Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma

• ClinicalTrials.gov Identifier: NCT02758717
• Recruitment Status: Active, not recruiting
• First Posted: May 2, 2016
• Results First Posted: September 22, 2020
• Last Update Posted: May 6, 2024
• Sponsor: Academic and Community Cancer Research United
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Academic and Community Cancer Research United

Tracking Information

• First Submitted Date: April 12, 2016
• First Posted Date: May 2, 2016
• Results First Submitted Date: June 24, 2020
• Results First Posted Date: September 22, 2020
• Last Update Posted Date: May 6, 2024
• Actual Study Start Date: May 13, 2016
• Actual Primary Completion Date: August 13, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2020)

Overall Metabolic Response Rate [ Time Frame: Up to 8 cycles of treatment (approximately 29 weeks) ]

The primary endpoint of this trial is the rate (percentage) of overall metabolic response. A metabolic response is defined as a participant who has achieved an objective status of Partial metabolic response (PMR) or Complete metabolic response (CMR) at the end of cycle 8. Response is based on PET/CT based on the revised 2014 Lugano Classification. (PMR: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size CMR: Score 1 (no uptake above background), 2 (uptake<=mediastinum), or 3 (uptake > mediastinum but <= liver) with or without a residual mass on PET Deauville 5-Point-Scale. The scale ranges from 1 to 5, where 1 is best and 5 is the worst.

Original Primary Outcome Measures (submitted: April 28, 2016)

Rate of complete metabolic response [ Time Frame: Through the completion of cycle 6. Cycle length for cycles 1-6 is 21 days. ]

The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Current Secondary Outcome Measures (submitted: February 19, 2024)

• Number of Participants With an Overall Response of Complete Metabolic Response [ Time Frame: Up to end of course 8 ]
  The number of participants with an overall response of Complete metabolic response. Response is based on PET/CT based on the revised 2014 Lugano Classification. (CMR: Score 1 (no uptake above background), 2 (uptake<=mediastinum), or 3 (uptake > mediastinum but <= liver) with or without a residual mass on PET Deauville 5-Point-Scale. The scale ranges from 1 to 5, where 1 is best and 5 is the worst.
• Duration of Response (DOR) [ Time Frame: 30 months ]
  DOR is time from the date at which the patient's objective status is first noted to be a CMR or PMR to the earliest date progression (progressive metabolic disease [PMD] or progressive disease [PD]) is documented. Response is based on PET/CT based on the revised 2014 Lugano Classification. (PMR: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) CMR: Score 1 (no uptake above background), 2 (uptake<=mediastinum), or 3 (uptake > mediastinum but <= liver) with or without a residual mass on PET Deauville 5-Point-Scale. The scale ranges from 1 to 5, where 1 is best and 5 is the worst. PMD: Score 4 or 5 with an increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment PD: An individual node/lesion must be abnormal with: LDi > 1.5 cm and Increase by ≥ 50% from PPD nadir and, An increase in LDi or SDi from nadir, 0.5 cm for lesions ≤2 cm, 1.0 cm for lesions > 2 cm)
• Progression-free Survival [ Time Frame: 30 months ]
  Progression-free survival is defined as the time from registration to the earliest date of documentation of disease progression (Progressive metabolic disease (PMD) or Progressive disease (PD)) or death due to any cause. Response is based on PET/CT based on the revised 2014 Lugano Classification. (PMD: Score 4 or 5 with an increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment PD: An individual node/lesion must be abnormal with: LDi > 1.5 cm and Increase by ≥ 50% from PPD nadir and, An increase in LDi or SDi from nadir, 0.5 cm for lesions ≤2 cm, 1.0 cm for lesions > 2 cm)
• Overall Survival [ Time Frame: 30 months ]
  The distribution of overall survival will be estimated using the method of Kaplan-Meier.
• Number of Participants Experiencing at Least One Adverse Events Graded 3 or Higher Deemed at Least Possibly Related to Treatment [ Time Frame: Up to 8 cycles of treatment (approximately 29 weeks) ]
  Number of participants experiencing at least one toxicity. Toxicity is defined as an adverse event graded 3 or higher by Common Terminology Criteria for Adverse Events version 4.0 deemed at least possibly related to treatment.

Original Secondary Outcome Measures (submitted: April 28, 2016)

• Duration of response [ Time Frame: From date at which the patient's objective status is first noted to be a CMR or PMR to the earliest date progression (PMD or PD) is documented, assessed up to 7 years ]
  The distribution of duration of response will be estimated using the method of Kaplan-Meier.
• Incidence of adverse events graded by Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 7 years ]
  The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
• Overall response rate estimated by the total number of complete and partial metabolic responses (CMR or PMR) divided by the total number of evaluable patients [ Time Frame: Up to 7 years ]
  Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
• Overall survival [ Time Frame: Time from registration to death due to any cause, assessed up to 7 years ]
  The distribution of overall survival will be estimated using the method of Kaplan-Meier.
• Progression-free survival [ Time Frame: Time from registration to the earliest date of documentation of disease progression (PMD or PD) or death due to any cause, assessed up to 7 years ]
  The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: April 28, 2016)

• Change in genetic variability [ Time Frame: Day 1 to up to 7 years ]
  Baseline values and changes in these parameters over time will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (paired t-tests Wilcoxon signed rank tests and Fisher's exact tests for interval, ordinal and nominal level data, respectively) 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 to explore any differences between responders and non-responders and by depth of response (CMR vs. PMR) to iden
• Change in intratumoral cell populations [ Time Frame: Day 1 to up to 7 years ]
  Baseline values and changes in these parameters over time will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (paired t-tests Wilcoxon signed rank tests and Fisher's exact tests for interval, ordinal and nominal level data, respectively) 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 to explore any differences between responders and non-responders and by depth of response (CMR vs. PMR) to iden
• Change in serum cytokines [ Time Frame: Day 1 to up to 7 years ]
  Baseline values and changes in these parameters over time will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (paired t-tests Wilcoxon signed rank tests and Fisher's exact tests for interval, ordinal and nominal level data, respectively) 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 to explore any differences between responders and non-responders and by depth of response (CMR vs. PMR) to iden
• Change in T cell activation [ Time Frame: Day 1 to up to 7 years ]
  Baseline values and changes in these parameters over time will be both graphically and quantitatively summarized and explored. Standard paired comparisons methodologies (paired t-tests Wilcoxon signed rank tests and Fisher's exact tests for interval, ordinal and nominal level data, respectively) 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 to explore any differences between responders and non-responders and by depth of response (CMR vs. PMR) to iden

Descriptive Information

• Brief Title: Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma
• Official Title: Phase II, Multi-Center Trial of Nivolumab and Brentuximab Vedotin in Patients With Untreated Hodgkin Lymphoma Over the Age of 60 Years or Unable to Receive Standard Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) Chemotherapy
• Brief Summary: This phase II trial studies how well nivolumab and brentuximab vedotin work in treating older patients with untreated Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Biological therapies, such as brentuximab vedotin, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Nivolumab and brentuximab vedotin may work better in treating older patients with untreated Hodgkin lymphoma.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the efficacy based on overall metabolic response rate (partial metabolic response [PMR] + complete metabolic remission [CMR]) of brentuximab vedotin/nivolumab in previously untreated Hodgkin lymphoma patients 60 years of age or older, or those considered unsuitable for standard chemotherapy because of a low cardiac ejection fraction (< 50%) or impaired pulmonary or renal function.

SECONDARY OBJECTIVES:

I. The complete metabolic response (CMR) rate. II. Safety and tolerability of the regimen in this patient population. III. Duration of response (DOR). IV. Progression-free survival (PFS). V. Overall survival (OS).

CORRELATIVE RESEARCH OBJECTIVES:

I. T-cell/cytokine - peripheral blood specimens will be used to assess T-cell activation and cytokine up regulation as measures of treatment effect.

II. Biomarkers - intratumoral cell populations, genetic variability, serum cytokines and T-cell activation will be evaluated to identify potential biomarkers that correlate with response to therapy.

OUTLINE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for 7 cycles and 6-8 weeks in cycle 8 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 30 days for 90 days, every 90 days for 2.5 years, and then every 6 months until 5 years from registration.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Ann Arbor Stage IB Hodgkin Lymphoma
• Ann Arbor Stage II Hodgkin Lymphoma
• Ann Arbor Stage IIA Hodgkin Lymphoma
• Ann Arbor Stage IIB Hodgkin Lymphoma
• Ann Arbor Stage III Hodgkin Lymphoma
• Ann Arbor Stage IIIA Hodgkin Lymphoma
• Ann Arbor Stage IIIB Hodgkin Lymphoma
• Ann Arbor Stage IV Hodgkin Lymphoma
• Ann Arbor Stage IVA Hodgkin Lymphoma
• Ann Arbor Stage IVB Hodgkin Lymphoma
• Classic Hodgkin Lymphoma

Intervention

• 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: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Study Arms

Experimental: Treatment (brentuximab vedotin, nivolumab)

Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for 7 cycles and 6-8 weeks in cycle 8 in the absence of disease progression or unacceptable toxicity.

Interventions:

• Drug: Brentuximab Vedotin
• Biological: Nivolumab

• Publications *: Cheson BD, Bartlett NL, LaPlant B, Lee HJ, Advani RJ, Christian B, Diefenbach CS, Feldman TA, Ansell SM. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2020 Nov;7(11):e808-e815. doi: 10.1016/S2352-3026(20)30275-1. Epub 2020 Oct 1.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 21, 2019): 46
• Original Estimated Enrollment (submitted: April 28, 2016): 75
• Estimated Study Completion Date: May 13, 2024
• Actual Primary Completion Date: August 13, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Classical Hodgkin lymphoma determined by local hematopathology review

• One of the following:

  • Age >= 60 years
  • Age < 60 years but unsuitable for standard chemotherapy because of a cardiac ejection fraction of < 50%, a pulmonary diffusion capacity < 80%, or a creatinine clearance >= 30 and < 60 mL/min, or refused standard chemotherapy despite efforts to convince them otherwise
• Requirement for systemic chemotherapy: all stages except IA (not bulky disease), if involved field is considered radiotherapy (RT) curative
• Previously untreated with either chemotherapy, radiation therapy or either brentuximab vedotin or nivolumab, or another check point inhibitor
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1500/mm^3, unless secondary to bone marrow involvement; obtained =< 7 days prior to registration
• Leukocytes >= 3,000/mm^3, obtained =< 7 days prior to registration
• Platelet count >= 100,000/mm^3, obtained =< 7 days prior to registration
• Hemoglobin > 9.0 g/dL - unless determined by treating physician to be disease related, obtained =< 7 days prior to registration
• Total bilirubin =< 1.5 x upper limit of normal (ULN), obtained =< 7 days prior to registration
• Aspartate aminotransferase (aspartate transaminase [AST]) =< 2.5 x ULN, obtained =< 7 days prior to registration
• Alanine aminotransferase (alanine transaminase [ALT]) =< 2.5 x ULN, obtained =< 7 days prior to registration
• Creatinine =< 2.0 mg/dL, obtained =< 7 days prior to registration
• Amylase and/or lipase =< 1.5 x ULN, obtained =< 7 days prior to registration

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to registration

  • Note: women of child-bearing potential (WOCBP) must use appropriate method(s) of contraception; WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; 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; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

  • Note: during the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
• Ability to understand and willingness to sign an informed written consent
• Provide blood and tissue samples for mandatory correlative research purposes

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Active, known or suspected autoimmune disease; note: subjects 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
• Use of systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications =< 14 days of registration; Note: Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Immunocompromised patients, patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) and currently receiving antiretroviral therapy, patients with a prior history of known or suspected autoimmune disease, active hepatitis B virus surface antigen (HBV sAg+), active hepatitis C (if antibody [Ab]+ then polymerase chain reaction [PCR]+) indicating acute or chronic infection, and/or history of interstitial lung disease
• Allergy to brentuximab vedotin and/or nivolumab
• 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
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• Have had prior chemotherapy or radiotherapy for Hodgkin lymphoma
• Have received either of the study drugs
• < 60 years who are considered candidates for standard chemotherapy
• >= grade 2 peripheral neuropathy
• Other active malignancy =< 2 years prior to registration, unless treated with curative intent; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer
• Active central nervous system (CNS) involvement or leptomeningeal metastases involvement
• Known history of pancreatitis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02758717
• Other Study ID Numbers: RU051505I; NCI-2016-00468 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); RU051505I ( Other Identifier: Academic and Community Cancer Research United ); P30CA015083 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Academic and Community Cancer Research United
• Original Responsible Party: Same as current
• Current Study Sponsor: Academic and Community Cancer Research United
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Bruce D Cheson; Academic and Community Cancer Research United

• PRS Account: Academic and Community Cancer Research United
• Verification Date: August 2023