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A Phase 1b Study of Repeated Doses of Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35) in Combination With Fludarabine, Cyclophosphamide and Rituximab (FCR) in Subjects With Chronic Lymphocytic Leukemia (CLL)

Phase 1
18 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia

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Trial Information

A Phase 1b Study of Repeated Doses of Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35) in Combination With Fludarabine, Cyclophosphamide and Rituximab (FCR) in Subjects With Chronic Lymphocytic Leukemia (CLL)

ISF35 has already been used in two Phase I clinical trials. The trials demonstrated that
ISF35 treatment is well tolerated and patients did not experience any significant or
unexpected adverse events. Patients reported flu-like symptoms from ISF35, which disappeared
within one to three days.

The trials also showed that ISF35 stimulates the immune system to act against CLL cells and
sensitize leukemic cells to subsequent treatment. Repeat infusions of ISF35 administered as
a single agent to subjects with CLL resulted in durable reductions in circulating and
lymph-node bound leukemic cells. Furthermore, CLL patients with 17p deletion responded to
standard courses of FCR after receiving ISF35 and achieved durable remissions.

ISF35 is an abbreviation for Immune Stimulatory Factor 35, an offspring of technology
discovered by Dr. Thomas J. Kipps, MD, PhD, Professor, Department of Medicine and Deputy
Director for Research,UCSD Moores Cancer Center.

Inclusion Criteria

Inclusion Criteria

1. Subjects must have a diagnosis of B cell CLL including:

- Lymphocytosis of monoclonal B-cells co-expressing ≥ one B-cell marker (CD19,
CD20, or CD23) and CD5 in peripheral blood or lymph node AND

- Bone marrow with ≥ 30% mononuclear cells having the CLL/SLL phenotype

2. Measurable disease, and at least one of the IWCLL 2008 Guidelines "Indications for
Treatment" as follows:

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia.

- Massive (i.e., >6 cm below the left costal margin) or progressive or
asymptomatic splenomegaly.

- Massive nodes (i.e., >10 cm in longest diameter) or progressive or symptomatic

- Progressive lymphocytosis with an increase of >50% over a 2-month period, or
lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by
linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at
intervals of two weeks over an observation period of 2-3 months; patients with
initial blood lymphocyte counts of less than 30,000 per microliter may require a
longer observation period to determine the LDT. Also, factors contributing to
lymphocytosis or lymphadenopathy other than CLL (e.g, infections) should be

- Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids
or other standard therapy.

- A minimum of any one of the following disease-related symptoms must be present:

- Unintentional weight loss ≥10% within the previous 6 months.

- Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform
usual activities).

- Fevers of greater than 100.5 degrees F or 38.0 degrees C for 2 or more weeks
without other evidence of infection.

- Night sweats for more than 1 month without evidence of infection.
Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia does not by
itself constitute a basis to initiate treatment.

3. Subjects must have CLL that is documented to be resistant or refractory to standard
chemotherapy regimens containing alkylating agents and/or purine analogues.
Chemotherapy refractory or resistant is defined as the following:

- CLL progression during treatment (2 cycles) with chemotherapy; OR

- Failure to achieve a PR or CR after at least 2 cycles of chemotherapy; OR

- No response to treatment or stable disease after at least 2 cycles of
chemotherapy; OR

- Disease progression within 6 months of treatment with chemotherapy; OR

- CLL with cytogenetic changes documenting the loss of the short arm of chromosome
17 (17p-) associated with the loss of p53.

4. Subjects must be age 18 years or older

5. For men and women of child-bearing potential, use of effective barrier
contraceptive methods during the study and for one month following treatment

6. Subjects must have ECOG performance scale of ≤ 2

7. Subjects must have adequate hematologic, renal, hepatic, and coagulation function
defined as:

• Adequate hematologic function:

i) Platelet count ≥ 50,000/µL; AND

ii) Hemoglobin ≥ 10 g/dL (may be supported by erythropoietin or transfusion); AND

• Adequate renal function:

i) Calculated creatinine clearance ≥ 30 mL/min/1.73 m^2; OR

ii) Serum creatinine ≤ 2 times upper limit of normal; AND

• Adequate hepatic function:

i) Total bilirubin ≤ 2.5 times upper limit of normal; AND

ii) ALT ≤ 2.5 times upper limit of normal; AND

• Adequate coagulation tests:

i) Prothrombin time international normalized ratio (INR) ≤ 1.5; AND

ii) Partial thromboplastin time ≤ 1.5 times upper limit of normal

8. Ability to understand the requirements of the study, provide written informed consent
and authorization of use and disclosure of protected health information, and agree to
abide by the study restrictions and return for the required assessments

Exclusion Criteria

1. Presence of > 55% prolymphocytes or Richter's transformation

2. 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

3. Ongoing toxicity from prior anti-neoplastic therapy

4. Untreated autoimmune hemolytic anemia or immune thrombocytopenia

5. Active symptomatic fungal, bacterial and/or viral infection including active HIV or
viral (A, B or C) hepatitis

6. Positive serologies for HIV1,2 or HTLV I,II

7. CMV disease with positive DNA PCR

8. Syphilis with positive VDRL

9. Acute Hepatitis A and C with positive serologies, and Hepatitis B, acutely or
chronically infected based on CDC criteria

10. Any illness or condition that in opinion of the investigator may affect safety of
treatment or evaluation of any study's endpoints

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Assess toxicity, tolerability, and safety of repeat administration of three infusions of 3x10^8 ISF35 given intravenously in combination with a standard course of three treatments of fludarabine, rituximab and cyclophosphamide (FCR).

Outcome Time Frame:

Duration of the Trial

Safety Issue:


Principal Investigator

Januario Castro, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistant Clinical Professor in the Blood and Marrow Transplantation Division


United States: Food and Drug Administration

Study ID:




Start Date:

September 2008

Completion Date:

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Chronic lymphocytic leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, B-Cell
  • Immune System Diseases
  • Rituximab
  • Fludarabine
  • Cyclophosphamide
  • ISF35
  • Ad-ISF35
  • Refractory
  • Resistant
  • 17p-
  • del 17p
  • 17p
  • Resistant CLL
  • Refractory CLL
  • 17p- CLL
  • CLL
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



University of California, San Diego Moores Cancer Center San Diego, California  92093