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

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Brief Title

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

Official Title

A Phase II Study of A-dmDT390-bisFv(UCHT1) Fusion Protein in Patients With Cutaneous T Cell Lymphoma

Brief Summary

      This is a Phase II clinical trial aimed at treating a subgroup of patients with cutaneous
      T-cell lymphoma. The drug consists of a toxin, called diphtheria toxin, which is attached to
      an antibody that can specifically target cancerous T-cells. Our primary objectives are,
      therefore, to determine the patient subgroup with respect to disease burden who best responds
      to this experimental drug in treating CD3 positive T cell malignancies. We will be
      determining how the patient and their disease respond to this research agent.

      The Clinical Response Data analysis from October 2014 done at the completion of the Phase I
      portion of A-dmT390-bisFv(UCHT1) fusion protein clinical trial showed that there were 25
      evaluable patients who received all 8 doses varying between 2.5 and 11.25 µg/kg per dose.
      There were responses at all the lower dose levels up to 7.5 µg/kg per dose. The overall
      response rate was 36% and the complete response rate was 16% (when followed for 6 months). We
      have identified a subgroup of CTCL patients that have a very high response rate. If we
      exclude patients whose mSWAT scores never exceeded 50 (50% of skin surface area times a
      multiplier) and who never had lymph node involvement or stage III disease we are left with 9
      patients. This subgroup has an overall response rate of 89% and a complete response rate of
      50% (when followed for 6 months). Of these 4 patients currently in complete remission, three
      are long-term responders. Two are over 6 years in duration and one over 5 years duration.
      These may represent cures. The long time periods in the transition from partial response to
      complete response without treatment, 6 months to two years, suggests that the study drug in
      addition to exerting a direct killing effect on tumor also functions as an immunomodulator.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Remission status (complete, partial, stable disease, progressive disease)


Condition

T-cell Lymphomas

Intervention

A-dmDT390-bisFv(UCHT1)

Study Arms / Comparison Groups

 A-dmDT390-bisFv(UCHT1)
Description:  anti-T cell immunotoxin (antibody targeting CD3 on T-cells tagged with diptheria toxin)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

32

Start Date

January 2008

Completion Date

November 2016

Primary Completion Date

February 2015

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Arthur E Frankel, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00611208

Organization ID

FDA IND 100712


Responsible Party

Sponsor

Study Sponsor

Angimmune LLC

Collaborators

 James Graham Brown Cancer Center

Study Sponsor

Arthur E Frankel, MD, Principal Investigator, University of Texas Southwestern Medical Center


Verification Date

November 2016