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TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas

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ClinicalTrials.gov Identifier: NCT03410901
Recruitment Status : Recruiting
First Posted : January 25, 2018
Last Update Posted : April 20, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Ronald Levy, Stanford University

Brief Summary:
This phase I trial studies the side effects and best dose of the anti-OX40 antibody BMS-986178 when given together with the TLR9 agonist SD-101 and radiation therapy in treating patients with low-grade B-cell Non-Hodgkin lymphomas. TLR9 agonist SD-101 may stimulate the immune system in different ways and stop cancer cells from growing. Anti-OX40 antibody is a monoclonal antibody that enhances the activation of T cells, immune cells that are important for fighting tumors Radiation therapy uses high energy x-rays to kill cancer cells and may make them more easily detected by the immune system. Giving TLR9 agonist SD-101 together with anti-OX40 antibody BMS 986178 and radiation therapy may work better in treating patients with low-grade B-cell non-hodgkin lymphomas.

Condition or disease Intervention/treatment Phase
B-Cell Non-Hodgkin Lymphoma Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma Small Lymphocytic Lymphoma Biological: Anti-OX40 Antibody BMS 986178 Other: Laboratory Biomarker Analysis Radiation: Radiation Therapy Drug: TLR9 Agonist SD-101 Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of TLR9 agonist SD-101 (SD-101) in combination with anti-OX40 antibody BMS 986178 (BMS-986178) and local low-dose radiation in patients with low-grade B-cell lymphoma. Adverse events and grades to be assessed by Common Terminology Criteria for Adverse Events (CTCAE) II. To determine the recommended phase 2 dose (RP2D) of BMS-986178 in combination with intratumoral SD-101 and radiation in patients with low-grade B-cell lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate preliminary efficacy by assessing overall response rate and progression-free survival after treatment with intratumoral SD-101 in combination with BMS-986178 and radiation in patients with low-grade B-cell lymphoma.

OUTLINE: This is a phase I study of the combination of TLR9 agonist SD-101, anti-OX40 antibody BMS 986178, and local low-dose radiation therapy.

Patients receive radiation therapy on days 1-2, TLR9 agonist SD-101 intratumorally on days 2, 9, 16, 23, and 30, and anti-OX40 antibody BMS-986178 intravenously (IV) on days 3, 30, 58, 86, 114, and 142 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 72 weeks.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intratumoral Injection of SD-101, an Immunostimulatory CpG, in Combination With BMS-986178 and Local Radiation in Low-Grade B-Cell Lymphomas
Actual Study Start Date : April 9, 2018
Estimated Primary Completion Date : October 9, 2020
Estimated Study Completion Date : October 9, 2020


Arm Intervention/treatment
Experimental: Treatment (radiation therapy, SD-101, BMS-986178)
Patients receive radiation therapy on days 1-2, TLR9 agonist SD-101 and anti-OX40 antibody BMS-986178 intratumorally on days 2, 9, 16, 23, and 30, and anti-OX40 antibody BMS-986178 IV on days 2, 30, 58, 86, 114, and 142 in the absence of disease progression or unacceptable toxicity.
Biological: Anti-OX40 Antibody BMS 986178
Given IV, intratumoral
Other Names:
  • BMS 986178
  • BMS-986178

Other: Laboratory Biomarker Analysis
Correlative studies

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • RADIATION
  • Radiotherapeutics
  • radiotherapy
  • RT
  • Therapy, Radiation

Drug: TLR9 Agonist SD-101
Given intratumorally
Other Names:
  • ISS-ODN SD-101
  • SD-101




Primary Outcome Measures :
  1. Number of participants experiencing Dose-limiting Toxicities (DLT) within 8 weeks of treatment initiation [ Time Frame: Up to 8 weeks ]

    Dose-limiting toxicities (DLTs) as assessed as the following hematologic toxicities (grades per CTCAE) in all participants receiving at least 1 intratumoral (IT) injection of SD-101 and at least 1 dose of BMS-986178 (not including events due to disease progression or definitively unrelated to study drugs):

    • Febrile neutropenia
    • Thrombocytopenia Grade 4 or Grade 3 with bleeding or platelet transfusion
    • Anemia Grade 4
    • Non-hematological toxicity ≥ grade 3, except:

      • Alopecia controlled by medical management
      • Nausea controlled by medical management
      • Grade 3 or 4 electrolyte abnormalities not associated with adverse events, persist < 72 hours, and either spontaneously resolve or respond to intervention.
      • Grade 3 or 4 elevation of amylase or lipase not associated with pancreatitis
      • Grade 3 endocrinopathy
      • Grade 3 infusion reaction returning to ≤ Grade 1 in < 6 hours
      • Grade 3 skin rash not requiring systemic steroid or other immunosuppressive therapy


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Up to 96 weeks ]

    Overall Response Rate (ORR), assessed as the sum of the complete response (CR) and partial response (PR) rates, as determined by computed tomography (CT) or positron emission tomography (PET)/CT and evaluated per the Lugano classification for low-grade B-cell lymphomas, in all participants receiving at least 1 intratumoral (IT) injection of SD-101 and at least 1 dose of BMS-986178.

    Lugano classification:

    • CR: No detectable disease by CT or PET/CT scan
    • PR: ≥ 50% decrease in size of target lesions
    • No response (NR) / Stable disease (SD): < 50% decrease in size of target lesions
    • Progressive disease (PD): Target lesions larger; clear progression of non-target lesions; or new tumor lesions; new or recurrent bone marrow involvement; splenomegaly + 2 cm or +50%.

    Reported for 24, 48, 72 and 96 weeks.


  2. Progression-Free Survival (PFS) [ Time Frame: up to 96 weeks ]

    Progression-free survival (PFS) as determined for all participants receiving at least 1 intratumoral (IT) injection of SD-101 and at least 1 dose of BMS-986178, from start of treatment to disease progression per the Lugano classification or death from any cause, through 96 weeks. Progression assessed per the Lugano classification. Patients who were last known to be alive and progression-free will be censored at the latest disease assessment.

    Lugano classification:

    • CR: No detectable disease by CT or PET/CT scan
    • PR: ≥ 50% decrease in size of target lesions
    • No response (NR) / Stable disease (SD): < 50% decrease in size of target lesions
    • Progressive disease (PD): Target lesions larger; clear progression of non-target lesions; or new tumor lesions; new or recurrent bone marrow involvement; splenomegaly + 2 cm or +50%.

    Reported for 24, 48, 72 and 96 weeks.




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

Inclusion Criteria:

  • Biopsy confirmed low-grade B-cell lymphoma, excluding gastric MALT lymphoma, high-risk mantle cell lymphoma, and currently transformed lymphoma
  • Patients must have at least one site of disease (cervical, axillary, inguinal, or subcutaneous) that is accessible for intratumoral injection of SD-101 (diameter ≥10mm) percutaneously and presents a low risk for complications from direct injections.
  • Patients must have at least one site of measurable disease, other than the injection site, which is not included in the radiation field
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count (ANC) >= 1000/mm^3 independent of growth factor support
  • Platelets: >= 100,000/mm^3 or >= 50,000/mm^3 if known or suspected bone marrow involvement, independent of transfusion support in either situation
  • Hemoglobin: >= 8 g/dL (may be transfused)
  • Creatinine: Creatinine clearance > 25 ml/min
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): =< 3 x upper limit of normal (ULN)
  • Bilirubin: =< 1.5 x ULN (except for subjects with Gilbert's Syndrome or of non-hepatic cause)
  • Must be at least 4 weeks since treatment with standard or investigational chemotherapy, biochemotherapy, surgery, radiation, cytokine therapy, any monoclonal antibodies or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment
  • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; men must agree to not donate sperm during and after the study; for sexually active women of childbearing potential, these restrictions apply for 5 months after the last dose of study drug; for sexually active men, these restrictions apply for 7 months after the last dose of study drug
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening, within 24 hours of the first dose of anti-OX40 antibody, and every four weeks while on study treatment; women who are pregnant or breastfeeding are ineligible for this study
  • Life expectancy greater than 3 months
  • Ability to comply with the treatment schedule
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

  • Currently transformed lymphoma, high-risk mantle cell lymphoma, or gastric MALT lymphoma.
  • Need for immediate treatment or cytoreduction.
  • No easily accessible site for direct percutaneous injection with low-risk for potential complications.
  • Autoimmune disease requiring treatment within the last 5 years including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, uveitis, or other if clinically significant
  • Major surgery within 4 weeks of enrollment, or a wound that has not fully healed
  • Vaccinated with live, attenuated vaccines within 4 weeks of enrollment
  • Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection
  • Patients with active infection or with a fever > 38.5 degrees (^0) Celsius (C) within three days prior to the first treatment
  • Known central nervous system (CNS) lymphoma
  • Patients with a history of prior malignancy with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix, in situ carcinoma of the bladder, or other malignancy that has undergone potentially curative therapy with no evidence of disease for the last > 2 years and that is deemed by the investigator to be a low risk for recurrence
  • History of significant allergic reactions attributed to compounds of similar composition to SD-101 or BMS-986178
  • Treatment with an immunosuppressive regimen of corticosteroids or other immunosuppressive medication (e.g., methotrexate, rapamycin) within 30 days of study treatment; Note: patients may take up to 5 mg of prednisone or equivalent daily; topical and inhaled corticosteroids in standard doses are allowed
  • 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 with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)
  • Pregnant or breast feeding
  • Any other medical history, including laboratory results, deemed by the investigator 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): NCT03410901


Contacts
Contact: Destiny Phillips 650-498-1313 destinyp@stanford.edu

Locations
United States, California
Stanford University, School of Medicine Recruiting
Palo Alto, California, United States, 94304
Contact: Destiny Phillips    650-498-1313    destinyp@stanford.edu   
Principal Investigator: Ronald Levy         
Sponsors and Collaborators
Ronald Levy
National Cancer Institute (NCI)
Investigators
Principal Investigator: Ronald Levy Stanford University

Responsible Party: Ronald Levy, Robert K. and Helen K. Summy Professor, Stanford University
ClinicalTrials.gov Identifier: NCT03410901     History of Changes
Other Study ID Numbers: LYMNHL0144
NCI-2017-02452 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
LYMNHL0144 ( Other Identifier: Stanford Cancer Institute Palo Alto )
IRB-44250 ( Other Identifier: Stanford IRB )
R35CA197353 ( U.S. NIH Grant/Contract )
First Posted: January 25, 2018    Key Record Dates
Last Update Posted: April 20, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Leukemia, Lymphoid
Leukemia
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs