A Phase I Study of Subcutaneous "CYT 107" (Interleukin-7) in Refractory Metastatic Melanoma or Renal Cell Carcinoma
A Phase I Study of Subcutaneous "CYT 107" (Interleukin-7) in Refractory Metastatic Melanoma or Renal Cell Carcinoma
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.
OBJECTIVES:
Primary
Secondary
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.
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.
DISEASE CHARACTERISTICS:
Histologically confirmed diagnosis of 1 of the following:
Melanoma
Renal cell carcinoma
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:
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
Resting blood pressure ≤ 140/90 mm Hg on standard antihypertensive therapy
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
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)
No concurrent chronic medications for asthma
No other concurrent investigational agents