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Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01896999
First received: July 8, 2013
Last updated: March 17, 2017
Last verified: February 2017
  Purpose
This phase I trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin in treating patients with Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a combining monoclonal antibody with an anticancer drug that binds to a protein on the surface of lymphoma cells called cluster of differentiation (CD)30 and may kill the cells. Giving ipilimumab or nivolumab or both with brentuximab vedotin may kill more cancer cells.

Condition Intervention Phase
Classical Hodgkin Lymphoma
Recurrent Hodgkin Lymphoma
Refractory Hodgkin Lymphoma
Drug: Brentuximab Vedotin
Biological: Ipilimumab
Other: Laboratory Biomarker Analysis
Biological: Nivolumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase I Study With an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab, and Brentuximab Vedotin in Patients With Relapsed/Refractory Hodgkin Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of each combination defined as the highest dose level at which less than 33% of 6 patients experience a dose limiting toxicity, as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 21 days ]
    Upon completion of the trial, frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE version 4.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated.


Secondary Outcome Measures:
  • CR rate, assessed using the Revised Response Criteria for Malignant Lymphoma (Cheson et al.) [ Time Frame: Up to 3 years ]
    Reported along with the 95% confidence intervals.

  • DOR [ Time Frame: From the documented beginning of response (CR or PR) to the time of relapse, assessed up to 3 years ]
    DOR will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Descriptive statistics will be used to evaluate the DOR achieved with the protocol therapy and with the most recent prior systemic therapy.

  • ORR rate, assessed using the Revised Response Criteria for Malignant Lymphoma (Cheson et al.) [ Time Frame: Up to 3 years ]
    Reported along with the 95% confidence intervals.

  • OS [ Time Frame: From the date of study entry to the date of death, assessed up to 3 years ]
    OS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates.

  • PFS [ Time Frame: From entry onto study until lymphoma progression or death from any cause, assessed up to 3 years ]
    PFS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates.

  • PR rate, assessed using the Revised Response Criteria for Malignant Lymphoma (Cheson et al.) [ Time Frame: Up to 3 years ]
    Reported along with the 95% confidence intervals.


Other Outcome Measures:
  • Change in the percentage of activated T cells and natural killer cells [ Time Frame: Baseline (Time 1) to 9 weeks (Time 3, time of first re-staging) ]
    These quantities of interest will be calculated for each patient and the Wilcoxon signed-rank test will be used to test for significant difference between the time points. Using Wilcoxon rank sum test (two-sided type I error of 0.1), differences between those who progress or die within one year vs. those who are event-free at one year will be evaluated.

  • Change in the percentages of activated T cells and natural killer cells [ Time Frame: Day 1 of course 2 (Time 2) or 9 weeks (Time 3) to up to 6 weeks after completion of study treatment (Time 4, end of study) ]
    These quantities of interest will be calculated for each patient and the Wilcoxon signed-rank test will be used to test for significant difference between the time points. Using the Wilcoxon rank sum test (two-sided type I error of 0.1), differences between those who progress or die within one year vs. those who are event-free at one year will be evaluated.

  • Differentially expressed genes between two groups (patients who fail at 1-year vs. patients who are event-free at 1-year or responders vs. non-responders), assessed using GEP [ Time Frame: 1 year ]
    Differentially expressed genes will be identified using a rank-based method developed by Dr. Hong (RankProd, R package, Bioconductor Project) with multiple comparison adjustment using a false discovery rate approach. A two-way unsupervised hierarchical clustering analysis will be applied to both the genes and the samples to illustrate whether GEP can separate two groups or is associated with other clinical factors. The genes ranked as most significant will be assessed by gene ontology and pathway analysis for their potential functions in lymphoma biology and treatment failure.

  • Effects of combinations on systemic immunity [ Time Frame: Baseline to up to 6 weeks after completion of study treatment ]
  • Pre- and post-treatment levels of cytokines and T cell specific biomarkers [ Time Frame: Baseline to up to 6 weeks after completion of study treatment ]
    Pre- and post-treatment levels of these markers will be compared using the Wilcoxon signed-rank test with two-sided type I error of 0.1. Marker levels between patients who fail at 1-year vs. patients who are event-free at 1-year will be evaluated. Given limited data, the analyses of PD-1, co-expression of Tim-3 with PD-1, ICOS, sCD30, galectin-1 and the peripheral blood absolute lymphocyte to monocyte ratio will be mainly exploratory and will be summarized descriptively at the time-points described above. The association with PFS will be explored.


Estimated Enrollment: 70
Study Start Date: January 2014
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (ipilimumab and brentuximab vedotin)
Patients receive ipilimumab IV over 90 minutes on day 1 of courses 1-4, 8, 12, and 16 and brentuximab vedotin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm II (nivolumab and brentuximab vedotin)
Patients receive brentuximab vedotin IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days for up to 30 courses in the absence of disease progression or unacceptable toxicity.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
Experimental: Arm III (ipilimumab, nivolumab, brentuximab vedotin)
Patients receive ipilimumab IV over 30 minutes on day 1 of course 1 and then every 6 weeks for up to 18 doses. Patients receive brentuximab vedotin IV over 90 minutes on day 1 and nivolumab IV over 30 minutes on day 1. Treatment with brentuximab vedotin and nivolumab repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days for up to 30 courses in the absence of disease progression or unacceptable toxicity.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have pathologically confirmed relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including lymphocyte predominant (LP) HL are not permitted
  • Patients must have relapsed after first line chemotherapy; may have relapsed after autologous or allogeneic stem cell transplant, or have primary refractory disease; no upper limit for number of prior therapies; if status post allogeneic stem cell transplant, no active graft versus host disease
  • Patients may have received prior brentuximab vedotin, but must not have received brentuximab vedotin within 6 months prior to registration, and must not have relapsed within 6 months of receiving previous brentuximab vedotin; patients may not have received prior nivolumab or programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PDL1) axis agents; patients in the nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab
  • Patients may have received other prior activating immunotherapies (i.e. checkpoint inhibitors), but must not have received them within 6 months prior to registration, and there must be no serious unresolved complication of therapy at the time of registration; for the purposes of this study monoclonal antibodies and antibody drug conjugates are not considered to be activating immunotherapies and there are no additional time restrictions on prior exposure to these agents (except prior brentuximab vedotin)
  • Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) performance status between 0-2
  • Patients must have measurable disease; baseline measurements and evaluations must be obtained within 4 weeks of registration to the study; abnormal positron emission tomography (PET) scans will not constitute evaluable disease unless verified by a diagnostic quality computed tomography (CT) scan; patients must use the same imaging modality (CT or PET/CT) throughout the study
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Woman of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 23 weeks after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; these durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days
  • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
  • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
  • Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while breathing room air
  • Patients must have forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary function tests must be obtained within one month prior to registration
  • Absolute neutrophil count (ANC) >= 1500/mcL (1.5 x 10^9/L)
  • Platelets >= 75,000/mcL (75 x 10^9/L)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x upper limit of normal [ULN] is permitted)
  • Calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min
  • No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for >= 5 years so as not to interfere with interpretation of radiographic response
  • Patient must have no current or prior history of central nervous system (CNS) involvement
  • All prior therapy must have been completed at least 21 days prior to enrollment; no concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed; topical steroids are allowed
  • No history of Steven's Johnson's syndrome, toxic epidermal necrolysis (TENs) syndrome, or motor neuropathy
  • Human immunodeficiency virus (HIV) positive patients are allowed on this study if they have a cluster of differentiation 4 (CD4) count > 400, and are on a stable antiviral regimen; patients with poorly controlled HIV or other chronic active viral infections will be excluded
  • Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed

    • Replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study
    • Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis); other CNS autoimmune disease (e.g., multiple sclerosis); patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible
  • Patients must not have grade 2 or greater peripheral sensory neuropathy
  • Patients must not have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia
  • Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab
  • Patients must not have a serious medical or psychiatric illness likely to interfere with study participation
  • Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration
  • Patients may not receive routine vaccination for infectious disease within 30 days of receiving ipilimumab however it is suggested that routine vaccinations, including seasonal influenza, be given at least 2 weeks prior to study treatment
  • Patients registering to arms D, E, F, G, H, I, X, Y must not currently be smoking and must not currently be smoking and must not have smoked within the past 6 months
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01896999

Locations
United States, California
Stanford Cancer Institute Recruiting
Palo Alto, California, United States, 94304
Contact: Ranjana H. Advani    650-498-7061    clinicaltrials@med.stanford.edu   
Principal Investigator: Ranjana H. Advani         
United States, Georgia
Emory University/Winship Cancer Institute Suspended
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University Suspended
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University/Melvin and Bren Simon Cancer Center Active, not recruiting
Indianapolis, Indiana, United States, 46202
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Richard F. Ambinder    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Richard F. Ambinder         
United States, Massachusetts
Tufts Medical Center Recruiting
Boston, Massachusetts, United States, 02111
Contact: Andrew M. Evens    617-636-5000    ContactUsCancerCenter@TuftsMedicalCenter.org   
Principal Investigator: Andrew M. Evens         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Stephen M. Ansell    855-776-0015      
Principal Investigator: Stephen M. Ansell         
United States, New Jersey
Rutgers Cancer Institute of New Jersey Suspended
New Brunswick, New Jersey, United States, 08903
United States, New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone Suspended
New York, New York, United States, 10016
United States, Pennsylvania
Penn State Milton S Hershey Medical Center Suspended
Hershey, Pennsylvania, United States, 17033-0850
ECOG-ACRIN Cancer Research Group Recruiting
Philadelphia, Pennsylvania, United States, 19103
Contact: Catherine S. Diefenbach    212-731-5670    catherine.diefenbach@nyumc.org   
Principal Investigator: Catherine S. Diefenbach         
University of Pennsylvania/Abramson Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Jakub Svoboda    800-474-9892      
Principal Investigator: Jakub Svoboda         
Fox Chase Cancer Center Suspended
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: David S. Morgan    800-811-8480      
Principal Investigator: David S. Morgan         
United States, Wisconsin
Froedtert and the Medical College of Wisconsin Suspended
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Catherine Diefenbach ECOG-ACRIN Cancer Research Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01896999     History of Changes
Other Study ID Numbers: NCI-2013-01275
NCI-2013-01275 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
E4412
E4412 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E4412 ( Other Identifier: CTEP )
U10CA180820 ( US NIH Grant/Contract Award Number )
U10CA021115 ( US NIH Grant/Contract Award Number )
Study First Received: July 8, 2013
Last Updated: March 17, 2017

Additional relevant MeSH terms:
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoconjugates
Nivolumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on March 24, 2017