Clinical Trials /

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

NCT03038672

Description:

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 or do not respond to treatment. 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.

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • B-Cell Non-Hodgkin Lymphoma
  • Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma
  • Lymphomatoid Granulomatosis
  • Mediastinal Large B-Cell Lymphoma
  • Primary Central Nervous System Lymphoma
  • Primary Effusion Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00120
  • SECONDARY ID: NCI-2017-00120
  • SECONDARY ID: MC168D
  • SECONDARY ID: 10089
  • SECONDARY ID: 10089
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT03038672

Conditions

  • ALK-Positive Large B-Cell Lymphoma
  • Atypical Burkitt/Burkitt-Like Lymphoma
  • Burkitt-Like Lymphoma With 11q Aberration
  • 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
  • High-Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements
  • Human Herpesvirus 8-Positive Neoplastic Cells Present
  • Intravascular Large B-Cell Lymphoma
  • Large B-Cell Lymphoma With IRF4 Rearrangement
  • Plasmablastic Lymphoma
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma
  • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
  • Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System
  • Primary Effusion Lymphoma
  • Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma
  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Burkitt Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Lymphomatoid Granulomatosis
  • Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Burkitt Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Small Intestinal High Grade B-Cell Lymphoma, Not Otherwise Specified
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoGroup I (nivolumab)
VarlilumabCDX 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, DimerGroup II (varlilumab, nivolumab)

Purpose

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 or do not respond to treatment. 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 OBJECTIVES:

      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 60 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 60 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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (nivolumab)Active ComparatorPatients receive nivolumab IV over 60 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.
  • Nivolumab
Group II (varlilumab, nivolumab)ExperimentalPatients 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 60 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.
  • Nivolumab
  • Varlilumab

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 measureable 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

               -  Absolute CD4 count of >= 200 mm^3

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
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.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
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.
Measure:Survival time
Time Frame:From randomization to death due to any cause, assessed for up to 2 years
Safety Issue:
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.
Measure:Progression free survival (PFS)
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
Safety Issue:
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.
Measure:Incidence of adverse events
Time Frame:Up to 100 days after last dose of study drug
Safety Issue:
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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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