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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 : Suspended (Protocol Modification Anticipated)
First Posted : January 25, 2018
Last Update Posted : October 8, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Ronald Levy, Stanford University

Tracking Information
First Submitted Date  ICMJE January 19, 2018
First Posted Date  ICMJE January 25, 2018
Last Update Posted Date October 8, 2019
Actual Study Start Date  ICMJE April 9, 2018
Estimated Primary Completion Date October 9, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 23, 2018)
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
Original Primary Outcome Measures  ICMJE
 (submitted: January 19, 2018)
Dose-limiting toxicity [ Time Frame: Up to 8 weeks ]
Will be recorded, tabulated and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0.
Change History Complete list of historical versions of study NCT03410901 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 23, 2018)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 19, 2018)
  • Overall response rate assessed by computed tomography (CT) or positron emission tomography (PET)/CT [ Time Frame: Up to 96 weeks ]
    Tumor response rates (complete response, partial response, stable disease, progressive disease) will be calculated based on the Lugano classification for low-grade B-cell lymphomas. Response assessments will be summarized in waterfall plots and spider plots to best display the effect sizes as well as variation, timing and duration of responses.
  • Progression-free Survival assessed by CT or PET/CT [ Time Frame: From treatment initiation (day 1) and tumor progression or death from any cause, assessed for up to 96 weeks ]
    Will be summarized descriptively using the Kaplan-Meier method.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE Intratumoral Injection of SD-101, an Immunostimulatory CpG, in Combination With BMS-986178 and Local Radiation in Low-Grade B-Cell Lymphomas
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Biological: Anti-OX40 Antibody BMS 986178
  • Other: Laboratory Biomarker Analysis
  • Radiation: Radiation Therapy
  • Drug: TLR9 Agonist SD-101
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: January 19, 2018)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 9, 2020
Estimated Primary Completion Date October 9, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03410901
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ronald Levy, Stanford University
Study Sponsor  ICMJE Ronald Levy
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Ronald Levy Stanford University
PRS Account Stanford University
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP