A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer

Melanoma Clinical Trial

Official title: A Phase I Study of Intravenous Recombinant Human IL-15(rhIL-15) in Adults With Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer

Status Completed

Clinical Trial Summary

Background:

• Recombinant human interleukin-15 (rhIL-15) is a substance that is naturally produced in the body that has many properties that increase the activity and strength of the immune system, the body s natural defense system. It is hoped that rhIL-15 can boost or strengthen patients immune systems and restore immune responses against cancer and infectious diseases like HIV.

• rhIL-15 is being studied in patients with malignant melanoma, an aggressive type of skin cancer, and in patients with renal cell carcinoma, a type of kidney cancer that has spread to other parts of the body. Researchers are interested in determining if rhIL-15 can help stimulate the immune system and aid in the treatment process for cancers that have not responded well to standard therapies.

Objectives:

• To determine whether rhIL-15 is safe and effective in the treatment of metastatic malignant melanoma or metastatic renal cell carcinoma

• To examine how the body processes rhIL-15 after each infusion and determine how it acts on the treated cancer.

Eligibility:

• Patients older than 18 years of age that have been diagnosed with metastatic malignant melanoma or metastatic renal cell carcinoma that has not responded to standard treatments.

• Eligible patients may not have received prior treatment with interleukin-2.

Design:

• Prior to treatment, patients will have baseline blood tests and imaging scans.

• Participants will be admitted to an in-patient unit of the NIH Clinical Center for this treatment. rhIL-15 will be given intravenously once a day for 12 consecutive days, for a total of twelve doses of the drug. The injection of rhIL-15 will take about 30 minutes. Patients will be evaluated daily before each treatment and more frequently if necessary.

• During the 12-day treatment and for at least 42 days from the start of the treatment, patients will be closely followed for possible side effects and for tumor response. Blood will be drawn frequently for monitoring purposes, and other procedures such as chest x-rays and imaging scans will be performed to monitor the state of the tumor and the patient response to treatment.

• After completing the rhIL-15 treatment and discharge from the hospital, patients will have an evaluation with a member of the research team once a week from the end of the treatment period to 42 days from the start of the treatment.

• Study doctors may ask patients to return for evaluation (including blood draws) at 3 and 6 months after the completion of the treatment, checking for potential long-term effects or toxicity of the treatment.

Background:

• Recombinant human interleukin-15 (rhIL-15) is a substance that is naturally produced in the body that has many properties that increase the activity and strength of the immune system, the body s natural defense system. It is hoped that rhIL-15 can boost or strengthen patients immune systems and restore immune responses against cancer and infectious diseases like HIV.

• rhIL-15 is being studied in patients with malignant melanoma, an aggressive type of skin cancer, and in patients with renal cell carcinoma, a type of kidney cancer that has spread to other parts of the body. Researchers are interested in determining if rhIL-15 can help stimulate the immune system and aid in the treatment process for cancers that have not responded well to standard therapies.

Objectives:

• To determine whether rhIL-15 is safe and effective in the treatment of metastatic malignant melanoma or metastatic renal cell carcinoma

• To examine how the body processes rhIL-15 after each infusion and determine how it acts on the treated cancer.

Eligibility:

• Patients older than 18 years of age that have been diagnosed with metastatic malignant melanoma or metastatic renal cell carcinoma that has not responded to standard treatments.

• Eligible patients may not have received prior treatment with interleukin-2.

Design:

• Prior to treatment, patients will have baseline blood tests and imaging scans.

• Participants will be admitted to an in-patient unit of the NIH Clinical Center for this treatment. rhIL-15 will be given intravenously once a day for 12 consecutive days, for a total of twelve doses of the drug. The injection of rhIL-15 will take about 30 minutes. Patients will be evaluated daily before each treatment and more frequently if necessary.

• During the 12-day treatment and for at least 42 days from the start of the treatment, patients will be closely followed for possible side effects and for tumor response. Blood will be drawn frequently for monitoring purposes, and other procedures such as chest x-rays and imaging scans will be performed to monitor the state of the tumor and the patient response to treatment.

• After completi...

Clinical Trial Description

Background:

• Interleukin-15 (IL-15) is a powerful immunostimulatory cytokine with a broad range of biological activities.

• In contrast to IL-2, IL-15 inhibits the activation-induced cell death (AICD) of T-cells and is not involved in the maintenance of CD4+CD25+ T regulatory cells that act as inhibitory checkpoints on the immune response.

• IL-15 is involved in the proliferation, differentiation and activation of CD8+ T-cells and NK-cells, and the maintenance of long term CD8+ memory T-cells.

• In preclinical studies, vaccinia-based vaccines expressing IL-15 induced long lasting, high-avidity cytotoxic CD8+ T-lymphocyte (CTL) mediated immunity, whereas the immunity mediated by IL-2 expressing vaccines was short-lived. Furthermore, IL-15 can overcome the lack of CD4 help in CTL induction.

• IL-15 is highly active against a number of syngeneic mouse tumor models and it is also effective in augmenting the activity of NK-cells and CD8+ T-cells in rhesus macaques indicating that it may be active against human cancers.

Objectives:

• The primary objective of this trial is to determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of intravenous recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in subjects with metastatic malignant melanoma and renal cell cancer.

• Secondary objectives include determination of rhIL-15 pharmacokinetics, in particular the time course of the decline of rhIL-15 from the serum following intravenous administration and the definition of the immunogenicity of rhIL-15 in subjects receiving this drug.

• To characterize the biological effects of rhIL-15 on the proportions and absolute numbers of circulating NK-cells, and CD45RO+CD8+ T-cells and central or effector memory subsets based on expression of CD28, CD95, CCR7 and CD62L by flow cytometry and to determine its effects on the plasma levels of pro-inflammatory cytokines.

• Obtain preliminary information on the antitumor effects of repeat cycles of rhIL-15 in patients with metastatic malignant melanoma and renal cell cancer.

Eligibility Criteria:

• Patients greater than or equal to 18 years-old with pathologically confirmed metastatic malignant melanoma or metastatic renal cell cancer.

• Patients with metastatic renal cell cancer must either have refused treatment with, failed to tolerate, or have progressive disease after receiving sorafenib or sunitinib, and temsirolimus.

• Patients with measurable disease.

• Absolute granulocyte count (AGC) of at least 1500/mm(3) and a platelet count of at least 75,000/mm(3).

Design:

• This is a single institution, open-label, non-randomized 3 + 3 design phase I dose-escalation study to determine the safety, toxicity and MTD of rhIL-15 in patients with metastatic malignant melanoma and renal cell cancer.

• Groups of 3 to 6 patients will receive rhIL-15 at doses of 0.3, 1, 3, 7, 10, 15, 20 or 25 mcg/kg/day for 12 days provided that DLT had not been observed.

• Correlative protocol studies will be obtained prior to treatment and at specific times points during and after treatment including pharmacokinetics for the clearance of rhIL-15 from the serum, immunogenicity testing for the development of neutralizing anti-rhIL-15 antibodies and immunological study endpoint evaluation for the effect of rhIL-15 on immune cell subset populations and pro-inflammatory cytokine levels in the peripheral blood. ;

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Melanoma

• NCT number: NCT01021059
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: November 10, 2009
• Completion date: October 25, 2016