Study of Repeat Intranodal Injections of Ad-ISF35

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Repeat Intranodal Injections of Adenovirus-CD154 (Ad-ISF35) in Patients With Non-Hodgkin's Lymphoma (Follicular, Diffuse Large Cell, Mantle Cell and Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia)

Conditions
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Non-Hodgkin's Lymphoma, Follicular Lymphoma, Diffuse Large Cell Lymphoma, Mantle Cell Lymphoma, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: ISF35


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SLL / CLL PATIENTS 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. 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. Intermediate or High risk, poor prognosis SLL / CLL 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 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. Stage III or IV disease at any time in the past (Ann Arbor Staging System for Non-Hodgkin's Lymphomas). 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 Males and females 18 years of age and older 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 ECOG Performance Status ≤ 2 Anticipated survival of at least 3 months For men and women of child-producing potential, use of effective barrier contraceptive methods during the study and for one month following treatment. 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. 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.). Subjects must give written informed consent to participate in this trial. Exclusion Criteria: Pregnant or nursing women Treatment with chemotherapy or monoclonal antibody within 28 days prior to entering the study. Treatment with chemotherapy or monoclonal antibody during the time of participation in this trial. Grade 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, COPD). 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). Evidence of aggressive or highly aggressive lymphoma or Richter's transformation based on WHO/REAL classification criteria[1] Any T cell lymphoma. 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. Active symptomatic fungal, bacterial and/or viral infection including active HIV or viral (A, B or C) hepatitis. Any illness or condition that in the opinion of the Investigator may affect safety of treatment or evaluation of any the study's endpoints.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ad-ISF35<br>Ad-ISF35, intranodal injection, 3.3 x 10^10 ISF35 viral particles, every 2-4 weeks up to six total injections. | Biological: ISF35<br>* Subjects participating in this study 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate |  | 2 Years |