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

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.

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.