A Phase I/II Study of Intratumoral Injection of SD-101

Study Overview
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Brief Summary
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This phase 1-2 trial studies the side effects and best dose of ipilimumab in combination with toll-like receptor 9 (TLR9) agonist SD-101 and radiation therapy in treating patients with recurrent low-grade B-cell lymphoma.

Detailed Description
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Monoclonal antibodies, such as ipilimumab, may block cancer growth in different ways by targeting certain cells. Biological therapies, such as TLR9 agonist SD-101, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving ipilimumab in combination with TLR9 agonist SD-101 and radiation therapy may be a better treatment for B-cell lymphoma. Study objectives are dose-limiting toxicity (DLT) and the treatment assessments tumor response and time-to-progression. Cohort 1 dose level is 10 mg ipilimumab, subsequent cohort is 5 or 25 mg ipilimumab. If 2 out of 6 patients experience a DLT in the first cohort (10 mg ipilimumab), the dose will be de-escalated to 5 mg (Cohort -1). If 2 out of 6 patients experience a DLT at the 5 mg dose level, then the study will be stopped.

Official Title
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A Phase I/II Study of Intratumoral Injection of SD-101, an Immunostimulatory CpG, and Intratumoral Injection of Ipilimumab, an Anti-CTLA4 Monoclonal Antibody, in Combination With Local Radiation in Low-Grade B-Cell Lymphomas

Conditions
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Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma

Intervention / Treatment
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* Biological: Ipilimumab
* Drug: SD-101
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Biopsy-confirmed low-grade B-cell lymphoma, specifically, follicular grade 1 or 2, or 3A marginal zone or small lymphocytic lymphoma; patients must have relapsed from or are refractory to prior therapy Patients must have at least one site of disease that is accessible for intratumoral injection of SD-101 and of ipilimumab (diameter ≥ 10mm), percutaneously Tumor specimens must be available for immunological studies either from a previous biopsy or a new biopsy obtained before the initiation of the study Patients must have measurable disease other than the injection site or biopsy site Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 [corresponds to Karnofsky Performance Status (KPS) of ≥ 70] White blood cell count (WBC) ≥ 2000/µL (2 x 10^9/L) Absolute neutrophil count (ANC) ≥ 1000/µL (0.5 x 10^9/L) Platelets ≥ 75 x 10^3/µL (75 x 10^9/L) Hemoglobin ≥ 8 g/dL (may be transfused) Creatinine ≤ 2.0 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN for subjects without liver metastasis; ≤ 5 times for liver metastases Bilirubin ≤ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must have a total bilirubin of less than 3.0 mg/dL) No active or chronic infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C Must be at least 4 weeks since treatment with standard or investigational chemotherapy, biochemotherapy, surgery, radiation, cytokine therapy, and 8 weeks since any monoclonal antibodies or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment Patients of reproductive potential must agree to use an effective (> 90% reliability) form of contraception during the study and for 6 months following the last study drug administration Women of reproductive potential must have negative urine pregnancy test Life expectancy greater than 4 months Able to comply with the treatment schedule Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria 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 auto-antibodies without clinical autoimmune disease History of inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis), celiac disease, or other chronic gastrointestinal conditions associated with diarrhea, or current acute colitis of any origin Any history of diverticulitis, or evidence of diverticulitis at baseline, including evidence limited to computed tomography (CT) scan only (note diverticulosis is not an exclusion criterion) Severe psoriasis Active thyroiditis History of uveitis Known history of HIV; patients with Acquired Immunodeficiency Syndrome (AIDS) are excluded Patients with active infection or with a fever > 38.5 degrees C within 3 days prior to the first scheduled treatment Central nervous system (CNS) lymphoma 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 History of allergic reactions attributed to compounds of similar composition to SD-101 or ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] antibodies) Current anticoagulant therapy (EXCEPTION acetylsalicylic acid ≤ 325 mg per day allowed) Treatment with an immunosuppressive regimen of corticosteroids or other immunosuppressive medication (eg, methotrexate, rapamycin) within 30 days of study treatment; note patients with adrenal insufficiency may take up to 5 mg of prednisone or equivalent daily; topical and inhaled corticosteroids in standard doses are allowed Significant cardiovascular disease [ie, New York Heart Association (NYHA) class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias] Pregnant or lactating Any other medical history, including laboratory results, deemed by the investigator to be likely to interfere with their participation in the study, or to interfere with the interpretation of the results.

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: Treatment<br>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2. | Biological: Ipilimumab<br>* A dose of 10 mg in cohort 1 or 25mg in cohort 2 via intratumoral injection on day 2, week 1.<br>* Other names: monoclonal antibody CTLA-4;Drug: SD-101<br>* Started on day 2 week 1, then once every week x 4 successive weeks for a total of 5 injections.<br>* Other names: TLR9 agonist;Radiation: Radiation therapy<br>* Undergo low-dose radiation therapy to 1 site of disease<br>* Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week) | To determine the safety and tolerability of SD-101 (1 mg/week) and local low dose radiation plus escalating doses of subcutaneously (SC)-administered ipilimumab, the incidence of dose-limiting toxicities (DLT) will be assessed according to the following DLT definitions. Related adverse events (AEs) are toxicities. Treatment includes radiation therapy. Grade 4 treatment-related AE Any drug-related AE ≥ Grade 3, including injection site reaction ≥ Grade 3 treatment-related clinical autoimmune reaction involving major organs (defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow, eye, or central nervous system) which does not resolve to baseline or Grade 1 within 6 weeks Treatment-related AE ≥ Grade 3 that persists despite adequate/maximal medical therapy and/or prophylaxis, EXCEPT Treatment-related skin rash ≤ Grade 3, that does not require systemic steroid therapy or other immunosuppressive therapy OR Grade 3 flu-like AEs Uveitis ≥ Grade 2 | Up to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Tumor response was assessed per the Cheson Criteria for low-grade B-cell lymphomas. Complete Response (CR) - No evidence disease. Partial Response (PR) - Regression of measurable disease with no new sites Progressive Disease (PD) - Any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir. Stable Disease (SD) - Any status that is not CR; PR; or PD. See references (Cheson BD, et al. J Clin Oncol. Apr 1999;17(4):1244. PubMed ID 10561185. | Up to 2 years | 
| Median Time to Progression (TTP) | Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir. | Up to 2 years |