HTLV-1 Clinical Trial
Official title:
Phase I Study of HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Using the Humanized MiK-Beta-1 Monoclonal Antibody Directed Toward the IL-2L-15R-Beta; Subunit (CD122) That Blocks IL-15 Action
This study will examine the use of the humanized Mik-Beta-1 (Hu Mik-(SqrRoot) 1) monoclonal
antibody in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis
(HAM/TSP). Some patients infected with the human T-lymphotropic virus type 1 (HTLV-1) virus
develop HAM/TSP, a disease in which the immune response to HTLV-1 becomes directed against
the person's own body in what is called an autoimmune response. Hu-Mik-Beta-1 is a
genetically engineered antibody that blocks the action of a chemical produced by the body
during infection or inflammation called interleukin 15 (IL-15). Blocking IL-15 may prevent
the autoimmune response that results in HAM/TSP.
Patients 18 years of age and older with HAM/TSP may be eligible for this study. Candidates
are screened with a medical history and physical examination, blood and urine tests, and an
electrocardiogram. Participants undergo the following procedures:
1. Baseline visit(s): Repeat physical examination and blood and urine tests, as well as the
following:
- Lumbar puncture: A local anesthetic is injected to numb the skin of the lower back.
A needle is inserted in the space between the bones where the cerebrospinal fluid
that bathes the brain and spinal cord circulates below the spinal cord. About 4
tablespoons of fluid is collected through the needle.
- Magnetic resonance imaging (MRI): This test uses radio waves and magnets to produce
images of body tissues and organs. The patient lies on a table that slides into a
metal cylinder surrounded by a strong magnetic field. During part of the scan, a
contrast agent is injected to brighten the images.
- Apheresis: This procedure is used to collect large quantities of white blood cells.
Whole blood is collected through a needle in an arm vein and directed into a
machine that separates it into its components by spinning. The white cells and
plasma are removed and the rest of the blood (red cells and platelets) is returned
to the body through the same needle.
2. Hu Mik-Beta-1 treatment: Infusions of Hu Mik-Beta-1 are given through a vein every 3
weeks for nine doses. The first treatment requires at least an overnight hospital stay;
subsequent infusions are given in the outpatient clinic.
3. Blood and urine tests and a physical examination at every treatment visit and a skin
test at one treatment visit.
4. Research tests at the end of the 24-week treatment period, including lumbar puncture
(spinal tap), MRI scan, and apheresis.
5. After completing treatment, patients have three follow-up clinic visits for blood and
urine tests, and a skin test at one follow-up visit.
Objectives:
In a phase I trial we wish to determine the toxicity and provide preliminary clinical
response information following the administration of humanized MiK-beta-1 (Hu MiK-Beta1), a
monoclonal antibody directed toward IL-2/IL-15R Beta (CD122), in patients with
HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This antibody blocks the
action of IL-15, a cytokine involved in the pathogenesis of HTLV-I associated diseases and
autoimmune disorders such as rheumatoid arthritis and multiple sclerosis.
Study Population:
HAM/TSP affects about 1% of patients infected with the human T lymphotropic virus type 1
(HTLV-I), manifesting as progressive myelopathy. Several features of the immune response in
HAM/TSP indicate that IL-15 may be critical to its pathogenesis. HTLV-I transactivates IL-15
and IL-15 R alpha expression through its tax protein, and supports the activation of
lymphocytes in HAM/TSP, as evidenced by their spontaneous proliferation in ex vivo culture.
We showed that the antibody HuMiK-Beta1 could inhibit this spontaneous lymphoproliferation.
In addition, IL-15 has been shown to have a preferential positive effect on the survival of
CD8+ T-cells, especially those of the memory phenotype. In HAM/TSP, an extraordinarily high
frequency of tax specific CD8+ T-cells in the peripheral blood and cerebrospinal fluid is
postulated to participate in the damage to the central nervous system. We have demonstrated
that the addition of Hu MiK-Beta1 to ex vivo cells from HAM/TSP patients led to a marked
decline in tax specific CD8+ T-cells.
Design of the Study and Outcome Parameters
In this single center, open label trial, four subjects with HAM/TSP will receive 0.5 mg/kg Hu
MiK-beta1 dosed every three weeks for a total of five doses, and two subjects with HAM/TSP
will receive placebo (normal saline) under the same dosing schedule. In addition, following
the completion of the 0.5 mg/kg dose administration in four subjects with HAM/TSP, a dose
escalation study will be performed with three subjects with HAM/TSP receiving 1.0 mg/kg of Hu
MiK-beta1 at three week intervals for a total of five doses per subject, and three subjects
with HAM/TSP receiving 1.5 mg/kg of Hu MiK-beta1 at three week intervals for a total of five
doses per subject A Total of 10 subjects will receive study drug/placebo. We anticipate
consenting up to eighteen subjects to allow for up to eight dropouts. Participants who
withdraw voluntarily (not due to toxicity) after initiation of the study are considered
dropouts. If this occurs prior to receiving three doses of the study medication the subjects
can be replaced and should have three follow-up evaluations at four-week intervals following
the last dose of the study drug. Patients who voluntarily drop out after receiving at least 3
doses of the study drug will remain in the study and continue the protocol-specific
evaluations. Toxicity will be assessed using standard criteria. The clinical response will be
evaluated using standardized scales including expanded disability status scale, Scripps
neurologic rating scale and ambulation index. In addition, viral and immunologic outcome
measures will include assays of spontaneous lymphoproliferation analysis of HTLV-I tax
tetramer specific CD8+ cells, HTLV-I proviral load determination and T-cell phenotype
analysis.
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