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


Phase 1
18 Years
85 Years
Open (Enrolling)
Both
Melanoma, Carcinoma, Renal Cell

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Trial Information

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


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.

Inclusion Criteria


- INCLUSION CRITERIA:

- Age greater than or equal to 18 years.

- Diagnosis of metastatic malignant melanoma or metastatic renal cell cancer confirmed
by the Laboratory of Pathology, NCI.

- Patients must have metastatic malignant melanoma or metastatic renal cell cancer
(AJCC stage IV [M1] or equivalent disease). Metastatic renal cell cancer patients
must either have refused treatment with, have been unable to tolerate or have
experienced progressive disease after treatment with sorafenib or sunitinib, and
temsirolimus.

- Patients must have measurable disease.

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

- AST and ALT less than 3 times the upper limit of normal.

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

- Platelets greater than or equal to 75,000/mm(3).

- PT/PTT within 1.5 times upper limit of normal. Patients with a history of DVT and who
are on anticoagulation therapy may be eligible, provided their DVT was at least 8
weeks prior to enrollment and they have had no further complications.

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

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

- 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 greater than or equal to 3
months after completion of treatment and no signs of cerebral edema are eligible.

EXCLUSION CRITERIA:

- Patients must not have received any systemic corticosteroid therapy for 3 weeks prior
to the start of therapy with the exception of physiological replacement doses of
cortisone acetate or equivalent.

- Patients must not have received any cytotoxic therapy, immunotherapy, antitumor
vaccines or monoclonal antibodies in the 4 weeks prior to the start of the study.

- History of any hematopoietic malignancy.

- Life expectancy of less than 3 months.

- Presence of serum antibodies to IL-15.

- Patients must not have a marked baseline prolongation of QT/QTc interval (e.g.,
demonstration of a QTc interval greater than 500 milliseconds (ms)).

- Documented HIV, 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 HBV infection is not an
exclusion criterion.

- A positive hepatitis C serology is an exclusion criterion.

- Concurrent anticancer therapy (Including other investigational agents).

- History of severe asthma, presently on chronic medications (a history of mild asthma
not requiring therapy is eligible).

- History of autoimmune disease, with the exception of an autoimmune event associated
with prior ipilimumab (anti-CTLA-4) therapy that has completely resolved for a period
of 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 four months after completion of treatment).

- History of medical or psychiatric disease, active substance abuse or social
circumstances which in the view of the Principal Investigator, would preclude safe
treatment.

- Patients with cognitive impairment or likely to develop cognitive impairment while on
study.

- Inability to give informed consent.

Type of Study:

Interventional

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, dose-limiting toxicity and a maximum tolerated dose if IV recombinant Human IL-15 administered in melanoma and renal cell cancers.

Principal Investigator

Thomas A Waldmann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

100021

NCT ID:

NCT01021059

Start Date:

November 2009

Completion Date:

Related Keywords:

  • Melanoma
  • Carcinoma, Renal Cell
  • Biological Effects of rhIL-15
  • Estimate Antitumor Activity
  • rhIL-15 Pharmacokinetics
  • Dose and Safety Determination of IL-15
  • Kidney Cancer
  • Melanoma
  • Renal Cell Cancer
  • Carcinoma
  • Carcinoma, Renal Cell
  • Melanoma

Name

Location

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