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Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01896999
First Posted: July 11, 2013
Last Update Posted: November 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  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. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab 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: None (Open Label)
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:
  • Maximum tolerated dose (MTD) of each combination defined as the highest dose level at which less than 33% of 6 patients experience a dose limiting toxicity (DLT) [ Time Frame: 21 days ]
    Will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 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 (CI) around the toxicity proportions will be calculated.


Secondary Outcome Measures:
  • Complete response (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% CI.

  • Duration of response (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% CI 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.

  • Overall response rate (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% CI.

  • Overall survival (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% CI for the Kaplan-Meier estimates.

  • Partial response (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% CI.

  • Progression-free survival (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% CI for the Kaplan-Meier estimates.


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 ]
    Effects of combinations on systemic immunity will be assessed.

  • 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: 63
Actual Study Start Date: January 24, 2014
Estimated Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (brentuximab vedotin, ipilimumab)
Patients receive brentuximab vedotin IV over 90 minutes on day 1 and ipilimumab IV over 30 minutes on day 1 of courses 1-4, 8, 12, and 16. 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 (brentuximab vedotin, nivolumab)
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of courses 1-16 and nivolumab IV over 30 minutes on day 1 of courses 1-46. Treatment repeats every 21 days for up to 16 courses and every 14 days beginning course 17 for up to 46 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 (brentuximab vedotin, nivolumab, ipilimumab)
Patients receive brentuximab vedotin IV over 90 minutes on day 1 of courses 1-16, nivolumab IV over 30 minutes on day 1 of courses 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 courses and every 14 days beginning course 17 for up to 46 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

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab.

SECONDARY OBJECTIVES:

I. To evaluate complete response (CR) rate, partial response (PR) rate and overall response rate (ORR), for the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab.

II. To evaluate the duration of remission (DOR) to these combinations and compare with the DOR achieved with the most recent prior systemic therapy.

III. To evaluate the progression-free survival (PFS) and the overall survival (OS) in patients receiving the combination of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab.

TERTIARY OBJECTIVES:

I. To evaluate the ability of these combinations to alter tumor specific T cell immunity.

II. To evaluate the effects of these combinations on systemic immunity. III. To evaluate a panel of cytokine and T cell specific biomarkers from the peripheral blood as a potential immune signature of treatment response to therapy with these combinations for patients with relapsed/refractory Hodgkin lymphoma (HL).

IV. To evaluate using gene expression profiling (GEP) a signature of response to these novel combinations of an antibody drug conjugate with immunomodulatory therapy.

OUTLINE: This is a dose-escalation study of brentuximab vedotin, ipilimumab, nivolumab. Patients are assigned into 1 of 3 arms.

ARM I: Patients receive brentuximab vedotin intravenously (IV) over 90 minutes on day 1 and ipilimumab IV over 30 minutes on day 1 of courses 1-4, 8, 12, and 16. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of courses 1-16 and nivolumab IV over 30 minutes on day 1 of courses 1-46. Treatment repeats every 21 days for up to 16 courses and every 14 days beginning course 17 for up to 46 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of courses 1-16, nivolumab IV over 30 minutes on day 1 of courses 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 courses and every 14 days beginning course 17 for up to 46 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 2 years.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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 PD1/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 due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; 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)
  • Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one week prior to the start of the study drug and continuing for 23 weeks after the last dose of study drug (for female patients) and for 31 weeks after the last dose of study drug (for male patients who are sexually active with WOCBP); 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
  • 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 1 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) obtained within 2 weeks prior to registration
  • Platelets >= 75,000/mcL (75 x 10^9/L) obtained within 2 weeks prior to registration
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) obtained within 2 weeks prior to registration
  • 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) obtained within 2 weeks prior to registration
  • Calculated creatinine clearance by Cockroft-Gault formula >= 30 ml/min obtained within 2 weeks prior to registration
  • 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 (TEN)s syndrome, or motor neuropathy
  • Human immunodeficiency virus (HIV) positive patients are allowed on this study if they have a 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, Sjögren'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 have smoked within the past 6 months
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01896999


Locations
United States, California
Stanford Cancer Institute Palo Alto Recruiting
Palo Alto, California, United States, 94304
Contact: Ranjana H. Advani    650-498-7061    ccto-office@stanford.edu   
Principal Investigator: Ranjana H. Advani         
United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jonathon B. Cohen    404-778-1868      
Principal Investigator: Jonathon B. Cohen         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Leo I. Gordon    312-695-1301    cancer@northwestern.edu   
Principal Investigator: Leo I. Gordon         
United States, Indiana
Indiana University/Melvin and Bren Simon Cancer Center Suspended
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 Suspended
Boston, Massachusetts, United States, 02111
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 Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Kevin A. David    732-235-8675      
Principal Investigator: Kevin A. David         
United States, New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone Recruiting
New York, New York, United States, 10016
Contact: Catherine S. Diefenbach    212-263-4434    prmc.coordinator@nyumc.org   
Principal Investigator: Catherine S. Diefenbach         
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 Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Stefan K. Barta    718-904-2730    aecc@aecom.yu.edu   
Principal Investigator: Stefan K. Barta         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Suspended
Nashville, Tennessee, United States, 37232
United States, Wisconsin
Froedtert and the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Timothy S. Fenske    414-805-4380      
Principal Investigator: Timothy S. Fenske         
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) )
S14-00011
E4412
E4412 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E4412 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
U24CA196172 ( U.S. NIH Grant/Contract )
First Submitted: July 8, 2013
First Posted: July 11, 2013
Last Update Posted: November 7, 2017
Last Verified: November 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