evaluation of m40403 for the prevention of dose limiting toxicities of high dose il-2

Conditions: IL-2 Induced Hypotension

Summary: the clinical use of il-2 is currently limited by development of dose-dependent hypotension (systolic blood pressure (sbp) \< 90 mm hg). the overall outcome is constant across sites with 20-50% of the patients requiring icu management because of unresponsive hypotension and hyporeactivity (loss of response to vasoconstrictors). because of the dose-limiting side effects, the duration of il-2 dosing is frequently curtailed. thus, hemodynamic toxicities have limited the usefulness of il-2 therapy. m40403 has prevented both the hypotension and hyporeactivity associated with il-2 treatment in preclinical studies. this trial will study the safety and efficacy of m40403 in the prevention or reduction of hypotension in patients receiving il-2 therapy.

high-dose interleukin-2 (il-2) therapy is currently indicated for treatment of metastatic renal cell carcinoma and metastatic malignant melanoma, and has been associated with a 5-15% long-term clinical response. in addition, il-2 therapy is showing promise in treatment of acute myelogenous leukemia, non-hodgkin's lymphoma, and breast cancer, and in improving immunologic function in patients with aids. however, the major dose-limiting toxicity of il-2, hypotension, severely limits the usefulness of il-2 therapy. because of the unresponsive hypotension and loss of response to exogenously administered vasopressors, 20-50% of the patients receiving high dose il-2 therapy require icu management. these dose-limiting side effects frequently necessitate curtailing the full period of il-2 dosing in order to reverse the hypotension and prevent subsequent renal dysfunction. thus, hemodynamic toxicities have limited the usefulness of il-2 therapy. a course of il-2 therapy requires long hospitalization and intense patient monitoring during administration. as a consequence, despite favorable long-term response, few sites offer this treatment. the availability of an agent that prevents il-2-induced hypotension without adversely affecting the therapeutic mechanism of il-2, would markedly facilitate il-2 administration and at a minimum, would maximize the number of patients who could receive the full regimen of il-2. the reduction in il-2 toxicity may also enable higher doses and/or more frequent dosing of il-2 to be used, with the potential of higher success of tumor response. because m40403 may decrease the toxicity of il-2, co-administration of m40403 may make it possible to broaden the clinical use of il-2 to conditions where it is not currently indicated. the indication to be studied is for use in the prevention or reduction of hypotension associated with interleukin-2 (il-2) therapy in patients with metastatic melanoma and renal cell carcinoma. the study is divided into a sequential dose escalation phase followed by the expansion of the selected dose in a double-blind, placebo-controlled, evaluation phase. patients with metastatic or inoperable melanoma and renal cell carcinoma will be receiving high dose il-2 per approved labeling as two 5-day sequences. m40403 will be administered by intravenous infusion over 30 minutes prior to each intravenous administration of high dose il-2. sequential panels of patients will receive increasing doses of m40403 along with il-2 until an active dose is determined and an mtd is reached. patients will be followed to determine the effects of m40403 on development of markers of il-2 dose-limiting toxicity including hypotension, tachycardia, index of renal perfusion, cumulative dose of pressor required and cumulative dose of il-2 administered. approximately 48 patients will be studied.

Eligibility criteria:
inclusion criteria: * patient has given signed informed consent. * patient has documented histologically confirmed malignant melanoma or renal cell carcinoma which is metastatic. * patient is eligible for high dose iv il-2 therapy. * tumor dimension of at least one lesion is measurable in two dimensions. * patient is at least 18 years of age. * patient is ambulatory with good performance status (ecog ps 0,1; karnofsky 100-70%). * if the patient is a woman of child bearing potential, patient is not lactating and ahs a negative pregnancy test (beta-hcg test obtained within 72 hours of enrollment) and agrees to use an adequate method of contraception for the duration of the study. * patient has adequate organ function as defined by: * wbc count \>3,500 per cubic millimeter; platelet count\> 100,000 per cubic millimeter; * bilirubin within institutional normal range; creatinine less than or equal to 2.0 mg/dl or creatinine clearance \> 50 ml/min; * no evidence of congestive heart failure, symptoms of coronary artery disease, serious cardiac arrhythmias or evidence of prior myocardial infarction. a pretreatment cardiac stress test must be performed within 42 days of il-2 treatment. patients with documented ischemia on the pretreatment cardiac stress test will be excluded from the study; * adequate pulmonary reserve. pulmonary function tests (pfts) must be performed within 42 days of il-2 treatment and an fev1 \> 2.0 liters or 75% of predicted for height and age is the minimum acceptable criteria for patient entry. patients unable to perform pfts will be excluded from the study. * patient has recovered from all toxic effects of prior therapy. * patient has a life expectancy, in the opinion of the investigator, of at least 4 months. exclusion criteria: * patient has an organ allograft. * patient has brain metastases. a brain ct or mri scan should be performed within 42 days of il-2 treatment. * patient is know to be hiv antibody positive. hiv testing is not required for enrollment into this study. * patient has evidence of active infection which requires antibiotic therapy. * patient has received systemic corticosteroids in the four weeks prior to the first dose of study drug, or requires or is anticipated to require corticosteroids for intercurrent disease. * patient has received radiotherapy, chemotherapy, or immunotherapy in the four weeks prior to the first dose of study drug, or is scheduled to receive concurrent radiotherapy, chemotherapy, or immunotherapy. * patient has contraindication to treatment with pressor agents. * patient currently receives chronic medication for asthma. * patient has a history of another malignancy other than basal cell skin cancer within 5 years prior to the first dose of study drug. * patient has any significant medical disease other than the malignancy which, in the opinion of the investigator, may interfere with completion of the study. * patient has previously received any il-2 therapy. * patient has received another investigational medication within 4 weeks prior to m40403 administration or is scheduled to receive an investigational drug other than m40403 during the course of the study.

Keywords: metastatic melanoma renal cell carcinoma il-2 interleukin-2 hypotension