A Phase I Study of Intravenous Recombinant Human IL-15(rhIL-15) in Adults With Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer
- Interleukin-15 (IL-15) is a powerful immunostimulatory cytokine with a broad range of
- 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.
- 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
- 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.
- 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,
- Patients with measurable disease.
- Absolute granulocyte count (AGC) of at least 1500/mm(3) and a platelet count of at
- 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
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the safety, toxicity profile, dose-limiting toxicity and a maximum tolerated dose if IV recombinant Human IL-15 administered in melanoma and renal cell cancers.
Thomas A Waldmann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|