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

Safety and Effectiveness of A-dmDT390-bisFv(UCHT1) Fusion Protein (Resimmune®) in Subjects With Mycosis Fungoides: A Phase II Multi-center Randomized Clinical Trial

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.

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).