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Clinical Trial 19877

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT03038672

Phase: Phase II
Principal Investigator: Lazaryan, Aleksandr

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Study Title

A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in Combination with Nivolumab in Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas



Primary Objectives: - To determine the anti-tumor activity of combination therapy with CDX-1127 (varlilumab) and nivolumab as compared to nivolumab alone in patients with advanced aggressive B-cell non-Hodgkin lymphomas (NHL) based on the lymphoma response to immunomodulatory therapy criteria or LYRIC (Cheson et al., 2016). Secondary Objectives - To assess the safety and tolerability profile of treatment with a combination of CDX-1127 (varlilumab) and nivolumab in patients with advanced aggressive B-cell NHL. - To evaluate the duration of response, progression-free survival and overall survival Exploratory Objectives - To determine the effect of combination therapy with CDX-1127 (varlilumab) and nivolumab on the immune system as assessed by immunohistochemistry (IHC), mass cytometry (CyTOF), changes in serum cytokine profile and immunogenicity assays. - To describe the pharmacokinetic profile of CDX-1127 (varlilumab) and nivolumab when used in combination -





BMS-936558 (Nivolumab); Nivolumab (Opdivo); Varlilumab ()

Inclusion Criteria

  • Participants must have a histopathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma that is recurrent or refractory to standard therapy
  • For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma belonging to one of the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms
  • For the purposes of stratification, diagnoses are grouped into 2 categories:
  • Category A
  • Burkitt lymphoma
  • Burkitt-like lymphoma with 11q aberration
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
  • High-grade B-cell lymphoma, not otherwise specified (NOS)
  • Category B
  • Diffuse large B-cell lymphoma (DLBCL), NOS
  • Diffuse large B-cell lymphoma (DLBCL), NOS; germinal center B-cell type
  • Diffuse large B-cell lymphoma (DLBCL), NOS; activated B-cell type
  • Large B-cell lymphoma with IRF4 rearrangement
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg type
  • Epstein-Barr virus (EBV)+ DLBCL, NOS
  • EBV+ mucocutaneous ulcer
  • DLBCL associated with chronic inflammation
  • Lymphomatoid granulomatosis
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • ALK+ large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Human herpesvirus (HHV)-8+ DLBCL, NOS
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
  • Participants must have measurable disease, defined as at least one lesion that is > 15 mm (1.5 cm) in the longest axis on cross-sectional imaging and measureable in two perpendicular dimensions per computed tomography (spiral computed tomography [CT]), positron emission tomography (PET)-CT or magnetic resonance imaging (MRI)
  • Participants must have disease that has relapsed after or is refractory to at least 2 lines of standard therapy; the remaining standard treatment options are unlikely to be effective in the opinion of the treating physician, or participant is felt to be ineligible for such therapies or the participant refuses such therapies; participants who have undergone autologous stem cell transplant are eligible as long as they meet all other criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy of greater than 12 weeks
  • White blood cell (WBC) >= 2000/mm^3 (within 14 days of registration)
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of registration)
  • Platelet count >= 100,000/mm^3 (within 14 days of registration)
  • Hemoglobin > 9.0 g/dL (within 14 days of registration)
  • Total bilirubin =>Aspartate transaminase (aspartate aminotransferase [AST]) =>Calculated creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (within 14 days of registration)
  • Females of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])

  • Exclusion Criteria

  • Participant has received chemotherapy, targeted agent, or radiotherapy within 4 weeks or at least 5 half-lives, whichever is longer, prior to registration
  • Palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met:
  • Repeat imaging demonstrates no new sites of bone metastases
  • The lesion being considered for palliative radiation is not a target lesion
  • Participant has received immunotherapy (including monoclonal antibodies) within 4 weeks prior to registration
  • Participants who are receiving any other investigational agents
  • Participants should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
  • Participants who have received autologous stem cell transplant (ASCT) =>Participants with a prior history of allogeneic stem cell or solid organ transplantation
  • Participants with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on MRI obtained within 4 weeks of registration or progressive neurological decline
  • Participants with primary CNS lymphoma who develop systemic recurrence following standard therapy may be included as long as no active CNS disease is present at the time or enrollment; similarly, participants with secondary involvement of the CNS from a systemic lymphoma may be included as long as the CNS disease has been optimally treated and they demonstrate no evidence of active CNS disease
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to CDX-1127 (varlilumab) and/or nivolumab
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Participants with human immunodeficiency virus (HIV) are eligible for the study provided they meet the other protocol criteria in addition to the following:
  • Undetectable HIV load by standard polymerase chain reaction (PCR) clinical assay
  • No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count >Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma
  • Participants with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded
  • Participants should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

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