Interleukin-7 in Treating Patients With Metastatic Melanoma or Locally Advanced or Metastatic Kidney Cancer

Study Overview
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Brief Summary
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RATIONALE: Interleukin-7 may stimulate the white blood cells to kill tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of interleukin-7 in treating patients with metastatic melanoma or locally advanced or metastatic kidney cancer.

Detailed Description
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OBJECTIVES: Primary Determine the safety of recombinant interleukin-7 (IL-7) in patients with metastatic melanoma or locally advanced or metastatic renal cell carcinoma. Confirm the previously documented safety profile of non-glycosylated IL-7 in these patients. Determine the safety of higher doses of recombinant IL-7 in these patients. Determine the maximum tolerated dose of recombinant IL-7 in these patients. Determine the biologically active dose of recombinant IL-7 in these patients. Secondary Determine the pharmacokinetics and pharmacodynamics of recombinant IL-7 in these patients. Compare the biological and clinical effects of recombinant IL-7 with non-glycosylated IL-7 in these patients. Determine the potential antitumor effect of recombinant IL-7 in these patients. Determine the dose and administration schedule of recombinant IL-7 in these patients. OUTLINE: This is a dose-escalation study. Patients are stratified according to lymphocyte count (normal lymphocyte count [CD4+ T cells > 400/mm^3] vs lymphopenic [CD4+ T cells < 400/mm^3]). Patients are assigned to 1 of 2 treatment groups. Group 1 (normal lymphocyte count): Patients receive recombinant interleukin-7 (IL-7) subcutaneously once a week (to determine an active dose) for up to 3 weeks in the absence of disease progression or unacceptable toxicity. Group 2 (lymphopenic): Patients receive recombinant IL-7 subcutaneously once a week for up to 3 weeks at one dose level below the active dose determined in group 1. Cohorts of 3-6 patients from each group receive escalating doses of recombinant IL-7 until the maximum tolerated dose (MTD) is determined. The MTD is the defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 30 additional patients may be treated at the MTD. Patients undergo blood and bone marrow collection periodically for pharmacokinetic, pharmacodynamic, and immunological studies. Samples are analyzed for the presence of antibodies and proteins via ELISA; CD3, CD4, and CD8 T cell counts, CD127, Ki-67, and Bcl-2 expression in CD4+ and CD8+ T cells, and CD19 B cell counts via flow cytometry; and clonal B cell proliferation via PCR and flow cytometry. After completion of study treatment, patients are followed at 3 months.

Official Title
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A Phase I Study of Subcutaneous CYT 107 (Interleukin-7) in Refractory Metastatic Melanoma or Renal Cell Carcinoma

Conditions
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Kidney Cancer, Melanoma (Skin)

Intervention / Treatment
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* Biological: recombinant interleukin-7
* Genetic: gene expression analysis
* Genetic: polymerase chain reaction
* Genetic: protein expression analysis
* Other: flow cytometry
* Other: immunoenzyme technique
* Other: immunologic technique
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following: Melanoma Metastatic disease Renal cell carcinoma Locally advanced and unresectable disease OR metastatic disease Refractory to standard therapy OR ineligible to receive standard therapy Measurable or evaluable disease Previously received high-dose interleukin-2 OR have a contraindication for this treatment No previously untreated or unstable brain metastases No splenic metastasis PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 3 months Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 PT/PTT ≤ 1.5 times upper limit of normal (ULN) Creatinine < 1.5 times ULN AST and ALT < 2.5 times ULN Conjugated (Direct) bilirubin ≤ 1.25 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception LVEF ≥ 45% by cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) for patients meeting any of the following criteria: History of ECG abnormalities Symptoms of cardiac ischemia At least 50 years of age and over Familial or personal history of heart failure Previously treated with antimitotic agents susceptible to trigger heart failure FEV_1 > 60% of predicted (for patients with a prolonged smoking history or symptoms of respiratory dysfunction) No concurrent cognitive impairment or likelihood of developing cognitive impairment on study therapy No concurrent splenomegaly or proliferative hematologic disease No documented HIV positivity No acute hepatitis A or hepatitis B or C Positive hepatitis B serology indicative of previous immunization (i.e., HBs Ab positive and HBc Ab negative) allowed Positive hepatitis C serology allowed provided HCV RNA load by PCR is negative Resting blood pressure ≤ 140/90 mm Hg on standard antihypertensive therapy Untreated hypertensive patients who received standard antihypertensive therapy allowed provided hypertension is well controlled No QTc prolongation ≥ 470 msec No prior history of cardiovascular disease, arrhythmias, or significant ECG abnormalities No active infection requiring systemic treatment and/or hospitalization within the past 28 days Patients who have completed therapy or are clinically stable on therapy, in the opinion of the investigator, are eligible No history of autoimmune disease No history of severe asthma No history of medical or psychiatric disease that would preclude study treatment No documented cirrhosis or documented acute hepatitis PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 2 weeks since prior systemic corticosteroid therapy More than 4 weeks since prior and no other concurrent cytotoxic therapy, immunotherapy, biological agents (i.e., cytokines, growth factors, or monoclonal antibodies), or antitumor vaccines More than 7 days since prior hepatotoxic drugs unless medically necessary More than 2 days since prior alcohol consumption More than 1 day since prior acetaminophen use No prior splenectomy No prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation No concurrent palliative therapy No concurrent chemotherapy No concurrent chronic anticoagulation (i.e., high-dose warfarin or heparin) Warfarin dose 1 to 2 mg/day allowed No concurrent chronic medications for asthma No other concurrent investigational agents

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYT107 (r-hIL-7)<br> | Biological: recombinant interleukin-7<br> <br> Genetic: gene expression analysis<br> <br> Genetic: polymerase chain reaction<br> <br> Genetic: protein expression analysis<br> <br> Other: flow cytometry<br> <br> Other: immunoenzyme technique<br> <br> Other: immunologic technique<br> <br> Other: laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of recombinant interleukin-7 (IL-7) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics and pharmacodynamics of IL-7 |  |  | 
| Comparison of the biological and clinical effects of recombinant IL-7 with non glycosylated IL-7 |  |  | 
| Potential antitumor effect of recombinant IL-7 |  |  | 
| Dose and administration schedule of recombinant IL-7 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent renal cell cancer, stage IV renal cell cancer, stage III renal cell cancer, recurrent melanoma, stage IV melanoma