A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients With Cutaneous T-Cell Lymphoma (CTCL)

The purpose of this study is to further evaluate the clinical responses including response
rate and duration and correlate with patient disease stage, tumor burden, anti-DT titer and
degree of T cell depletion induced by A-dmDT390-bisFv(UCHT1) fusion protein for patients
with surface CD3+ malignant diseases. The secondary objective is to further explore the
toxicity profile of A-dmDT390-bisFv(UCHT1) fusion protein for a high-response subgroup of
patients with CTCL whose disease stage has not progressed beyond stage IB/IIB with mSWAT <
50%. 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. Treatment will consist of one 4 day cycle consisting of 2
daily infusions for a total of 8 treatments given on an outpatient basis. Patients will be
monitored until day 14 for signs of late drug toxicity by a daily phone call from their
health care provider. Subjects will be instructed on how to monitor their own blood pressure
at home and encouraged to measure and chart their daily weights that they can report to
their health care provider. Off-treatment follow-up will be based upon response. Patients
who experience a partial or complete remission who later relapse can receive radiation
treatment of new lesions and remain on study as this course is typical of responses to an
immunomodulating drug. Patients will have a follow-up visit and testing on day 37. 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. To
accommodate patients, we are offering a travel reimbursement program. Due to the 4 days of
consecutive infusions, we will reimburse the expense the patient would incur to travel to
the participating institution for treatment.

Objectives:

1. Evaluate the overall clinical responses including response rate and duration in a
larger group of CTCL high-response patients to see if is higher than current therapies
(>49%).

2. Determine the complete response rate and duration of response of A-dmDT390-bisFv(UCHT1)
fusion protein in a larger group of CTCL high-response patients to see if is higher
than current therapies (>20%).

3. Further define toxicities of A-dmDT390-bisFv(UCHT1) regimen in patients with CTCL who
have been selected to be free from preexisting cardiac disease and never treated with
Campath.

4. Determine if correlations exist between disease stage, tumor burden, anti-DT titer and
degree of T cell depletion and response rate and response duration.

Inclusion Criteria:

- Patients must have signed the current Institutional Review Board (IRB) approved
informed consent prior to registration (see Informed Consent).

- All patients must have CTCL diagnosed by morphologic, histochemical or cell surface
marker criteria with stage never exceeding IB / IIB disease and mSWAT < 50%. 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 bone marrow involvement but without
lymph node involvement are eligible. Patients with a diagnosis of angioimmunoblastic
T cell lymphoma are eligible, even with lymph node involvement. Age ≥ 18 years.
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. Patients who have had albumin < 3 gm/dL boosted by an
albumin infusion must be observed to maintain albumin at > 3gm dL for 30 days without
an additional infusion.

- Patients must have a normal echocardiogram (EF > 50% normal) without any evidence of
cardiac chamber hypertrophy, dilatation or hypokinesis. The Sponsor must be provided
with copies of these tests BEFORE Sponsor will approve enrollment. In addition, the
sponsor must receive a list of current medications taken by the patient before
Sponsor will approve enrollment.

- 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 criteria set forth in Section 3.1.

- Inability to give informed consent because of psychiatric problems, or complicated
medical problems.

- Allergic to diphtheria toxin a component of the study drug A-dmDT390-bisFv(UCHT1).

- Serious concurrent medical problems, uncontrolled infections, or disseminated
intravascular coagulopathy (DIC), hepatic cirrhosis, or chronic kidney disease.

- CNS leukemia.

- Preexisting cardiovascular disease. The only exception being well controlled
essential hypertension with a sitting blood pressure (B.P.) of < 160 systolic and <
90 diastolic without any evidence of structural heart disease or one episode of
myocardial infarction > 8 months ago. A past history of any of the following
conditions is considered as exclusions to study participation:

- Congestive heart failure,

- Atrial fibrillation,

- Pulmonary hypertension,

- Anticoagulant drug therapy,

- Thromboembolic events,

- Cardiomyopathy or a myocardial infarction within the past 8 months.

- The PI and the Clinical Coordinator will be asked to verify that their referred
patients do not have these exclusionary histories listed in 3.2 and a copy of
this verification must be sent to the Sponsor before the Sponsor will approve of
enrollment. Referring physicians will not need to sign. (Template for
verification letter Appendix C).

- Pregnant or nursing women will be excluded from study.

- History of cirrhosis of the liver based on the Child-Pugh score of Class B or C are
not eligible to participate. (Appendix B.)

- Prior treatment with alemtuzumab (Campath) or similar agents or procedures that
depress blood T cell counts to below 50% of the lower limit of normal.