Official Title: “Study of the Modulatory Activity of an LHRH-Agonist (Leuprolide) on Melanoma Peptide Vaccines as Adjuvant Therapy in Melanoma Patients”

Primary Objective:

1. To compare the tumor-specific immune responses to melanoma-specific peptide vaccines, gp100 and MAGE-3 in the presence or absence of a luteinizing hormone-releasing hormone (LHRH) agonist-Leuprolide, in patients with stage IIb and III melanoma, uveal melanoma or stage IV melanoma that the metastatic lesion(s) has been surgically removed.

Secondary Objectives:

1. To evaluate the kinetics of enhanced thymic activity measured by TREC analysis and flow cytometric analysis following sex hormone ablation by Leuprolide in melanoma patients.

2. To assess whether there are significant differences in overall quality of life (QOL) between patients receiving Leuprolide to those not receiving leuprolide.

Study Type: Interventional

Study Design: Prevention, Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2008

The incidence of melanoma is rising in the US. Patients with stage IIb-IV melanoma have significant risk of recurrence after definitive or palliative surgery. With the discovery of numerous antigens for melanoma capable of recognition by T-cells, current goals are focused on defining the best approaches to immunize melanoma patients with these antigens in order to elicit tumor-specific immune responses, and ultimately tumor regression or prevention of disease recurrence. We have previously shown that melanoma patients can be immunized with peptides derived from melanoma associated antigens, such as gp100, resulting in increased numbers of circulating T-cells capable of recognizing the tumor. However, maximum immune response to the vaccines required up to a year of immunizations and new strategies are needed for more efficient vaccination. One potential strategy is to increase thymic activity.

T-cells develop in the thymus, which involutes with progressively diminished activity following puberty. This might adversely affect the ability to immunize adults against specific antigens. In addition, aging has been correlated with decreased immune responses against new antigens. Therefore, methods to enhance thymic activity in adults may potentiate antigen-specific immune responses. Ablation of sex steroids has been shown to increase thymic activity. In murine models, surgical castration of aged mice can restore the responsiveness to herpes simplex virus to levels similar to those seen in young mice. Sex steroid ablation by the LHRH-agonist Leuprolide in elderly men for prostate cancer resulted in increased thymic dependent T cell production, particularly naïve (TREC+) CD4+ T cells. Regeneration of adult thymic function by sex steroid ablation therefore may provide a means to improve antitumor T cell immune responses. Our hypothesis is that sex hormone blockade will result in enhanced thymic activity in melanoma patients that will lead to improved anti-tumor T cell responses following antigen-specific immunization.

Intervention(s) in this Clinical Trial

• Drug: Leuprolide
  • A 3-month 11.25 mg sustained-release formulation will be administrated intramuscularly at time 0, and approximately 12 wks (2 injections).
• Biological: GP100: 209-217(210M) Peptide
  • 1.0 ml subcutaneous injection in extremities.
• Biological: MAGE-3 Peptide
  • 1.0 ml subcutaneous injection in extremities.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • HLA-A*0201 positive/HLA-DP4 negative treated with gp100 + Leuprolide
• Experimental: 2
  • HLA-A*0201 positive/HLA-DP4 negative treated with gp100 - No Leuprolide
• Experimental: 3
  • HLA-A*0201positive/HLA-DP4 positive treated with gp100 + MAGE-3 + Leuprolide
• Experimental: 4
  • HLA-A*0201positive/HLA-DP4 positive treated with gp100 + MAGE-3 - No Leuprolide

Primary Measures

• To learn if the drug leuprolide will increase the level of immune cells in your body.
  • Time Frame: 3 Years
    Safety Issue?: No

Secondary Measures

• To know if this drug given together with melanoma vaccines (gp100 and MAGE-3) can improve the ability of tumor fighting immune cells (T cells) to fight melanoma cells.
  • Time Frame: 3 Years
    Safety Issue?: No

Inclusion Criteria:

• HLA-A2 positive
• Patients ≥ 18 years old with histologically documented diagnosis of stage IIb-IV melanomas and are clinically rendered free of disease after surgery
• Karnofsky performance status of 60% or better (see appendix E).
• WBC ≥ 3000/mm3.
• Platelet count ≥ 90,000mm3.
• Serum creatinine ≤ 2.0mg/dl.
• Serum ALT ≤ 3 X upper limit of normal(ULN)).
• Total bilirubin ≤ 2X ULN), except for patient with Gilbert's syndrome who must have a total bilirubin less than 3.0mg/dl.
• Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
• Negative pregnancy test for women who have menstruation in the past 12 months and without sterilization surgery.
• Unless surgically sterile by bilateral tubal-ligation or vasectomy of partner(s), the subject agrees to continue to use a barrier method of contraception throughout the study such as: condom, or diaphragm, or sponge plus spermicide. Abstinence is an acceptable form of birth control.

Exclusion Criteria:

• Prior systemic therapy (including immunomodulatory agents), radiation or surgery requiring general anesthesia for melanoma within 28 days of starting study treatment.
• Autoimmune diseases.
• Concurrent systemic or inhaled steroid therapy.
• Any form of active primary or secondary immunodeficiency.
• History of immunization with gp100, or MAGE-3.
• Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, surgically treated Stage I or II cancer from which the patient is currently in complete remission (at least for 5 years), or any other cancer from which the patient has been disease-free for 5 years.
• Received a LHRH agonist within the past 5 years.
• Use of oral contraceptive, hormone replacement therapy or androgen preparations.
• Hypersensitivity to gonadotropin-releasing hormone analogues.
• Active systemic infections requiring intravenous antibiotics.
• Lactating women or women planning lactation during the study.
• Inclusion of women and minorities:
• Both men and women and members of all ethnic groups are eligible for this trial. Lactating women are ineligible.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Patrick Hwu, MD Principal Investigator U.T.M.D. Anderson Cancer Center  

Overall Contact: Patrick Hwu, MD 713-563-1727 phwu@mdanderson.org

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00254397

Study ID Number: 2004-0502

ClinicalTrials.gov Identifier: NCT00254397

Health Authority: United States: Food and Drug Administration