A Phase I, Multicenter, Dose Escalation Study of CAT-8015 in Patients With Non-Hodgkin's Lymphoma (NHL)

A dose-escalation study to estimate the maximum tolerated dose(MTD) of CAT-8015 that can be safely administered to a patient.

To estimate the maximum tolerated dose (MTD), defined as the highest dose that can be safely administered to a patient, and to establish a safe dose, based on MTD, for subsequent clinical testing.

Inclusion Criteria:

Subjects must meet all of the following criteria to be eligible to participate in the study:

• Confirmed diagnosis of B-cell non-Hodgkin's lymphoma
• Measurable disease
• Evidence of CD22-positive malignancy by the following criteria, > 30% of malignant cells from a disease site CD22+ by FACS analysis or, > 15% of malignant cells from a disease site must react with anti-CD22 by immunohistochemistry
• Disease characteristics: Patients with indolent subtypes of CD22+ B-cell non- Hodgkin's lymphoma, including, but not limited to mantle cell lymphoma, follicular lymphoma and Waldenström's macroglobulinemia, are eligible if stage III-IV. if stage III-IV. Patients must have failed at least two or more courses of prior standard chemotherapy and/or biologic therapy (e.g. Rituxan). Patients with progressive mantle cell lymphoma may be eligible if they have failed one prior standard therapeutic regimen.
• ECOG performance status of 0-2
• Patients with other cancers who meet eligibility criteria and have less than 5 years of disease free survival will be considered on a case-by-case basis
• Life expectancy of less than 6 months, as assessed by the principal investigator
• Must be able to understand and sign informed consent
• Must be at least 18 years old
• Female and male patients must agree to use an approved method of contraception during the study

Exclusion Criteria:

Subjects meeting any of the following criteria are not eligible for participation in the study:

• History of allogeneic bone marrow transplant
• Documented and ongoing central nervous system involvement with their malignant disease (history of CNS involvement is not an exclusion criterion)
• Pregnant or breast-feeding females
• HIV positive serology (due to increased risk of severe infection and unknown interaction of CAT-8015 with antiretroviral drugs)
• Hepatitis B surface antigen positive
• Uncontrolled, symptomatic, intercurrent illness including but not limited to: infections requiring systemic antibiotics, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements
• Patients whose plasma contains either a significant level of antibody to CAT-8015 as measured by ELISA, or antibody that neutralizes the binding of CAT-8015 to CD22 as measured by a competition ELISA.

Hepatic function Serum transaminases (either ALT or AST) or bilirubin:

• ≥ Grade 2, unless bilirubin is due to Gilbert's disease

Renal function:

• serum creatinine clearance ≤ 60mL/min as estimated by Cockroft-Gault formula

Hematologic function:

• The ANC < 1000/cmm, or platelet count <50,000/cmm, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy).
• A patient will not be excluded because of pancytopenia ≥ Grade 3, or erythropoietin dependence, if it is due to disease, based on the results of bone marrow studies
• Baseline coagulopathy greater than or equal to Grade 3 unless due to anticoagulant therapy.

Pulmonary function:

• Patients with < 50% of predicted forced expiratory volume (FEV1) or <50% of predicted diffusing capacity for carbon monoxide (DLCO), corrected for hemoglobin concentration and alveolar volume. Note: Patients with no prior history of pulmonary illness are not required to have PFTs. FEV1 will be assessed after bronchodilator therapy.

Recent prior therapy:

• Cytotoxic chemotherapy, corticosteroids (except stable doses of prednisone), whole body electron beam radiation therapy, hormonal, biologic or other standard or any investigational therapy of the malignancy for 3 weeks prior to entry into the trial
• Less than or equal to 1 month prior monoclonal antibody therapy (i.e. rituximab)
• Patients who are receiving or have received radiation therapy less than 3 weeks prior to study entry will be not be excluded providing the volume of bone marrow treated is less than 10% and also the patient has measurable disease outside the radiation port
• Any history of prior pseudomonas-exotoxin immunotoxin (PE) administration.