Safety and Effectiveness of A-dmDT390-bisFv(UCHT1) Fusion Protein in Subjects With Mycosis Fungoides

This study evaluates the effectiveness - as judged by complete response - of a single four-day treatment with the fusion protein A-dmDT390-bisFv(UCHT1) compared to oral Zolinza (Vorinostat), in a randomized 2-arm trial after a maximum of 12 months of treatment. Patient eligibility is stage IB/IIB mycosis fungoides with mSWAT \< 50 who have never had lymphoid disease or a prior bone marrow / HSCT transplant.

Primary Objective: This study objective is to document the incidence of complete responses compared to oral vorinostat, in a randomized 2-arm trial after a maximum of 12 months of treatment for subjects with stage IB/IIB mycosis fungoides with mSWAT \< 50 who have never had lymphoid disease or a prior bone marrow / HSCT transplant.

Secondary Objective: To further explore the toxicity profile of A-dmDT390-bisFv(UCHT1) fusion protein for subjects with mycosis fungoides who have been selected to be free from preexisting cardiac disease and never treated with Campath.

Number of Subjects: Lead-in Dosing: 12 / Randomized: 162

Patients will receive full supportive care during the course of the study. Participation in the study will require IV infusions of the research agent 2 times a day for four days (protocol FDA outpatient approved), as well as frequent outpatient 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.

Eligibility Criteria:
Inclusion Criteria:

* Subjects must have signed the current IRB approved informed consent prior to registration (see Informed Consent).
* Mycosis fungoides, confirmed by biopsy or flow cytometry, without large cell transformation.
* Relapse or progression after 2 or more systemic therapies. Note: Total electron beam therapy can be counted as a systemic therapy.
* Disease stage as follows:

  * Stage IB with no lymph node involvement including lymphadenopathy with mSWAT \<50;
  * Stage IIB with no lymph node involvement including lymphadenopathy with mSWAT \<50.
* Age 18 years.
* Subjects must have a performance status of \< 2 on Eastern Cooperative Oncology Group scale (see Appendix A).
* Subjects must have normal lung function evaluated by pulse oximetry with O2 saturation values between 95-100%.
* Subjects must have fully recovered from toxicity of prior chemotherapy or radiation therapy.
* Subjects must have:

  * bilirubin \< 1.5 mg/dL,
  * transaminases \< 2.5 X ULN,
  * albumin \> 3 gm/dL,
  * creatinine \< 2.0 mg/dL.
  * Subjects who have had albumin \< 3 gm/dL boosted by an albumin infusion must be observed to maintain albumin at \> 3gm dL for 14 days without an additional infusion.
* Subjects must have a normal echocardiogram (EF \> 50% normal) without any evidence of cardiac chamber hypertrophy, dilatation or hypokinesis.
* Females and males must be willing to use an approved form of birth control while on this study and for 2 weeks after completion.
* Subjects must have a pretreatment anti-DT titer of 20 μg/ml or less. Subjects with titers between 21 and 35 μg/ml will have an additional anti-DT neutralization test using subject's serum and A-dmDT390-bisFv(UCHT1). If neutralization is not found these titers will be considered acceptable.

Exclusion Criteria:

* Failure to meet any of the criteria.
* 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. Subjects receiving a beta-blocker for hypertension should be converted to another antihypertensive drug class 2-3 weeks before receiving the study drug to prevent a drug-drug interaction reactive tachycardia. Angiotensin inhibitors, angiotensin receptor blockers and calcium channel blockers are all acceptable. 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 subjects 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.
* 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.
* 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.
* Prior history of bone marrow transplant or HSCT is an exclusion.
* Prior treatment with vorinostat (Prior treatment with vorinostat for lead-in dosing arm is acceptable).