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

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ClinicalTrials.gov Identifier: NCT02254772
Recruitment Status : Completed
First Posted : October 2, 2014
Results First Posted : September 29, 2017
Last Update Posted : November 27, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Robert Lowsky, Stanford University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Biological: Ipilimumab Drug: SD-101 Radiation: Radiation therapy Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : September 2014
Actual Primary Completion Date : November 10, 2016
Actual Study Completion Date : January 26, 2017

Arm Intervention/treatment
Experimental: Treatment
Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
Biological: Ipilimumab
A dose of 10 mg in cohort 1 or 25mg in cohort 2 via intratumoral injection on day 2, week 1.
Other Names:
  • Yervoy
  • MDX-010
  • MDX-CTLA-4
  • monoclonal antibody CTLA-4

Drug: SD-101
Started on day 2 week 1, then once every week x 4 successive weeks for a total of 5 injections.
Other Names:
  • ISS-ODN SD-101
  • TLR9 agonist

Radiation: Radiation therapy
Undergo low-dose radiation therapy to 1 site of disease
Other Names:
  • Irradiation
  • Radiotherapy

Primary Outcome Measures :
  1. Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week) [ Time Frame: Up to 10 weeks ]

    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

Secondary Outcome Measures :
  1. Tumor Response [ Time Frame: Up to 2 years ]

    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.

  2. Median Time to Progression (TTP) [ Time Frame: Up to 2 years ]
    Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02254772

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United States, California
Stanford University Hospitals and Clinics
Stanford, California, United States, 94305
Sponsors and Collaborators
Robert Lowsky
National Cancer Institute (NCI)
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Principal Investigator: Ronald Levy, MD Stanford University Hospitals and Clinics
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Robert Lowsky, Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT02254772    
Other Study ID Numbers: IRB-31133
NCI-2014-01978 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
LYMNHL0119 ( Other Identifier: OnCore number )
5R01CA188005-02 ( U.S. NIH Grant/Contract )
First Posted: October 2, 2014    Key Record Dates
Results First Posted: September 29, 2017
Last Update Posted: November 27, 2019
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma, Follicular
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Leukemia, Lymphoid
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action