NIH Clinical Research Studies

Protocol Number: 04-C-0083

Active Accrual, Protocols Recruiting New Patients

Title:
A Study of Intra-Patient Escalating Doses of MDX-010 Given Alone or in Combination with Two gp100 Peptides Emulsified with Montanide ISA-51 in the Treatment of Patients with Stage IV Melanoma
Number:
04-C-0083
Summary:
This study will examine the safety and effectiveness of MDX-010, an experimental immune booster, to shrink melanoma tumors and test its side effects. MDX-010 is a laboratory-produced antibody to the CTLA-4 protein found on certain lymphocytes (a type of white blood cell). When lymphocytes recognize a foreign substance, such as a virus or bacteria, they initiate an immune response to fight the infection. Once this is achieved, CTLA-4 proteins help stop the immune response, decreasing the number of immune cells fighting against the virus or bacteria. When an immune response is mounted against tumor cells, however, it may be beneficial not to stop the immune response, but instead, to keep a large number of lymphocytes available to recognize and fight tumor cells. In this study, MDX-010 is used to block CTLA-4 and maintain immune activity until the melanoma shrinks or a severe autoimmune reaction (e.g., diarrhea, severe skin rash) develops. Patients who have a specific tissue type called HLA-A*0201 may also receive two anti-melanoma vaccines that contain pieces of proteins (gp100 peptides) produced by melanoma tumors. The vaccines are mixed with a substance called Montanide ISA-51, which is intended to increase the immune response to the peptides.

Patients 16 years of age and older with Stage IV melanoma may be eligible for this study. Candidates are screened with a physical examination, eye examination, blood and urine tests, electrocardiogram, and imaging studies (x-rays and scans) to check the size and extent of tumor. Some candidates may have lung function studies, if medically indicated. Patients' tissue type is determined with a blood test.

Participants with HLA-A*0201 positive tissue type are randomly assigned to receive or not to receive the gp100 peptide vaccine along with the MDX-010. Participants with HLA-A *0201 negative tissue type will receive MDX-010 alone. Patients get MDX-010, with or without vaccine, every 3 weeks. The dose is increased (up to 9 mg/kg body weight) every other treatment until the patient's tumor shrinks or a severe autoimmune reaction develops. MDX-010 is given intravenously (IV) over 90 minutes through a catheter (plastic tube) placed in a vein. The vaccine is given in four injections under the skin of the thighs or arms. Blood is drawn before and after each treatment to measure MDX-010 levels in the blood. Other blood tests and a physical examination are done before each treatment and at each clinic visit to look for changes in the blood that signal reactions to the vaccine or antibody, and to check for side effects. Patients who have complete tumor shrinkage or whose tumors begin to shrink and then stabilize get two additional treatments at the dose level that resulted in tumor shrinkage. Further treatment is stopped and the patient is followed with scans. Patients who develop severe side effects from the treatment are taken off the study and their symptoms are treated.

Patients also undergo plasmapheresis-a procedure to collect quantities of white blood cells-before treatment begins and possibly again after every two treatments. For this procedure, blood is drawn through a needle in the arm and circulated through a machine that spins it to separate the components. The white cells are removed and the plasma and red cells are returned through a needle in the other arm. Some patients may also have a biopsy of their tumor or lymph node tissue to examine the effects of the vaccine on the tumor immune cells. This involves drawing a small amount of tissue through a needle injected in the skin.

Patients return to the clinic 3 weeks after each treatment for a physical examination and blood tests prior to receiving the next treatment After every two treatments, patients have scans to re-evaluate the tumor size and discuss options for further treatment, at the next higher dose.

Sponsoring Institute:
National Cancer Institute (NCI)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): None

Eligibility Criteria:
INCLUSION CRITERIA:

A. Any patient greater than or equal to 16 years of age with a histologic diagnosis of Stage IV melanoma (except mucosal or ocular melanoma) that is clinically evaluable and measurable.

B. Greater than or equal to 3 weeks receiving a systemic treatment (Greater than or equal to 6 weeks since nitrosurea treatment) for melanoma and recovered from any serious toxicity experienced during treatment to less than or equal to Grade I.

C. Women should be either: Post-menopausal for greater than or equal to 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception. Women of childbearing potential must have a negative urine pregnancy test conducted during screening.

D. Because the risk of a negative influence of this therapy on reproductive processes, men who have the capacity to father a child must agree to the use of male contraception for the duration of their participation in the trial.

E. Life expectancy greater than or equal to 6 months.

F. ECOG Performance Status less than or equal to 2.

G. Required values for initial laboratory test:

-WBC greater than or equal to 2500/mL

-ANC greater than or equal to 1500/mL

-Platelets greater than or equal to 100x10(3)/mL

-Hemoglobin greater than or equal to 9g/dL

-Hematocrit greater than or equal to 28%

-Creatinine less than 2.0 mg/dL

-AST less than or equal to 3 x ULN

-Bilirubin less than or equal to 1.0 x ULN, (except patients with Gilbert's Syndrome who must have Total Bilirubin less than 3.0 mg/dl)

-HBsAg Negative

-HIV Negative

-Anti-HCV Nonreactive

EXCLUSION CRITERIA:

A. Any other prior malignancy, except for the following: Adequately treated basal or equamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the patient has been disease-free for greater than or equal to 5 years.

B. Autoimmune disease: (1) Active autoimmune disease requiring active therapy with any form of steriod or immunosuppressive therapy, or (2) A documented history of any of the following: inflammatory bowel disease; regional enteritis; connective tissue disorders such as systemic lupus erythematosis; rheumatoid arthritis; autoimmune inflammatory eye disease; sjorgen's syndrome; inflammatory neurologic disorder such as multiple sclerosis; or any autoimmune disease that can cause life-threatening symptoms or severe organ/tissue damage in the opinion of the principal investigator. Note: A history of vitiligo, autoimmune thyroiditis, or skin rashes associated with previous therapy is NOT an exclusion if the patient has recovered to less than or equal to grade I .

C. Active infection, this includes positive results from HIV, HBsAg and anti-HCV.

D. Pregnancy or nursing: Due to the possibility that MDS-010 could have a detrimental effect on the developing immune system of the fetus or infant, exposure in utero or via breast milk will not be allowed.

E. Systemic hypersensitivity to any of the investigational agents. A history of local reactions (such as delayed hypersensitivity or glaucomatous reactions) to Montanide ISA-51 or gp100 injections is NOT an exclusion.

F. Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events.

G. Any concurrent medical condition requiring the use of systemic or topical corticosteriods or immunosuppressive agents (e.g., cyclosporin or chemotherpy agents). All steriod use must be discontinued greater than or equal to 4 weeks prior to trial entry.

H. Prior treatment with MDX-010

I. Prior treatment with gp100 is NOT an exclusion; previous treatment with gp100 or any other immunotherapy (not involving MDX-010) is allowed.

Special Instructions: Currently Not Provided
Keywords:
Monoclonal Antibody (mAb)
Toxicity
Pharmacokinetic Studies
Measurable Disease
Tumor Response
Recruitment Keywords:
Melanoma
Conditions:
Melanoma
Investigational Drug(s):
MDX-010
gp100: 209-217(210M)
gp100:280-288(288V)
Montanide ISA-51
Investigational Device(s):
None

Contacts:
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:
Lang PG Jr. Malignant melanoma. Med Clin North Am. 1998 Nov;82(6):1325-58. Review. PMID: 9889751

Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065-8. Review. No abstract available. PMID: 1335362

Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, McGowan P, Linsley PS. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093-102. PMID: 1335364

Active Accrual, Protocols Recruiting New Patients

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