A Phase Ib Study of ISF35 in Combination With Chemotherapy (FCR) in Subjects With Relapsed, Refractory, and/or 17p- CLL

Inclusion Criteria

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

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.

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.
Subjects must be age 18 years or older
For men and women of child-bearing potential, use of effective barrier contraceptive methods during the study and for one month following treatment
Subjects must have ECOG performance scale of ≤ 2

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

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

Presence of > 55% prolymphocytes or Richter's transformation
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
Ongoing toxicity from prior anti-neoplastic therapy
Untreated autoimmune hemolytic anemia or immune thrombocytopenia
Active symptomatic fungal, bacterial and/or viral infection including active HIV or viral (A, B or C) hepatitis
Positive serologies for HIV1,2 or HTLV I,II
CMV disease with positive DNA PCR
Syphilis with positive VDRL
Acute Hepatitis A and C with positive serologies, and Hepatitis B, acutely or chronically infected based on CDC criteria
Any illness or condition that in opinion of the investigator may affect safety of treatment or evaluation of any study's endpoints