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A Phase I Study of a Continuous Intravenous Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults With Metastatic Cancers

Phase 1
18 Years
Open (Enrolling)
Carcinoma, Lymphoma

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Trial Information

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
are underway.

- 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
IL-2-expressing vaccines.

- 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.


Primary Objective:

- 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.

Secondary Objectives:

- 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
escalation study.

- 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

Inclusion Criteria


- Age greater than or equal to 18 years.

- Patients must have histologically confirmed (by the NCI Pathology Department) solid
tumor malignancy or lymphoma that is metastatic or unresectable and for which
standard curative or palliative measures do not exist or are associated with minimal
patient survival benefit (as defined the Metabolism Branch physicians or if the
patient refuses standard of care treatment ). Enrollment of patients with tumors that
can be safely biopsied is encouraged.

- Patients must have evaluable or measurable disease, defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded for non-nodal lesions and short axis for nodal lesions) as greater than or
equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with
spiral CT scan.

- Patients must have recovered to < grade 1 CTCAEv4 from toxicity of prior
chemotherapy or biologic therapy and must not have had prior chemotherapy or biologic
therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks for UCN-01).

- Patients must be at least 1 month since any prior radiation or major surgery.

- Patients on bisphosphonates for any cancer or on hormone therapy for prostate cancer
will not need to discontinue this therapy to be eligible. However, patients with
prostate cancer will need to have metastatic prostate cancer that has progressed
despite hormonal therapy. Castrate testosterone levels occur within hours after
castration and within 2 to 3 weeks of a luteinizing hormone-releasing hormone
agonist. The current standard is to continue androgen suppression despite progressive

- DLCO/VA and FEV-1.0 > 50% of predicted on pulmonary function tests.

- Serum creatinine of less than or equal to 1.5 X the upper limit of normal.

- AST and ALT < 2.5 x the upper limit of normal.

- Absolute neutrophil count greater than or equal to 1,500/mm(3) and platelets greater
than or equal to 100,000/mm(3).

- Karnofsky performance status greater than or equal to 70% or ECOG less than or equal
to 1

- CNS metastases: Patients who remain asymptomatic after successful definitive
treatment of brain metastases (i.e., surgical resection, curative whole brain
irradiation, stereotactic radiation therapy, or a combination of these) demonstrating
stable or improved radiographic appearance on MRI scan at least 3 months after
completion of treatment with no signs of cerebral edema are eligible.


- Patients who have received any systemic corticosteroid therapy within 3 weeks prior
to the start of therapy with the exception of physiological replacement doses of
cortisone acetate or equivalent.

- Patients who have received any cytotoxic therapy, immunotherapy, antitumor vaccines
or monoclonal antibodies in the 4 weeks prior to the start of the study.

- Life expectancy of less than 3 months.

- Documented HIV, active bacterial infections, active or chronic hepatitis B, hepatitis
C or HTLV-I infection.

- A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb
positive and HBc Ab negative), or a fully resolved acute hepatitis B infection is not
an exclusion criterion.

- A positive hepatitis C serology is an exclusion criterion.

- Concurrent anticancer therapy (including other investigational agents), with the
exception of hormone therapy for prostate cancer.

- Active CNS metastases (inactive CNS metastases are defined).

- History of severe asthma or presently on chronic inhaled corticosteroid medications
(patients with a history of mild asthma not requiring therapy are eligible).

- History of autoimmune disease, with the exception of an autoimmune event associated
with prior ipilimumab (anti-CTLA-4) therapy that has been completely resolved for
more than 4 weeks.

- Inability or refusal to practice effective contraception during therapy or the
presence of pregnancy or active breastfeeding (men and women of childbearing
potential must use an effective method of birth control or abstinence during
treatment and for 4 months after completion of treatment).

- Cognitive impairment, history of medical or psychiatric disease, other uncontrolled
intercurrent illness, active substance abuse, or social circumstances, which in the
view of the Principal Investigator (PI), would preclude safe treatment or the ability
to give informed consent.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety, toxicity profile, DLT and MTD of IL-15 in subjects with metastatic cancers.

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Kevin C Conlon, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

April 2012

Completion Date:

April 2016

Related Keywords:

  • Carcinoma
  • Lymphoma
  • Immunotherapy
  • Effects of rhlL-15 on T-cells and NK cells
  • Pharmacokinetics of lL-15
  • Cytokine Therapy
  • Carcinoma
  • Lymphoma



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892