Continuous Infusion of rhIL-15 for Adults With Advanced Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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BACKGROUND: Interleukin-15 (IL-15) is a stimulatory cytokine with a number of desirable immunotherapeutic features, and clinical trials evaluating recombinant human interleukin-15 (rhIL-15) are underway. In contrast to IL-2, IL-15 treatment does not stimulate activation-induced cell death of T-cells; potentially inhibits immunosuppressive cluster of differentiation 4 (CD4) + Interleukin-2 receptor alpha chain (CD25) + T regulatory cells, contributes to the proliferation, differentiation and activation of CD8+ T-cells and NK-cells and the maintenance of long-term cluster of differentiation 8 (CD8) + memory T-cells. IL-15 is active in a number of syngeneic mouse preclinical tumor models, and vaccinia-based constructs expressing IL-15 induced long-lasting, high-avidity cytotoxic CD8+ T-lymphocyte 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 intravenous (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 continuous intravenous (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, Eastern Cooperative Oncology Group (ECOG) performance status (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 CIV rhIL-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.

Official Title
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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

Conditions
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Lymphoma, Carcinoma

Intervention / Treatment
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* Biological: rh IL-15 (10 DAYS)
* Biological: rh IL-15 (5 DAYS)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Age greater than or equal to 18 years. Patients must have histologically confirmed (by the National Cancer Institute (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 computed tomography (CT) scan. Patients must have recovered to < grade 1 Common Terminology Criteria for Adverse Events (CTCAE)v4 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 7-hydroxystaurosporine (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. Diffusing capacity for carbon monoxide (DLCO)/alveolar volume (VA) and forced expiratory volume (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. Aspartate aminotransferase (AST) and alanine aminotransferase (AST) < 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 Eastern Cooperative Oncology Group (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 magnetic resonance imaging (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 human immunodeficiency virus (HIV), active bacterial infections, active or chronic hepatitis B, or hepatitis C infection. A positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antigen (HBsAb) positive and hepatitis B core antibody (HBcAb) 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 central nervous system (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-cluster of differentiation 152 (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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A1 (Dose Escalation, 10-day Dosing)<br>Maximum tolerated dose (MTD) determination in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days | Biological: rh IL-15 (10 DAYS)<br>* Continuous infusion of recombinant human Interleukin-15 (rh IL-15) intravenous (IV) for first 10 days of each cycle<br>* Other names: Recombinant human Interleukin-15;|
| Experimental: Arm A2 (Dose Expansion, 10-day Dosing)<br>Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 10 consecutive days | Biological: rh IL-15 (5 DAYS)<br>* Continuous infusion of recombinant human Interleukin-15 (rh IL-15) for first 5 days of each cycle<br>* Other names: Recombinant human Interleukin-15;|
| Experimental: Arm B1 (Dose Escalation, 5-day Dosing)<br>Maximum tolerated dose (MTD) determination in subjects with metastatic unresectable cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days | Biological: rh IL-15 (5 DAYS)<br>* Continuous infusion of recombinant human Interleukin-15 (rh IL-15) for first 5 days of each cycle<br>* Other names: Recombinant human Interleukin-15;|
| Experimental: Arm B2 (Dose Expansion, 5-day Dosing)<br>Clinical activity evaluation in subjects with metastatic cancers receiving recombinant human Interleukin-15 (rhIL-15) intravenous (IV) for 5 consecutive days | Biological: rh IL-15 (5 DAYS)<br>* Continuous infusion of recombinant human Interleukin-15 (rh IL-15) for first 5 days of each cycle<br>* Other names: Recombinant human Interleukin-15;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 10 Day Dosing | The MTD is the dose level at which less than one-third of patients (0/3 or 0-1/6 participants) treated at that dose experience a dose-limiting toxicity (DLT), with the next higher dose level demonstrating a one-third or greater number of participants (≥ 2/3 or ≥ 2/6 participants) having DLT. A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by the principal investigator during the first cycle of treatment. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening. | After one cycle (one cycle is 42 days for 10-day dosing) | 
| Maximum Tolerated Dose (MTD) of Recombinant Human Interleukin-15 (rhIL-15) for 5 Day Dosing | The MTD is the dose level at which less than one-third of patients (0/3 or 0-1/6 participants) treated at that dose experience a dose-limiting toxicity (DLT), with the next higher dose level demonstrating a one-third or greater number of participants (≥ 2/3 or ≥ 2/6 participants) having DLT. A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by the principal investigator during the first cycle of treatment. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening. | After one cycle (one cycle is 21 days for 5-day dosing) | 
| Number of Participants With Grades 3, 4 or 5 Dose-Limiting Toxicity (DLT) Related to Study Drug | A DLT is Grade 2 diarrhea lasting more than 24 hours or any grade 3 or 4 toxicity, if deemed possibly, probable or definitely related to the study drug by the principal investigator during the first cycle of treatment; and/or Grade 5 death related to adverse event. Toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4. Grade 3 is severe, and Grade 4 is life-threatening. | After one cycle (one cycle is either 42 or 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Both cycles 1 and 2 (each cycle is 42 days) for the 10 day treatment, up to 84 days. And clinical responses for the 5-day treatment cohorts (21 day cycle length) were assessed after cycles 2, 4, 6, 8 and so on treatment cycles. | 
| Time to Progression (TTP) | TTP is defined as the date of protocol consent until date of progressive disease is documented. Progressive disease was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions. | From the date of protocol consent until date of progressive disease is documented, up to 263 days | 
| Maximum Observed Plasma Concentration (Cmax) of Recombinant Human Interleukin-15 (rhIL-15) | The maximum observed analyte concentration in serum was reported. | Prior to 1st dose, at 10 minutes after 1st dose, once daily on days 7-10 at completion of treatment, at 10 and 30 minutes after completion of treatment and at 1, 2, 4, and approximately 24 hours after completion of treatment. | 
| Concentration of Drug in Plasma at Steady State (Css) | Concentration of drug in plasma at steady state (Css). | Days 7 through 10 | 
| Area Under the Curve (AUClast) | AUClast is from dosing to the time of the last measured concentration >/= lower limit of quantitation (LLOQ)(Clast) of that dosing period. | Prior to 1st dose, at 10 minutes after 1st dose, once daily on days 7-10 at completion of treatment, at 10 and 30 minutes after completion of treatment and at 1, 2, 4, and approximately 24 hours after completion of treatment. | 
| Inflammatory Cytokines | Serum samples was obtained from participants and inflammatory cytokine analyses was performed by flow cytometry to determine levels of Interleukin - 1, Interferon γ, Interleukin-6 and Tumor Necrosis Factor ἁ. | Pre, 0.16, 1, 2, 4, 8, 12, and 24 hours on Day 1. Days 2, 7, 8, 9, and 10. 0, 0.16, 0.32, 1, 2, 4, and 12 hours on Day 11. And 24 hours on Day 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics of lL-15, Cytokine Therapy, Effects of rhlL-15 on T-cells and NK cells, Immunotherapy