Clinical Trials /

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

NCT03410901

Description:

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.

Related Conditions:
  • Diffuse Follicular Lymphoma
  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Marginal Zone Lymphoma
  • Primary Cutaneous Follicle Center Lymphoma
  • Small Lymphocytic Lymphoma with Immunoglobulin Heavy Chain Variable-Region Gene Somatic Hypermutation
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas
  • Official Title: Intratumoral Injection of SD-101, an Immunostimulatory CpG, in Combination With BMS-986178 and Local Radiation in Low-Grade B-Cell Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: LYMNHL0144
  • SECONDARY ID: NCI-2017-02452
  • SECONDARY ID: LYMNHL0144
  • SECONDARY ID: IRB-44250
  • SECONDARY ID: R35CA197353
  • NCT ID: NCT03410901

Conditions

  • 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

Interventions

DrugSynonymsArms
Anti-OX40 Antibody BMS 986178BMS 986178, BMS-986178Treatment (radiation therapy, SD-101, BMS-986178)
TLR9 Agonist SD-101ISS-ODN SD-101, SD-101Treatment (radiation therapy, SD-101, BMS-986178)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (radiation therapy, SD-101, BMS-986178)ExperimentalPatients 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.
  • Anti-OX40 Antibody BMS 986178
  • TLR9 Agonist SD-101

Eligibility 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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants experiencing Dose-limiting Toxicities (DLT) within 8 weeks of treatment initiation
Time Frame:Up to 8 weeks
Safety Issue:
Description: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

Measure:Overall Response Rate (ORR)
Time Frame:Up to 96 weeks
Safety Issue:
Description: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.
Measure:Progression-Free Survival (PFS)
Time Frame:up to 96 weeks
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ronald Levy

Last Updated

December 13, 2019