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Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

Primary Purpose

ALK-Positive Large B-Cell Lymphoma, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nivolumab
Varlilumab
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ALK-Positive Large B-Cell Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients 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
  • 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)
  • 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
  • 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 =< 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)
  • Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days of registration)
  • 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])
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patient 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
  • Patient has received immunotherapy (including monoclonal antibodies) within 4 weeks prior to registration
  • Patients who have not recovered to grade 1 or less from any adverse events due to agents administered more than 4 weeks earlier (excluding alopecia)
  • Patients who are receiving any other investigational agents
  • Patients 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
  • Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to the first dose of study drug
  • Patients with a prior history of allogeneic stem cell or solid organ transplantation
  • Patients 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

    • Patients 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, patients 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
  • Pregnant women are excluded from this study because CDX-1127 (varlilumab) and nivolumab are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CDX-1127 (varlilumab) or nivolumab, breastfeeding should be discontinued if the mother is treated with CDX-1127 (varlilumab) or nivolumab
  • Patients 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 within 60 days prior to registration
    • Absolute CD4 count of >= 200 mm^3 within 60 days prior to registration
    • Willing to maintain adherence to combination antiretroviral therapy
    • No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count < 200 mm^3)
    • Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma

      • Patients with evidence of hepatitis B virus (HBV) are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy; patient must be willing to maintain adherence to HBV therapy
      • Patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible
  • Patients 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; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  • Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
  • Patients 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
  • Patients with other active malignancy =< 3 years prior to registration for which active treatment is required must be excluded; patients with composite lymphomas that have a non-B-cell component must be excluded EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

Sites / Locations

  • Mayo Clinic Hospital in Arizona
  • Mayo Clinic in Arizona
  • Mayo Clinic in Florida
  • Moffitt Cancer Center-International Plaza
  • Moffitt Cancer Center - McKinley Campus
  • Moffitt Cancer Center
  • Northside Hospital
  • Northwestern University
  • University of Chicago Comprehensive Cancer Center
  • University of Kansas Clinical Research Center
  • HaysMed University of Kansas Health System
  • University of Kansas Cancer Center
  • Lawrence Memorial Hospital
  • Olathe Health Cancer Center
  • University of Kansas Cancer Center-Overland Park
  • University of Kansas Hospital-Indian Creek Campus
  • Ascension Via Christi - Pittsburg
  • Salina Regional Health Center
  • University of Kansas Health System Saint Francis Campus
  • University of Kansas Hospital-Westwood Cancer Center
  • Mayo Clinic in Rochester
  • Siteman Cancer Center at West County Hospital
  • Truman Medical Centers
  • University of Kansas Cancer Center - North
  • University of Kansas Cancer Center - Lee's Summit
  • University of Kansas Cancer Center at North Kansas City Hospital
  • Washington University School of Medicine
  • Siteman Cancer Center-South County
  • Siteman Cancer Center at Saint Peters Hospital
  • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
  • Roswell Park Cancer Institute
  • Laura and Isaac Perlmutter Cancer Center at NYU Langone
  • UT Southwestern/Simmons Cancer Center-Dallas

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Group I (nivolumab)

Group II (varlilumab, nivolumab)

Arm Description

Patients 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. Patients may cross over to Group II at the time of disease progression.

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.

Outcomes

Primary Outcome Measures

Overall response rate
Will be assessed by computed tomography (CT)-based criteria or positron emission tomography (PET)-CT based criteria. A response will be defined as an objective status of partial remission (PR) or complete remission (CR) for patients evaluated by CT-based criteria and complete metabolic response (CMR) or partial metabolic response (PMR) for patients evaluated by PET-CT based criteria. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. Comparison of overall response rates between the two treatment groups will be performed using a one-sided Fisher's exact test at significance level 0.15.

Secondary Outcome Measures

Duration of response
Defined as the date at which the patient's objective status is first noted to be a PR or CR for patients evaluated by CT-based criteria or CMR or PMR for patients evaluated by PET-CT based criteria to the earliest date progression (documentation of disease progression [PMD] or progressive disease [PD]) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. The comparison of duration of response between two treatment arms will be based on the log-rank test.
Survival time
The distribution of survival time will be estimated using the method of Kaplan-Meier. The comparison of overall survival between two treatment arms will be based on the log-rank test.
Progression free survival (PFS)
The distribution of PFS will be estimated using the method of Kaplan-Meier. The comparison of progression-free survival between two treatment arms will be based on the log-rank test.
Incidence of adverse events
Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The overall adverse event rates for grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Full Information

First Posted
January 31, 2017
Last Updated
September 23, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03038672
Brief Title
Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas
Official Title
A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in Combination With Nivolumab in Patients With Relapsed or Refractory Aggressive B-cell Lymphomas
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 21, 2018 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ALK-Positive Large B-Cell Lymphoma, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation, Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type, Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, EBV-Positive Mucocutaneous Ulcer, HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements, High Grade B-Cell Lymphoma, Not Otherwise Specified, Intravascular Large B-Cell Lymphoma, Large B-Cell Lymphoma With 11q Aberration, Large B-Cell Lymphoma With IRF4 Rearrangement, Plasmablastic Lymphoma, Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System, Primary Effusion Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Gray-Zone Lymphoma, Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Recurrent Lymphomatoid Granulomatosis, Recurrent Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Recurrent Primary Mediastinal Large B-Cell Lymphoma, Recurrent T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Burkitt Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Gray-Zone Lymphoma, Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Refractory Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Refractory Primary Mediastinal Large B-Cell Lymphoma, Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
106 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group I (nivolumab)
Arm Type
Active Comparator
Arm Description
Patients 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. Patients may cross over to Group II at the time of disease progression.
Arm Title
Group II (varlilumab, nivolumab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
ABP 206, BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Varlilumab
Other Intervention Name(s)
CDX 1127, CDX-1127, Immunoglobulin G1, Anti-(Human CD Antigen CD27) (Human Monoclonal CDX-1127 Clone 1f5 Heavy Chain), Disulfide with Human Monoclonal CDX-1127 Clone 1f5 Kappa-chain, Dimer
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Overall response rate
Description
Will be assessed by computed tomography (CT)-based criteria or positron emission tomography (PET)-CT based criteria. A response will be defined as an objective status of partial remission (PR) or complete remission (CR) for patients evaluated by CT-based criteria and complete metabolic response (CMR) or partial metabolic response (PMR) for patients evaluated by PET-CT based criteria. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. Comparison of overall response rates between the two treatment groups will be performed using a one-sided Fisher's exact test at significance level 0.15.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Duration of response
Description
Defined as the date at which the patient's objective status is first noted to be a PR or CR for patients evaluated by CT-based criteria or CMR or PMR for patients evaluated by PET-CT based criteria to the earliest date progression (documentation of disease progression [PMD] or progressive disease [PD]) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. The comparison of duration of response between two treatment arms will be based on the log-rank test.
Time Frame
Up to 2 years
Title
Survival time
Description
The distribution of survival time will be estimated using the method of Kaplan-Meier. The comparison of overall survival between two treatment arms will be based on the log-rank test.
Time Frame
From randomization to death due to any cause, assessed for up to 2 years
Title
Progression free survival (PFS)
Description
The distribution of PFS will be estimated using the method of Kaplan-Meier. The comparison of progression-free survival between two treatment arms will be based on the log-rank test.
Time Frame
From randomization to the earliest date of documentation of disease progression (PMD or PD) or death due to any cause, assessed for up to 2 years
Title
Incidence of adverse events
Description
Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The overall adverse event rates for grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).
Time Frame
Up to 100 days after last dose of study drug
Other Pre-specified Outcome Measures:
Title
Change in CD27 expression in tissue
Description
Will be assessed by immunohistochemistry. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, overall survival [OS]) will be evaluated using Cox's proportional hazards models and log-rank tests. Logistic regression will be used to model the response rate as a function of treatment and CD27 (as a continuous variable). The distribution of CD27 will be estimated empirically in the entire trial population and used to calculate CD27 values corresponding to each fixed percentile.
Time Frame
Baseline up to 100 days after last dose of study drug
Title
Change in peripheral blood immune cells
Description
Will be assessed by cytometry by time of flight (CyTOF). The relationship between presence/absence of a particular subtype of cell and association with outcomes will be evaluated. Evaluation of particular combinations of immune cells (immune signature) and whether they are predictive of outcome will also be evaluated. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, OS) will be evaluated using Cox's proportional hazards models and log-rank tests.
Time Frame
Baseline up to 12 weeks
Title
Change in the identification/characterization of intratumoral immune cells in tissue
Description
Will be assessed by immunohistochemistry and CyTOF. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, OS) will be evaluated using Cox's proportional hazards models and log-rank tests.
Time Frame
Baseline up to time of disease progression
Title
Change in genetic alterations of chromosome 9p24.1 in tissue
Description
Will be assessed by fluorescence in situ hybridization. The proportion of patients in each of these groups who achieve a response will be evaluated. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, OS) will be evaluated using Cox's proportional hazards models and log-rank tests.
Time Frame
Baseline up to time of disease progression
Title
Change in serum cytokine profile
Description
Will be assessed by enzyme-linked immunosorbent assay. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, OS) will be evaluated using Cox's proportional hazards models and log-rank tests.
Time Frame
Baseline up to 12 weeks
Title
Change in mutation burden in tissue
Description
Will be assessed by whole exome sequencing. Will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (Wilcoxon signed rank and McNemar's tests) will be used to assess changes in these variables before and after therapy. In addition, baseline values and changes over time in each measure will be explored in relation to clinical outcome. Differences between responders and non-responders will be assessed using Wilcoxon's rank sum (continuous data) or Fisher's exact (categorical data) test. The relationship between each measure and time to event measures (PFS, OS) will be evaluated using Cox's proportional hazards models and log-rank tests.
Time Frame
Baseline up to time of disease progression

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients 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 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) 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 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 =< 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) Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days of registration) 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]) Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patient 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 Patient has received immunotherapy (including monoclonal antibodies) within 4 weeks prior to registration Patients who have not recovered to grade 1 or less from any adverse events due to agents administered more than 4 weeks earlier (excluding alopecia) Patients who are receiving any other investigational agents Patients 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 Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to the first dose of study drug Patients with a prior history of allogeneic stem cell or solid organ transplantation Patients 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 Patients 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, patients 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 Pregnant women are excluded from this study because CDX-1127 (varlilumab) and nivolumab are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CDX-1127 (varlilumab) or nivolumab, breastfeeding should be discontinued if the mother is treated with CDX-1127 (varlilumab) or nivolumab Patients 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 within 60 days prior to registration Absolute CD4 count of >= 200 mm^3 within 60 days prior to registration Willing to maintain adherence to combination antiretroviral therapy No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count < 200 mm^3) Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma Patients with evidence of hepatitis B virus (HBV) are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy; patient must be willing to maintain adherence to HBV therapy Patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible Patients 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; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) Patients 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study Patients with other active malignancy =< 3 years prior to registration for which active treatment is required must be excluded; patients with composite lymphomas that have a non-B-cell component must be excluded EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen M Ansell
Organizational Affiliation
Dana-Farber - Harvard Cancer Center LAO
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Hospital in Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Facility Name
Moffitt Cancer Center-International Plaza
City
Tampa
State/Province
Florida
ZIP/Postal Code
33607
Country
United States
Facility Name
Moffitt Cancer Center - McKinley Campus
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Northside Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Kansas Clinical Research Center
City
Fairway
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
HaysMed University of Kansas Health System
City
Hays
State/Province
Kansas
ZIP/Postal Code
67601
Country
United States
Facility Name
University of Kansas Cancer Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Lawrence Memorial Hospital
City
Lawrence
State/Province
Kansas
ZIP/Postal Code
66044
Country
United States
Facility Name
Olathe Health Cancer Center
City
Olathe
State/Province
Kansas
ZIP/Postal Code
66061
Country
United States
Facility Name
University of Kansas Cancer Center-Overland Park
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66210
Country
United States
Facility Name
University of Kansas Hospital-Indian Creek Campus
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66211
Country
United States
Facility Name
Ascension Via Christi - Pittsburg
City
Pittsburg
State/Province
Kansas
ZIP/Postal Code
66762
Country
United States
Facility Name
Salina Regional Health Center
City
Salina
State/Province
Kansas
ZIP/Postal Code
67401
Country
United States
Facility Name
University of Kansas Health System Saint Francis Campus
City
Topeka
State/Province
Kansas
ZIP/Postal Code
66606
Country
United States
Facility Name
University of Kansas Hospital-Westwood Cancer Center
City
Westwood
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Siteman Cancer Center at West County Hospital
City
Creve Coeur
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Facility Name
Truman Medical Centers
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
University of Kansas Cancer Center - North
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64154
Country
United States
Facility Name
University of Kansas Cancer Center - Lee's Summit
City
Lee's Summit
State/Province
Missouri
ZIP/Postal Code
64064
Country
United States
Facility Name
University of Kansas Cancer Center at North Kansas City Hospital
City
North Kansas City
State/Province
Missouri
ZIP/Postal Code
64116
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Siteman Cancer Center-South County
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63129
Country
United States
Facility Name
Siteman Cancer Center at Saint Peters Hospital
City
Saint Peters
State/Province
Missouri
ZIP/Postal Code
63376
Country
United States
Facility Name
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Laura and Isaac Perlmutter Cancer Center at NYU Langone
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
UT Southwestern/Simmons Cancer Center-Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

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