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

Sponsor
Robert Lowsky (Other)
Overall Status
Completed
CT.gov ID
NCT02254772
Collaborator
National Cancer Institute (NCI) (NIH)
9
1
1
28.8
0.3

Study Details

Study Description

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.

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.

Study Design

Study Type:
Interventional
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 :
Sep 1, 2014
Actual Primary Completion Date :
Nov 10, 2016
Actual Study Completion Date :
Jan 26, 2017

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week) [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 [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) [Up to 2 years]

      Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    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 103/µL (75 x 109/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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Stanford University Hospitals and Clinics Stanford California United States 94305

    Sponsors and Collaborators

    • Robert Lowsky
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Ronald Levy, MD, Stanford University Hospitals and Clinics

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Robert Lowsky, Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT02254772
    Other Study ID Numbers:
    • IRB-31133
    • NCI-2014-01978
    • LYMNHL0119
    • 5R01CA188005-02
    First Posted:
    Oct 2, 2014
    Last Update Posted:
    Nov 27, 2019
    Last Verified:
    Feb 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    Period Title: Overall Study
    STARTED 9
    COMPLETED 7
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    Overall Participants 9
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    3
    33.3%
    >=65 years
    6
    66.7%
    Sex: Female, Male (Count of Participants)
    Female
    5
    55.6%
    Male
    4
    44.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    11.1%
    Not Hispanic or Latino
    8
    88.9%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    11.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    7
    77.8%
    White
    0
    0%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    11.1%

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    Only the starting dose level of 10 mg ipilimumab plus SD-101 (1 mg/week) was evaluated. The dose level of ipilimumab could not be escalated due to inability to obtain a higher concentration of ipilimumab.
    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    Measure Participants 7
    Number [Dose-limiting toxicity events]
    0
    2. Secondary Outcome
    Title Tumor Response
    Description 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.
    Time Frame Up to 2 years

    Outcome Measure Data

    Analysis Population Description
    Note that 1 participants initially experienced a partial response (PR), but later had progressive disease (PD).
    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    Measure Participants 7
    Complete Response (CR)
    0
    0%
    Partial Response (PR)
    1
    11.1%
    Stable Disease (SD)
    1
    11.1%
    Progressive Disease (PD)
    6
    66.7%
    3. Secondary Outcome
    Title Median Time to Progression (TTP)
    Description Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.
    Time Frame Up to 2 years

    Outcome Measure Data

    Analysis Population Description
    1 participant had stable disease, but did not provide a final follow-up at 2 years.
    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    Measure Participants 6
    Median (Full Range) [Months]
    3.33

    Adverse Events

    Time Frame 2 years
    Adverse Event Reporting Description
    Arm/Group Title Treatment (SD-101 + Ipilimumab + Radiation)
    Arm/Group Description Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
    All Cause Mortality
    Treatment (SD-101 + Ipilimumab + Radiation)
    Affected / at Risk (%) # Events
    Total 1/9 (11.1%)
    Serious Adverse Events
    Treatment (SD-101 + Ipilimumab + Radiation)
    Affected / at Risk (%) # Events
    Total 1/9 (11.1%)
    Infections and infestations
    Neutropenia 1/9 (11.1%) 1
    Sepsis 1/9 (11.1%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (SD-101 + Ipilimumab + Radiation)
    Affected / at Risk (%) # Events
    Total 9/9 (100%)
    Blood and lymphatic system disorders
    Pancytopenia 1/9 (11.1%) 1
    Anemia 1/9 (11.1%) 1
    Gastrointestinal disorders
    Nausea 1/9 (11.1%) 1
    Diarrhea 1/9 (11.1%) 1
    Bloating 2/9 (22.2%) 2
    Dysphagia 1/9 (11.1%) 1
    General disorders
    Fatigue 9/9 (100%) 13
    Fever 5/9 (55.6%) 5
    Injection site reaction 5/9 (55.6%) 5
    Swelling 3/9 (33.3%) 3
    Chills 4/9 (44.4%) 4
    Flu Like Symptoms 1/9 (11.1%) 1
    Malaise 1/9 (11.1%) 1
    Infections and infestations
    Neutropenia 1/9 (11.1%) 1
    Injury, poisoning and procedural complications
    Bruising 3/9 (33.3%) 3
    Investigations
    Increased Creatinine 1/9 (11.1%) 1
    Metabolism and nutrition disorders
    Anorexia 1/9 (11.1%) 1
    Musculoskeletal and connective tissue disorders
    Myalgia 9/9 (100%) 10
    Arthralgia 9/9 (100%) 9
    Back pain 1/9 (11.1%) 1
    Nervous system disorders
    Headache 9/9 (100%) 11
    Reproductive system and breast disorders
    Cough 3/9 (33.3%) 3
    Respiratory, thoracic and mediastinal disorders
    Nasal Congestion 3/9 (33.3%) 3
    Dyspnea 1/9 (11.1%) 1
    Skin and subcutaneous tissue disorders
    Induration 2/9 (22.2%) 2
    Rash 3/9 (33.3%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Ronald Levy, MD, Professor of Medicine
    Organization Stanford Univeristy Medical Center
    Phone 650-725-6452
    Email levy@stanford.edu
    Responsible Party:
    Robert Lowsky, Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT02254772
    Other Study ID Numbers:
    • IRB-31133
    • NCI-2014-01978
    • LYMNHL0119
    • 5R01CA188005-02
    First Posted:
    Oct 2, 2014
    Last Update Posted:
    Nov 27, 2019
    Last Verified:
    Feb 1, 2017