Protocol Number: 03-C-0109

Title:

An Open-Label Study of MDX-010 Combined With Interleukin-2 for the Treatment of Patients With Metastatic Melanoma

Number:

03-C-0109

Summary:

This study will determine the highest dose of MDX-010 that can safely be given in conjunction with interleukin2 (IL-2) to patients with advanced melanoma, and to examine its effectiveness against the cancer. MDX-010 is designed to increase immunity to cancer. It 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 and control the infection. Once this is achieved, CTLA-4 proteins help stop the immune response, decreasing the number of immune cells 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 will be used to block CTLA-4 and maintain immune activity. IL-2 is a naturally occurring substance whose main function is to signal immune cells to become active. FDA has approved IL-2 for treating patients with advanced melanoma and kidney cancer.

Patients 16 years of age and older with stage IV melanoma (melanoma that has spread to the lymph nodes or other sites) and whose tumor is not responding to standard treatments may be eligible for this study. Each candidate will be screened with a history, physical examination, blood test, and electrocardiogram (EKG). X-rays and scans will be done to evaluate the size and extent of their tumor, if current ones are not available.

Participants will receive up to four MDX-010 treatments 21 days apart. Each treatment consists of a dose of MDX-010 given intravenously (through a vein) via a catheter (thin plastic tube) over 90 minutes. IL-2 will also be given after the second and third injection of MDX-010 through a small catheter over a 15-minute period every 8 hours for as many doses as are tolerated. In addition to treatment, patients will have the following tests and procedures:

- Blood tests before and during the first injection of MDX-010 and blood tests before, during and for 6 days after the second injections of MDX-010 to measure levels of the antibody, and then blood tests every 21 days (every treatment visit) to examine the body's reaction to the treatment.

-Leukapheresis to study the effects of treatment on the immune system. For this procedure, blood is drawn through a needle in an arm vein and circulated through a machine that separates the blood into its components (red cells, white cells, platelets, and plasma). The lymphocytes are extracted and the rest of the blood is returned to the patient through a needle in the other arm. Leukapheresis is done just before beginning treatment and may be repeated about three weeks after the fourth treatment.

- Biopsy of normal skin and tumor or lymph node to examine the effects of antibody on the immune cells in the tumor. For this procedure, a needle is put into the skin or tumor and a small amount of tissue is pulled out with the needle. Biopsies are optional; they are not required for participation in the study.

- Follow-up visit 3 weeks after the fourth treatment for a checkup examination, scans and X-rays, and blood tests.

Patients will be watched closely for treatment side effects. Those who develop severe drug side effects, whose bodies develop an immune reaction against the MDX-010 antibody, or whose conditions worsen during treatment may be withdrawn from the study. Those whose tumors have stabilized or shrunk will continue follow-up visits.

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:

Any patient greater than or equal to 16 years of age with a histologic diagnosis of stage IV melanoma (may include mucosal or ocular melanoma) that is clinically evaluable, with at least one site of measurable disease.

Patients may not have received prior therapy with MDX-010 antibody or high-dose IL-2 (greater than or equal to 600,000 IU/kg q8h).

Greater than or equal to 3 weeks since treatment (chemo-, radiation, hormone, immuno-, etc., therapy) for melanoma and recovered from any serious toxicity experienced during treatment.

Women should be either: post-menopausal for at least one (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.

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

Life expectancy greater than or equal to 3 months.

ECOG Performance Status less than 2.

For patients greater than 50 years of age or history of cardiovascular disease, a normal thallium stress test is required.

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 100 x 10(3)/ml.

Hemoglobin greater than or equal to 10 g/dl.

Hematocrit greater than or equal to 30%.

Creatinine less than or equal to 2.0 mg/dl.

AST less than or equal to 3 x ULN (unless definitely attributable to disease).

Bilirubin less than or equal to 1.0 x ULN (unless definitely attributable to disease) [except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dl].

HbsAg is negative.

HIV is negative.

Anti-HCV is nonreactive.

EXCLUSION CRITERIA:

Patients will be excluded who have any of the following:

Any other prior malignancy, except for the following: adequately treated basal or squamous 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 five (5) years or more.

Autoimmune disease (including uveitis and autoimmune inflammatory eye disease) prior to the study.

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

Pregnancy or nursing.

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.

Any concurrent medical condition requiring the use of systemic or topical corticosteroids or the use of immunosuppressive agents (e.g. cyclosporin and its analog, or chemotherapy agents). All corticosteroid use must have been discontinued greater than or equal to four (4) weeks prior to trial entry.

Prior treatment with MDX-010 or high-dose IL-2.

Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of high-dose IL-2 unsafe.

Special Instructions: Currently Not Provided

Keywords:

Monoclonal Antibody (mAb)

Maximum Tolerated Dose

Pharmacokinetic Studies

Measurable Disease

Tumor Response

Recruitment Keywords:

Melanoma

Metastatic Melanoma

Conditions:

Melanoma

Investigational Drug(s):

MDX-010

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

Duran Garcia E, Santolaya R, Requena T. Treatment of malignant melanoma. Ann Pharmacother. 1999 Jun;33(6):730-8. Review. PMID: 10410188

Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-58. Review. PMID: 8717514

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