A Phase I Study of a Continuous Intravenous Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults With Metastatic Cancers
- Interleukin-15 (IL-15) is a stimulatory cytokine with a number of desirable
immunotherapeutic features, and clinical trials evaluating recombinant human (rh) IL-15
- In contrast to IL-2, IL-15 treatment does not stimulate activation-induced cell death
of Tcells; potentially inhibits immunosuppressive CD4+CD25+ T regulatory cells,
contributes to the proliferation, differentiation and activation of CD8+ T-cells and
NK-cells and the maintenance of long-term CD8+ memory T-cells.
- IL-15 is active in a number of syngeneic mouse preclinical tumor models, and
vacciniabased constructs expressing IL-15 induced long-lasting, high-avidity cytotoxic
CD8+ Tlymphocyte response that appears to be more effective than similar
- Pharmacology/toxicology (pharm/tox) experiments in non-human primate (NHP) rhesus
macaques and preliminary results from the first-in-human phase I trial examining
rhIL-15 given as an IV bolus (IVB) for 12 consecutive days indicate significant
stimulation and expansion of NK-cells and CD8+ T-cells.
- rhIL-15 given as an IVB at 1 mcg/kg dose level appears to be well tolerated despite the
presence of some common cytokine-related side effects indicating that 0.1 mcg/kg/day is
an appropriate initial dose level for a phase I safety trial of continuous intravenous
infusion (CIV) of rhIL-15.
- Comparison of the pharmacokinetic and immunologic assessments from the IVB phase I
trial with the data from both sets of NHP pharm/tox experiments suggest that CIV of
rhIL-15 may have greater potential for stimulating an anticancer cellular immune
response with a more manageable safety profile.
- Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated
dose (MTD) of rhIL-15 administered as a CIV for 10 consecutive days (240 hours) in subjects
with metastatic unresectable cancers for which curative or palliative measures either do not
exist or are not associated with a survival advantage.
- Determine rhIL-15 pharmacokinetics, including time to reach serum steady state, decline
if any at later timepoints, changes in serum concentration associated with the expected
lymphocytosis and decline following discontinuation of the CIV infusion.
- Characterize the biological effects of rhIL-15 on the percentages and absolute numbers
of circulating lymphocytes (T and NK cells) and T-cell subsets (na ve, central or
effector memory subsets) based on expression of CD56, CD4, CD8, CD45RO, CD45RA, CD28,
CD95, CCR7 and CD62L by flow cytometry and the plasma levels of pro-inflammatory
- Evaluate the potential antitumor activity of rhIL-15 by assessing the clinical response
rate and time to progression in this patient population.
- Assess the nature of the T-cell infiltration and immunologic gene expression by
analysis of pre- and post-treatment fine-needle biopsies obtained from selected
patients with easily accessible tumor deposits.
- Patients greater than or equal to18 years-old, ECOG PS less than or equal to 1, with
pathologically confirmed metastatic unresectable cancers for which curative or
palliative measures either do not exist or are not associated with a survival
- Patients with measurable or evaluable disease, normal organ and bone marrow function.
- This is a single-institution, open-label, non-randomized 3 + 3 design phase I dose
- Groups of 3 to 6 subjects will receive CIV rhIL-15 at doses of 0.1, 0.25, 0.5 1 and 2
mcg/kg/day for 10 days provided that DLT had not been observed.
- Patients with evidence of response and the absence of significant toxicities will be
eligible for repeat cycles of treatment.
- Samples for correlative studies will be obtained prior to treatment and at specific
times points during and after treatment to assess pharmacokinetics of rhIL-15, the
effect of rhIL-15 on immune cell subset populations and pro-inflammatory cytokine
levels in the peripheral blood and for the development of neutralizing anti-rhIL-15
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the safety, toxicity profile, DLT and MTD of IL-15 in subjects with metastatic cancers.
Kevin C Conlon, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|