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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.

Phase 1/Phase 2
18 Years
Not Enrolling
IL-2 Induced Hypotension

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Trial Information

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
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.

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

- 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

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.

Type of Study:


Study Design:

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

Study ID:




Start Date:

December 2001

Completion Date:

Related Keywords:

  • IL-2 Induced Hypotension
  • Metastatic Melanoma
  • Renal Cell Carcinoma
  • IL-2
  • Interleukin-2
  • Hypotension
  • Carcinoma, Renal Cell
  • Hypotension



Huntsman Cancer Institute Salt Lake City, Utah  84112
Northwestern University Medical School Chicago, Illinois  60611-2927
Providence Portland Medical Center Portland, Oregon  97213-3635