Non Hodgkin Lymphoma Clinical Trial
CpG-STAT3 siRNA CAS3/SS3 and Localized Radiation Therapy for the Treatment of Relapsed/Refractory B-Cell NHL
This phase I trial identifies the best dose and side effects of CpG-STAT3 siRNA CAS3/SS3 (CAS3/SS3) in combination with localized radiation therapy in treating patients with B-cell non-Hodgkin lymphoma that has come back (relapsed) or does not respond to treatment (refractory). CAS3/SS3 simultaneously targets two molecules, TLR9 receptor and STAT3. This investigational drug combines a CpG oligonucleotide and an siRNA in one molecule that act together to interfere with the ability of the cancer cells to grow. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving CAS3/SS3 with localized radiation therapy may kill more cancer cells.
I. Determine the recommended phase 2 dose (RP2D) of CAS3/SS3 when given in combination with local fixed-dose radiation therapy (RT).
II. Evaluate the safety and feasibility of intratumoral injections of CAS3/SS3 when combined with local fixed-dose RT, by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration.
I. Characterize the clinical activity (overall and per dose level) of CAS3/SS3 through the assessment of disease response, and response duration. (Clinical) II. Characterize the biologic activity (overall and per dose level) of CAS3/SS3 when combined with local fixed-dose RT by assessing. (Biologic [Immunologic Correlative Studies]) IIa. Silencing of the STAT3 gene and its key downstream genes. IIb. Local and systemic immune responses, including: evidence/extent of immune cell intratumoral infiltration, immune cell activation within the tumor and in the peripheral blood, and changes in proinflammatory mediators in plasma.
Patients undergo radiation therapy on days 1 and 2 tumor-bearing lymph node, and receive CAS3/SS3 intratumorally on days 2, 4, 16, and 18. Patients assigned to dose level 3 also receive CAS3/SS3 intratumorally on days 9, 11, 23, and 25.
After completion of study treatment, patients are followed up every 3 months.
All subjects must have the ability to understand and the willingness to sign a written informed consent
Age 18 and older
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (corresponds to Karnofsky Performance Status [KPS] of >= 70)
Life expectancy greater than 16 weeks
Relapsed/refractory disease; patients must have failed >= 2 prior systemic therapies and have no treatment options known to provide clinical benefit
Biopsy confirmed relapsed or refractory B-cell lymphoma of the following subtypes; patients with a partial response to a previous treatment are allowed.
Follicular grade 1 or 2, or 3 marginal zone or small lymphocytic lymphoma
Diffuse large B-cell lymphoma, non-germinal center B-cell like (GCB) type determined by immunohistochemistry using Han's algorithm
Mantle cell lymphoma
Patients must have at least two separate tumor sites, one of which is at least 2 cm in diameter and peripherally accessible and amenable for intratumoral injection of CAS3/SS3 with stabilization by palpation, and the other is at least 1.5 cm in diameter
Tumor specimens must be available for immunological studies either from a previous biopsy or a new biopsy obtained before the initiation of the study. Paraffin-embedded specimens are acceptable
Required wash out periods for prior therapy:
Topical therapy: 2 weeks
Chemotherapy: 4 weeks
Radiotherapy: 4 weeks
Other investigational therapy: 4 weeks
Monoclonal antibody or immunotherapy: 4 weeks
Targeted therapies: 4 weeks
Allogeneic transplant: 6 months
Absolute neutrophil count (ANC) >= 1,000/mm^3
NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
Platelets >= 75,000/mm^3
NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
Hemoglobin >= 8 g/dl
Total serum bilirubin (mg/dL): =< 1.5 x upper normal limit (ULN)
Aspartate aminotransferase (AST) < 3 x ULN without liver metastasis and < 5 x ULN with liver metastasis
Alanine aminotransferase (ALT) < 3 x ULN without liver metastasis and < 5 x ULN with liver metastasis
Adequate renal function as determined by serum creatinine =< 2.0 mg/dL or creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula
International normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN
Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
Female of childbearing potential: serum pregnancy test
Cardiac function 12-lead electrocardiogram (ECG) to confirm the absence of clinically significant arrhythmias
Left ventricular ejection fraction (LVEF) >= 45%
Oxygen saturation on room air of >= 92%
The effects of CAS3/SS3 on the developing fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
Current use of anticoagulant therapy (aspirin [ASA] =< 325 mg per day allowed) or history of significant bleeding diathesis
Treatment with corticosteroids or other systemic immunosuppressive medication (e.g., methotrexate, rapamycin) within 28 days of study treatment. Note: patients with adrenal insufficiency may take up to 7.5 mg of prednisone or equivalent daily. Topical and inhaled corticosteroids in standard doses are allowed
Patients with rapid progression of disease requiring immediate anti lymphoma therapy
Patients should not have any uncontrolled illness including ongoing or active infection
Pregnant or lactating women are excluded from this study because CAS3/SS3is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAS3/SS3, breastfeeding should be discontinued if the mother is treated with CAS3/SS3
Prior malignancy (active within 5 years of screening) except basal cell or completely excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell carcinoma of the cervix
Pre-existing autoimmune or antibody mediated disease including: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, Addison's disease, but excluding the presence of autoantibodies without clinical autoimmune disease
History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), celiac disease, or other chronic gastrointestinal conditions associated with diarrhea, or current acute colitis of any origin
History of diverticulitis (even a single episode) or evidence of diverticulitis at baseline, including evidence limited to computed tomography (CT) scan only. Note: diverticulosis is not an exclusion criterion per se
Graft versus host disease
History of uveitis
Known history of human immunodeficiency virus (HIV) with detectable viral load or patients with acquired immuno-deficiency syndrome (AIDS) are excluded
Known active or chronic viral hepatitis B or C infection
Patients with active infection or with a fever > 38.5 degrees Celsius (C) within three days prior to the first scheduled treatment
Active central nervous system (CNS) metastases
History of allergic reactions attributed to compounds of similar composition to agatolimod sodium (PF-3512676) or tremelimumab
History of allergic reactions attributed to compounds of similar chemical or biologic composition to CAS3/SS3
Significant cardiovascular disease (i.e. New York Heart Association [NYHA] >= class 3 congestive heart failure; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty within the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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