A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer
Condition: Melanoma; Carcinoma, Renal Cell
MeSH terms: Melanoma; Carcinoma, Renal Cell
Study type: Interventional
Phase: Phase 1

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...
    

Detailed 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.
    

Intervention name(s): rh IL-15
Intervention type(s): Biological
Intervention description(s): rh IL-15 daily for 12 days of 42 days cycle. Additional cycles may be given if patient is responding to therapy.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Biological Effects of rhIL-15; Estimate Antitumor Activity; rhIL-15 Pharmacokinetics; Dose and Safety Determination of IL-15; Kidney Cancer; Melanoma; Renal Cell Cancer