treatment (enzyme inhibitor therapy)
Description:  Patients receive oral imatinib mesylate twice daily for up to 12 weeks in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

April 2007

Completion Date

October 2014

Primary Completion Date

December 2013

Eligibility 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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Richard Carvajal, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00470470

Organization ID

NCI-2009-00216

Secondary IDs

NCI-2009-00216

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Richard Carvajal, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

January 2014