Summary

This phase II trial studies how well nivolumab with or without varlilumab works in treating patients with aggressive B-cell lymphomas that have come back (recurrent) or do not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as varlilumab and nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Objectives

PRIMARY OBJECTIVE:
I. 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.

SECONDARY OBJECTIVES:
I. 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.
II. To evaluate the duration of response, progression-free survival and overall survival.

EXPLORATORY OBJECTIVES:
I. 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.
II. To describe the pharmacokinetic profile of CDX-1127 (varlilumab) and nivolumab when used in combination.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks for 4 months and every 4 weeks for a total of up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may cross over to Group II at the time of disease progression.

GROUP II: Patients receive varlilumab IV over 90 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes every 2 weeks for 4 months and every 4 weeks for a total of up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days.

Eligibility

1. Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma that is recurrent or refractory to standard therapy
2. 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
3. Patients 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 measurable in two perpendicular dimensions per computed tomography (spiral computed tomography [CT]), positron emission tomography (PET)-CT or magnetic resonance imaging (MRI)
4. Patients 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 patient is felt to be ineligible for such therapies or the patient refuses such therapies; patients who have undergone autologous stem cell transplant are eligible as long as they meet all other criteria
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Life expectancy of greater than 12 weeks
7. White blood cell (WBC) >= 2000/mm^3 (within 14 days of registration)
8. Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of registration)
9. Platelet count >= 100,000/mm^3 (within 14 days of registration)
10. Hemoglobin > 9.0 g/dL (within 14 days of registration)
11. Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 14 days of registration)
12. Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days of registration)
13. Calculated creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (within 14 days of registration)
14. 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])
15. Ability to understand and the willingness to sign a written informed consent document

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