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.
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
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|
|Northwestern University Medical School||Chicago, Illinois 60611-2927|
|Providence Portland Medical Center||Portland, Oregon 97213-3635|