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
Conditions
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.
Interventions
Given IV
Given IV
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 2 years | 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
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | 2 years | 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. |
| Overall Survival | 37 months | 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) | 37 months | 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. |
| Proportion of Patients With Grade 3 or Higher Adverse Events | 25 months | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in CD27 Expression in Tissue | Baseline up to 100 days after last dose of study drug | 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. |
| Change in Mutation Burden in Tissue | Baseline up to time of disease progression | 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. |
| Change in Peripheral Blood Immune Cells | Baseline up to 12 weeks | 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. |
| Change in the Identification/Characterization of Intratumoral Immune Cells in Tissue | Baseline up to time of disease progression | 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. |
| Change in Genetic Alterations of Chromosome 9p24.1 in Tissue | Baseline up to time of disease progression | 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. |
| Change in Serum Cytokine Profile | Baseline up to 12 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I (Nivolumab) 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. | 27 |
| Group II (Varlilumab, Nivolumab) 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. | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Initial Treatment | No treatment per protocol | 1 | 0 |
| Initial Treatment | Progression prior to treatment | 1 | 0 |
| Initial Treatment | Unacceptable chemistry | 0 | 1 |
Baseline characteristics
| Characteristic | Group II (Varlilumab, Nivolumab) | Total | Group I (Nivolumab) |
|---|---|---|---|
| Age, Continuous | 69 years | 67.5 years | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 51 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 51 Participants | 27 Participants |
| Sex: Female, Male Female | 7 Participants | 15 Participants | 8 Participants |
| Sex: Female, Male Male | 20 Participants | 39 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 27 | 5 / 27 | 0 / 7 |
| other Total, other adverse events | 24 / 27 | 24 / 27 | 7 / 7 |
| serious Total, serious adverse events | 10 / 27 | 12 / 27 | 3 / 7 |
Outcome results
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.
Time frame: 2 years
Population: All eligible patients that had a disease evaluation after being treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I (Nivolumab) | Overall Response Rate | 0.16 proportion of participants |
| Group II (Varlilumab, Nivolumab) | Overall Response Rate | 0.08 proportion of participants |
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.
Time frame: 2 years
Population: All eligible and treated patients that achieve a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I (Nivolumab) | Duration of Response | NA years |
| Group II (Varlilumab, Nivolumab) | Duration of Response | 0.2 years |
Overall Survival
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: 37 months
Population: All eligible and treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I (Nivolumab) | Overall Survival | 8.6 Months |
| Group II (Varlilumab, Nivolumab) | Overall Survival | 10.2 Months |
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.
Time frame: 37 months
Population: All eligible and treated patients that had a disease evaluation.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (Nivolumab) | Progression Free Survival (PFS) | 2.6 Months |
| Group II (Varlilumab, Nivolumab) | Progression Free Survival (PFS) | 1.5 Months |
Proportion of Patients With Grade 3 or Higher 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).
Time frame: 25 months
Population: All eligible and treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I (Nivolumab) | Proportion of Patients With Grade 3 or Higher Adverse Events | 0.76 proportion of patients |
| Group II (Varlilumab, Nivolumab) | Proportion of Patients With Grade 3 or Higher Adverse Events | 0.84 proportion of patients |
Change in CD27 Expression in Tissue
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
Change in Genetic Alterations of Chromosome 9p24.1 in Tissue
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
Change in Mutation Burden in Tissue
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
Change in Peripheral Blood Immune Cells
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
Change in Serum Cytokine Profile
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
Change in the Identification/Characterization of Intratumoral Immune Cells in Tissue
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