A Phase I Extension Trial of Repeated Infusions of ISF35

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00783588
Recruitment Status : Completed
First Posted : October 31, 2008
Last Update Posted : October 31, 2008
Information provided by:
Memgen, LLC

Brief Summary:
The study is a Phase Ib extension trial that will assess the toxicity, tolerability, and safety of up to two repeated administrations of 1x10^8, 3x10^8, or 1x10^9 autologous Ad-ISF35-transduced CLL B cells given intravenously to patients with CLL who tolerated ISF35 in the prior Phase I infusion trial at M.D. Anderson.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Biological: ISF35 Phase 1

Detailed Description:

In a previous Phase I clinical trial at M.D. Anderson, patients with CLL received an intravenous infusion of autologous leukemia cells transduced ex vivo with an adenovirus encoding the wild-type murine CD154. This treatment was well tolerated and without dose-limiting toxicity. Patients each experienced acute reductions in the leukemia-cell blood count and in the size of enlarged lymph nodes and spleen.

The infusion induced changes in circulating bystander, non-infected CLL cells and both acute and long-term clinical responses. The changes in bystander CLL cells were similar to those observed in CLL cells following ligation of CD40, which included enhanced or de novo expression of CD54, CD80, and CD86, allowing the modified CLL cells to function more effectively in presenting antigens to autologous T cells. Following CD40 ligation, CLL cells are induced to express CD95 and DR5 and to undergo changes in expression of pro- and anti-apoptotic proteins, ultimately favoring apoptosis in the CLL cells.

To build upon these results, an extension to this trial will be completed in order to assess the tolerability of repeated infusions of ISF35 and to test whether additional administrations will enhance the anti-leukemic activity exhibited in the previous Phase I trial.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Extension Trial to Allow Repeat Dosing of Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35) in Subjects Previously Treated in MDACC Protocol 2004-0914
Study Start Date : May 2007
Actual Primary Completion Date : September 2008
Actual Study Completion Date : September 2008

Intervention Details:
    Biological: ISF35
    Subjects participating in this study will receive up to two doses of 1x10^8, 3x10^8, or 1x10^9 autologous Ad-ISF35-transduced CLL B cells, depending on the dose they received in the previous Phase I trial.
    Other Names:
    • Ad-ISF35
    • AdISF35

Primary Outcome Measures :
  1. Assess the toxicity, tolerability, and safety of the repeat administration of 1x10^8, 3x10^8, or 1x10^9 autologous Ad-ISF35-transduced CLL B cells in up to 9 patients with CLL who tolerated previous treatment in MDACC Protocol 2004-0914. [ Time Frame: Duration of the trial ]

Secondary Outcome Measures :
  1. Assess the anti-leukemia activity of the repeat administration of Ad-ISF35 transduced CLL B cells by evaluating reduction in leukemia count, reduction in adenopathy and splenomegaly, and improvement in bone marrow function. [ Time Frame: Duration of the trial ]
  2. Assess the quality of life with repeat Ad-ISF35 treatment. [ Time Frame: Two months ]
  3. Assess pharmacodynamic endpoints including induction of T cell anti-leukemia immune responses, antibody production against autologous CLL B cells, and changes in bystander leukemia cell phenotype. [ Time Frame: Two months ]

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subjects must have been enrolled and tolerated the single dose ISF35 in MDACC Protocol 2004-0914.
  2. Subjects must have adequate Ad-ISF35 transduced CLL B cells to allow for at least one additional treatment.
  3. Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. Both men and women participants must agree to use contraception for the duration of the study.
  4. Subjects must have Zubrod performance status of ≤ 2.
  5. Subjects must have adequate hematologic, renal, hepatic, and coagulation function:

    • Adequate hematologic function:

      • Platelet count ≥ 50,000/μl; AND
      • Hemoglobin ≥ 10 g/dl (may be supported by erythropoietin or transfusion).
    • Adequate renal function:

      • Serum creatinine ≤ 1.5 times upper limit of normal; OR
      • Measured creatinine clearance ≥ 40 mL/min/1.73 m^2.
    • Adequate hepatic function:

      • Total bilirubin ≤ 2.5 times upper limit of normal; AND
      • ALT ≤ 2.5 times upper limit of normal; AND
    • Adequate coagulation tests:

      • Prothrombin time international normalized ratio (INR) ≤ 2; AND
      • Partial thromboplastin time ≤ 1.66 times upper limit of normal
  6. Subjects must give written informed consent for the Phase 1B extension trial.

Exclusion Criteria:

  1. Unresolved toxicity (Grade ≥ 2) from single administration of Add-ISF35 transduced autologous CLL B cells.
  2. Presence of more than 55% prolymphocytes.
  3. Chemotherapy (e.g., purine analogues, alkylating agents, or corticosteroids), antibody therapy, immunotherapy, radiation therapy, or participation in any investigational drug treatment within 4 weeks of enrollment into protocol or at any time during the study.
  4. Ongoing toxicity from prior anti-neoplastic therapy.
  5. Prior gene therapy (EXCEPT Ad-ISF35) or allogeneic stem cell transplantation.
  6. Untreated autoimmune hemolytic anemia or immune thrombocytopenia.
  7. Active infection requiring parenteral antibiotics.
  8. HIV/HBV/HCV seropositivity.
  9. Uncompensated hypothyroidism (defined as TSH greater than 4x upper limit of normal not treated with replacement hormone).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00783588

United States, Texas
University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Memgen, LLC
Principal Investigator: William G. Wierda, M.D., Ph.D. M.D. Anderson Cancer Center

Publications of Results:
Other Publications:
Castro JE, Cantwell MJ, Prusak CE, Bole J, Wierda WG, Kipps TJ. long-term followup of chronic lymphocytic leukemia patients treated with CD40-ligand (CD154) gene therapy. Blood 2003; 102(11):491a (Abstract #1790).
Saville W, Kipps TJ, Cantwell MJ, et al. A phase II trial of immune therapy for chronic lymphocytic leukemia. Blood. 2003; 102(11 ):437a (Abstract #1592).

Responsible Party: William G. Wierda, M.D., Ph.D., M.D. Anderson Cancer Center Identifier: NCT00783588     History of Changes
Other Study ID Numbers: CLL-35-102
First Posted: October 31, 2008    Key Record Dates
Last Update Posted: October 31, 2008
Last Verified: October 2008

Keywords provided by Memgen, LLC:
Chronic lymphocytic leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Immune System Diseases
Immune therapy
Active immune therapy

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell