A-dmDT390-bisFv (UCHT1) Immunotoxin Therapy for Patients With T-cell Diseases

This is a Phase I/II clinical trial aimed at treating patients with T-cell lymphomas (T-cell blood cancers). The drug consists of a toxin, called diphtheria toxin, which is attached to an antibody that can specifically target cancerous T-cells. As this is a Phase I/II trial, it has not been tested in humans. Our primary objectives are, therefore, to determine how much of the drug can be given to an individual and what are the toxicities associated with the drug. It is anticipated that approximately 40 patients will be enrolled in this study over two years. Patients will receive full supportive care during the course of the study. Participation in the study will require a 5 day stay in the hospital, as well as frequent (2-3 times/week) outpatient labs (blood draws) for the first 30 days. Patients with partial or complete remissions at their 1 month follow up visit will have another follow-up visit on day 60, then every three months for 1 year, followed by annual visits to assess duration of the response.

This is a Phase I/II, open-label, dose-escalation, multi-dose study of A-dmDT390-bisFv (UCHT1) Fusion Protein, an antibody tagged with diphtheria toxin targeting CD3ε surface membrane protein found on malignant T-cells. It is anticipated that approximately 40 patients will be enrolled in this study over two years. Patients will receive full supportive care including transfusions of irradiated washed blood and blood products, antibiotics, antiemetics, etc, when appropriate. However, other anti-neoplastic drugs or hematopoietic growth factors (e.g., erythropoietin, interleukin-11, G-CSF and GM-CSF) are not allowed. Patients will be hospitalized for 5 days (4 day administration cycle of A-dmDT390-bisFv (UCHT1))and will be monitored two to three times weekly for 30 days. Patients will then have a follow-up visit and testing on day 30. Patients with partial or complete remissions will have another follow-up visit on day 60, then every three months for 1 year, followed by annual visits to assess duration of the response.

Objectives:

1. Determine the maximal tolerated dose (MTD) of A-dmDT390-bisFv (UCHT1) fusion protein as a bolus infusion on days 1-4 in patients with CD3+ T-cell malignant diseases.
2. Define the dose-limiting toxicities (DLTs) of this A-dmDT390-bisFv (UCHT1) regimen in patients with CD3+ T-cell malignant diseases.
3. Measure the pharmacokinetics, immune responses, and cytokine responses to this course of bolus infusions of A-dmDT390-bisFv (UCHT1) fusion protein.
4. Evaluate responses and correlate with the in vitro sensitivity of patient malignant T-cells to A-dmDT390-bisFv (UCHT1).
5. Determine the extent and kinetics of resting and malignant T-cell depletion and repopulation in the treatment groups by flow cytometry of samples obtained from blood and marrow aspirations.

• T-cell Lymphomas
• T-cell Leukemia
• Sezary Syndrome
• Mycosis Fungoides

Inclusion Criteria:

• All patients must have either surface CD3+ T-cell malignant diseases diagnosed by morphologic, histochemical or cell surface marker criteria. Patients with T-ALL must have surface CD3 on at least 10% of the lymphoblasts as determined by flow cytometry. CTCL patients with stage IA disease are not eligible for enrollment. CTCL patients with stage IB disease are eligible provided that they have failed a systemic treatment (this includes radiation). CTCL patients with stage II to IV disease are eligible.
• Patients with CD3+ T-cell malignant diseases must have failed or be refractory to approved therapeutic agents or choose to decline or defer, after adequate informed consent, clinically meaningful palliative therapy.
• Age >/= 18 years.
• Patients >/= 12 years may be accrued beginning at dose level 2.5 mcg/kg, provided that they are under the supervision of a pediatrician at Texas Children's Hospital, Baylor College of Medicine.
• Patients >/= 12 years of age with CD3+ T-cell malignant diseases must have failed or be refractory to approved therapeutic agents.
• Patients must have a performance status of </= 2 on Eastern Cooperative Oncology Group scale (see Appendix). Patients must have fully recovered from toxicity of prior chemotherapy or radiation therapy.
• Patients must have bilirubin </= 1.5 mg/dL, transaminases < 2.5 X ULN, albumin >/= 3 gm/dL, creatinine </= 2.0 mg/dL, adequate pulmonary function by physical exam and pulse oximetry and adequate cardiac reserve (EF >/= 50% normal).
• Patients must give written informed consent prior to registration (see Informed Consent).
• Females and males must be willing to use an approved form of birth control while on this study and for 2 weeks after completion.

Exclusion Criteria:

• Failure to meet any of the inclusion criteria.
• Inability to give informed consent because of psychiatric problems, or complicated medical problems.
• Serious concurrent medical problems, uncontrolled infections, or disseminated intravascular coagulopathy (DIC).
• CNS leukemia.
• Preexisting cardiovascular disease (e.g. CHF, CAD, cardiomyopathy, myocardial infarction within past 3 months, arrhythmia) requiring ongoing treatment.
• Pregnant or nursing women will be excluded from study.
• History of congestive heart failure.
• History of cirrhosis of the liver.