Study of Repeat Intranodal Injections of Ad-ISF35
Study of Repeat Intranodal Injections of Ad-ISF35
This is a Phase II, open label, fixed dose, repeat injection, single institution study.
 Eligible subjects will receive up to six doses of Ad-ISF35 injected directly into a selected
 lymph node under ultrasound guidance. The primary goal is to determine and monitor clinical
 and biological responses in patients treated with repeat intranodal injections of Ad-ISF35.
This is a phase II clinical trial in which study subjects will be treated with multiple doses
 of Ad-ISF35 given via intranodal injection using a fixed dose of 3.3 x 10^10 ISF35 viral
 particles. Intranodal injections will be administered every 2-4 weeks up to six total
 injections.

 This will be the first time that repeat administration of Ad-ISF35 will be performed via
 intranodal injection in subjects with a diagnosis other than CLL/SLL. Therefore, in order to
 allow sufficient time to evaluate the safety and toxicity of this procedure in non-CLL/SLL
 patients, we will treat the first three non-CLL/SLL subjects with inpatient admission for 24
 hours observation at the GCRC-UCSD. If no serious adverse events are observed in these first
 three patients after they have received their first two injections of ISF35 and have been
 observed for at least 28 days, then we will proceed with enrollment of cohorts of four
 subjects per month. This will be done at one week intervals until study enrollment is
 completed. These subjects will be treated as outpatients at the GCRC and observed for 3 hours
 prior to discharge.

 All subjects with a diagnosis of CLL or SLL will be treated as outpatients at the GCRC and
 observed for 3 hours prior to discharge. These subjects will not need to be treated in an
 inpatient setting, based on our previous clinical experience with subjects enrolled on the
 phase II study of repeat intranodal injections of Ad-ISF35 in CLL/SLL

 ISF35 has already been used in 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.

 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:

 SLL / CLL PATIENTS

 1. Diagnosis of B-cell SLL/ 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 SLL / CLL phenotype.

 2. Presence of at least ONE single accessible AND palpable lymph node in the cervical,
 supraclavicular, axillary, or inguinal regions. The size of the lymph nodes must be
 larger than 2x2 cm in the horizontal and perpendicular axes.

 3. Intermediate or High risk, poor prognosis SLL / CLL

 4. Indication for treatment as defined by the NCI Working Group Guidelines:

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

 -  Massive lymph nodes or nodal clusters (i.e. > 10 cm in longest diameter), or
 progressive lymphadenopathy OR

 -  Grade 2 or 3 fatigue OR

 -  Fever ≥ 100.5˚F or night sweats for greater than 2 weeks without documented
 infection OR

 -  Presence of weight loss ≥ 10% over the preceding 6 months OR

 -  Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or an
 anticipated doubling time of less than 6 months.

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

 -  Autoimmune anemia and / or thrombocytopenia poorly responsive to corticosteroid
 therapy.

 NHL PATIENTS

 5. Non-Hodgkin's Lymphoma patients that have received at least one prior treatment
 (Antibodies and / or chemotherapy). Patients must have one of the following subtypes
 according to the WHO/REAL Classification[1]: follicular lymphoma, diffuse large cell
 lymphoma, mantle cell lymphoma and small lymphocytic lymphoma / chronic lymphocytic
 lymphoma.

 6. Stage III or IV disease at any time in the past (Ann Arbor Staging System for
 Non-Hodgkin's Lymphomas).

 7. Presence of at least ONE single accessible AND palpable lymph node in the cervical,
 supraclavicular, axillary, or inguinal regions. The size of the lymph nodes must be
 larger than 2x2 cm in the horizontal and perpendicular axes.

 ALL PATIENTS

 8. Males and females 18 years of age and older

 9. Laboratory parameters as specified below:

 -  Hematologic: Hemoglobin ≥ 10 g/dL (may be post-transfusion); platelet count ≥ 50
 x103/mm3

 -  Hepatic: Total Bilirubin < 2 X ULN, and ALT and AST < 2 x ULN

 -  Renal: Creatinine ≤ 2 X ULN

 10. ECOG Performance Status ≤ 2

 11. Anticipated survival of at least 3 months

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

 13. 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.

 14. Negative test results for current/active infection with HIV-1, HIV-2, HTV-1, HTLV-2,
 hepatitis A, B, C within 30 days of registration. (Antibody, antigen and nucleic acid
 tests acceptable, depending on institutional standards.).

 15. Subjects must give written informed consent to participate in this trial.

 Exclusion Criteria:

 1. Pregnant or nursing women

 2. Treatment with chemotherapy or monoclonal antibody within 28 days prior to entering
 the study.

 3. Treatment with chemotherapy or monoclonal antibody during the time of participation in
 this trial.

 4. Grade 3 or 4 cardiac disease as defined by the New York Heart Association Functional
 Classification

 5. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of
 breath, COPD).

 6. Participation in any investigational drug study within 28 days prior to ISF35
 administration. (Patient must have recovered from all acute effects of previously
 administered investigational agents).

 7. Evidence of aggressive or highly aggressive lymphoma or Richter's transformation based
 on WHO/REAL classification criteria[1]

 8. Any T cell lymphoma.

 9. History of malignancy other than NHL or SLL/CLL or within five years of registration,
 except patients with adequately treated basal, squamous cell carcinoma or localized
 cervical cancer.

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

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