Continuous Infusion of rhIL-15 for Adults With Advanced Cancer
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Cancer, Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 8/12/2018 |
| Start Date: | April 4, 2012 |
| End Date: | July 1, 2019 |
A Phase I Study of a Continuous Intravenous Infusion of Recombinant Human Interleukin IL-15 (rhIL-15) in Adults With Metastatic Cancers
Background:
- People with cancer can have a weak immune system as a result of the cancer itself, or from
prior treatments. . Still, treatments that stimulate the immune system have been shown to be
effective against a number of different cancers. Recombinant human interleukin-15 (rhIL-15)
is a drug that is designed to boost the immune system. Researchers are interested in seeing
if rhIL-15 can strengthen the immune system's response against cancer. The drug will be given
through a vein without a break for 10 days (240 hours).
Objectives:
- To see rhIL-15 given as a continuous infusion over 10 days can be used to treat advanced
cancer
- Identify the side effects associated with this treatment.
Eligibility:
- Individuals at least 18 years of age with advanced cancer for which there are no effective
treatments.
Design:
- Participants screening procedures will include a physical exam and medical history,
laboratory (blood) tests and x-rays (Imaging studies) to determine suitability for the
protocol. --Appropriate participants with easily accessible tumor deposits may also be
asked to have one pretreatment and one post (cycle 1) treatment tumor biopsy. .
- Eligible participants will be admitted to the hospital for the rhIL-15 treatment and
will spend about 12 days in the hospital. .
- Participants will receive one 10 day infusion each cycle (about every 42 days) for as
long as there are no serious side effects and the disease does not progress.
- Participants will continue treatment as long as imaging studies show that the tumor
continues to shrink or for two additional cycles after it has disappeared from the
x-rays to make that the cancer is completely gone.
- Participants who stop treatment for side effects or because their tumor did not shrink
or stopped responding to the treatment will continue to have follow-up visits to monitor
the outcome of the rhIL-15 treatment until there is evidence their cancer has progress
or they begin another treatment.
- People with cancer can have a weak immune system as a result of the cancer itself, or from
prior treatments. . Still, treatments that stimulate the immune system have been shown to be
effective against a number of different cancers. Recombinant human interleukin-15 (rhIL-15)
is a drug that is designed to boost the immune system. Researchers are interested in seeing
if rhIL-15 can strengthen the immune system's response against cancer. The drug will be given
through a vein without a break for 10 days (240 hours).
Objectives:
- To see rhIL-15 given as a continuous infusion over 10 days can be used to treat advanced
cancer
- Identify the side effects associated with this treatment.
Eligibility:
- Individuals at least 18 years of age with advanced cancer for which there are no effective
treatments.
Design:
- Participants screening procedures will include a physical exam and medical history,
laboratory (blood) tests and x-rays (Imaging studies) to determine suitability for the
protocol. --Appropriate participants with easily accessible tumor deposits may also be
asked to have one pretreatment and one post (cycle 1) treatment tumor biopsy. .
- Eligible participants will be admitted to the hospital for the rhIL-15 treatment and
will spend about 12 days in the hospital. .
- Participants will receive one 10 day infusion each cycle (about every 42 days) for as
long as there are no serious side effects and the disease does not progress.
- Participants will continue treatment as long as imaging studies show that the tumor
continues to shrink or for two additional cycles after it has disappeared from the
x-rays to make that the cancer is completely gone.
- Participants who stop treatment for side effects or because their tumor did not shrink
or stopped responding to the treatment will continue to have follow-up visits to monitor
the outcome of the rhIL-15 treatment until there is evidence their cancer has progress
or they begin another treatment.
BACKGROUND:
- 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.
OBJECTIVES:
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.
ELIGIBILITY CRITERIA:
- 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 advantage.
- Patients with measurable or evaluable disease, normal organ and bone marrow function.
DESIGN:
- 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, 2, 4, 6
and 8 mcg/kg/day for 10 days provided that DLT has not been observed.
- After assessments of the 10-day dosing cohorts have been completed, new groups of 3 to 6
subjects will receive CIVrhIL-15 at doses of 3, 4 and 5 mcg/kg/day for 5 days provided
that a DLT has 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 antibodies.
- 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.
OBJECTIVES:
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.
ELIGIBILITY CRITERIA:
- 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 advantage.
- Patients with measurable or evaluable disease, normal organ and bone marrow function.
DESIGN:
- 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, 2, 4, 6
and 8 mcg/kg/day for 10 days provided that DLT has not been observed.
- After assessments of the 10-day dosing cohorts have been completed, new groups of 3 to 6
subjects will receive CIVrhIL-15 at doses of 3, 4 and 5 mcg/kg/day for 5 days provided
that a DLT has 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 antibodies.
- 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 disease.
- DLCO/VA and FEV-1.0 > 60% 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
- Subjects with inactive central nervous system (CNS) metastasis are eligible. Inactive
CNS metastasis is defined as: no signs of cerebral edema after successful definitive
treatment of brain metastases (surgical resection, whole brain irradiation,
stereotactic radiation therapy, or a combination of these) with stable or improved
radiographic appearance on MRI scan at least 1 month after completion of treatment.
EXCLUSION CRITERIA:
- 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,
monoclonal antibodies or major surgery in the 4 weeks prior to the start of the study.
- Life expectancy of less than 3 months.
- Patients with more than 30% replacement of hepatic parenchyma by tumor or any history
of drug related hepatic encephalopathy.
- History of complex ventricular or supraventricular arrhythmias
- Documented HIV, active bacterial infections, active or chronic hepatitis B, or
hepatitis C 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 controlled with inhaled bronchodilators 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: (888) NCI-1937
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