Evaluation of M40403 for the Prevention of Dose Limiting Toxicities of High Dose IL-2
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.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Phase I/II Open Label Dose Escalation and Double-Blind, Placebo-Controlled Evaluation of M40403, for the Prevention of the Dose Limiting Toxicities of High Dose IV Bolus IL-2 Treatment of Metastatic Melanoma or Renal Cell Carcinoma.|
|Study Start Date:||December 2001|
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.
|United States, Illinois|
|Northwestern University Medical School|
|Chicago, Illinois, United States, 60611-2927|
|United States, Oregon|
|Providence Portland Medical Center|
|Portland, Oregon, United States, 97213-3635|
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|