The study is a Phase 1b open label, non-randomized, single institution clinical trial that is designed to evaluate the safety and tolerability of three repeat infusions of ISF35 followed by a standard regimen of three cycles of fludarabine, cyclophosphamide and rituximab (FCR) in subjects with refractory, resistant, and/or 17p- 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

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 lymphadenopathy.
   • 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 excluded.
   • 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