Phase II Study of Aldesleukin (IL-2) Following the Administration of Zanolimumab (Anti-CD4mAb) in Metastatic Melanoma and Metastatic Renal Cancer

Study Overview
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Brief Summary
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Background: Aldesleukin (IL-2) is a drug that can help to shrink tumors in some patients with metastatic renal cancer and metastatic melanoma. It is possible that removing certain white blood cells (known as CD4 cells) before IL-2 treatment may improve the treatment effects. Zanolimumab is an antibody that works by destroying CD4 cells in the blood. Researchers are interested in determining whether zanolimumab can improve the results of IL-2 treatment if it is given before, during, and after IL-2 treatment. In addition, further research with zanolimumab may provide more information on how IL-2 treatment causes tumors to stop growing or shrink. Objectives: - To evaluate the effectiveness of IL-2 treatment in conjunction with zanolimumab in individuals with metastatic cancer. Eligibility: - Individuals at least 18 years of age who have been diagnosed with metastatic melanoma or metastatic kidney cancer. Design: Eligible participants will be screened with a full physical examination and medical history, imaging studies, and blood samples, including leukapheresis, to remove a sample of white blood cells for testing purposes. Participants may also have a colonoscopy and biopsies if they have received previous treatments that have been known to cause colon damage. Participants will be treated with zanolimumab and IL-2 treatment for 9 weeks. Zanolimumab will be given on an outpatient basis during weeks 1 through 4, 6, 8, and 9. In weeks 5 and 7, participants will receive zanolimumab as an inpatient in addition to IL-2 therapy. Inpatient IL-2 treatment will be given during weeks 5 and 7. Up to 15 doses of IL-2 treatment will be given over a maximum of 5 days, followed by inpatient recovery time. During week 5, participants will have tumor imaging studies prior to receiving zanolimumab and IL-2 treatment. About 2 weeks after the treatment period, participants will return to the clinical center for a 2-day evaluation with a physical examination, imaging studies, and blood samples. Participants whose tumors have responded to treatment will be offered up to two additional courses of treatment, starting 6 to 8 weeks after the last IL-2 dose. Subsequent courses will be given exactly as described above in the initial course of treatment. Participants whose tumors do not respond to treatment will have follow-up evaluations as required by the study researchers.

Detailed Description
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Background: Zanolimumab is a human monoclonal antibody (mAb) that specifically recognizes CD4 protein expressed on a subset of T lymphocytes and on monocytes from humans, and non-human primates. Ongoing clinical studies have identified a 14 mg/kg dose of zanolimumab weekly as a safe and efficacious dose. Toxicities of zanolimumab included headache, influenza-like illness, injection/infusion site reaction, nasopharyngitis, pyrexia, diarrhea, fatigue, and cytokine release syndrome at the time of infusion. The current protocol is based on the hypothesis that transient elimination of CD4+ T-regulatory cells with zanolimumab will enhance the clinical effectiveness of aldesleukin (IL-2) administration by decreasing T-regulatory cell generation. Objectives: Primary objective: Determine the ability of a combination of aldesleukin and zanolimumab (anti-CD4 mAb) administration to mediate tumor regression in patients with metastatic melanoma and metastatic kidney cancer. Secondary objectives: Determine the rate of depletion and repopulation of CD4+ cells. Determine the toxicity of this treatment. Determine the potential for pharmacokinetic interaction between zanolimumab and aldesleukin. Eligibility: Patients who are 18 years of age or older must have: measurable metastatic melanoma or metastatic kidney cancer; clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, or 1. Patients may not have: previously received high dose aldesleukin. Design: Patients will receive zanolimumab at a dose of 14 mg/kg as an intravenous (i.v.) infusion weekly for 9 weeks. After the fifth and seventh dose of zanolimumab, aldesleukin will administered as an i.v. bolus at a dose of 720,000 IU/kg every 8 hours for a maximum of 15 doses. Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) and clinical laboratory evaluation 2 weeks after zanolimumab administration. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will be followed with this evaluation every 3-4 months until off study criteria are met. If patients have stable disease or a partial response to treatment after the initial evaluation, or if a patient recurs or progresses after a clinical response, they may be eligible for re-treatment. Patients will be entered into one of two strata: metastatic melanoma or metastatic renal cancer. Each of the strata will be conducted using an optimal two-stage phase II design to rule out an unacceptably low 15% clinical response rate, in favor of a modestly high response rate of 35% (p1=0.35).

Official Title
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Phase II Study of Aldesleukin (IL-2) Following the Administration of Zanolimumab (Anti-CD4mAb) in Metastatic Melanoma and Metastatic Renal Cancer

Conditions
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Metastatic Melanoma, Metastatic Renal Cancer

Intervention / Treatment
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* Drug: Zanolimumab
* Drug: Aldesleukin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Measurable metastatic melanoma or metastatic renal cancer. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI). Patients must never have received high dose aldesleukin. Greater than or equal to 18 years of age. Willing to sign a durable power of attorney Able to understand and sign the Informed Consent Document Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Life expectancy of greater than three months. Patients of both genders must be willing to practice birth control for four months after receiving treatment. Serology: Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the therapy on the fetus. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. White blood cell (WBC) (greater than 3000/mm^3). Platelet count greater than 100,000/mm^3. Hemoglobin greater than 8.0 g/dl. Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives zanolimumab, and patient's toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Six weeks must have elapsed since prior anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody therapy to allow antibody levels to decline, and patients who have previously received anti-CTLA4 antibody and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies. EXCLUSION CRITERIA: Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the therapy on the fetus or infant. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Concurrent systemic steroid therapy History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of coronary revascularization or ischemic symptoms Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%. Documented LVEF of less than or equal to 45% tested in patients with: History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block Age greater than or equal to 60 years old. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with: A prolonged history of cigarette smoking (20 pack year of smoking within the past 2 years). Symptoms of respiratory dysfunction

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HD IL-2 + Zanolimumab - Melanoma<br>Patients with metastatic melanoma Zanolimumab 14 mg/kg as an intravenous infusion weekly (+/- 3 days) for 9 weeks. Aldesleukin (IL-2) 720,000 IU/kg every 8 hours for a maximum of 15 doses. | Drug: Zanolimumab<br>* 14 mg/kg as an intravenous infusion weekly (+/- 3 days) for 9 weeks.<br>* Other names: HuMax-CD4;Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses.<br>* Other names: IL-2;|
| Experimental: HD IL-2 + Zanolimumab - Renal Cell<br>Patients with metastatic renal cancer Zanolimumab 14 mg/kg as an intravenous infusion weekly (+/- 3 days) for 9 weeks. Aldesleukin (IL-2) 720,000 IU/kg every 8 hours for a maximum of 15 doses. | Drug: Zanolimumab<br>* 14 mg/kg as an intravenous infusion weekly (+/- 3 days) for 9 weeks.<br>* Other names: HuMax-CD4;Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses.<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Ability of a Combination of Aldesleukin (IL-2) and Zanolimumab (Anti-CD4 mAb) Administration to Mediate Tumor Regression in Patients With Metastatic Melanoma and Metastatic Kidney Cancer. | Tumor regression was assessed by the Response Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% in the sum of the longest diameter (LD) recorded since the treatment started. Stable disease (SD) is neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the smallest sum LD. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of Zanolimumab and IL-2 Treatment Regimen | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. | 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Melanoma, Metastatic Kidney Cancer, Clinical Performance, Tumor Regression, Toxicity