Brentuximab Vedotin and Nivolumab for the Treatment of Patients With Relapsed Classical Hodgkin Lymphoma

Sponsor

City of Hope Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04561206

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

23.1

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial investigates how well brentuximab vedotin and nivolumab work in treating patients with classical Hodgkin lymphoma that has come back (relapsed). Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. Nivolumab is an antibody that enhances the immune system to better fight Hodgkin lymphoma cells. Giving brentuximab vedotin and nivolumab may be able to defer stem cell transplant treatment and spare the considerable cost and toxicity on transplantation.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Classic Hodgkin Lymphoma	Drug: Brentuximab Vedotin Biological: Nivolumab	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

Assess the durability of response to brentuximab vedotin (BV) plus nivolumab (nivo) by 24-month progression-free survival (PFS) in participants with 1st relapse of classical Hodgkin lymphoma (RcHL) who achieved early complete metabolic response (CMR) (CMR after 4 cycles).

SECONDARY OBJECTIVES:

Estimate CMR and overall response rate (ORR) after 4 cycles and at the end of BV-nivo therapy.
Estimate the PFS and overall survival (OS) for the entire cohort and for subgroups of patients defined by their response.
Estimate the PFS and OS separately for responders who did and did not receive radiotherapy.
Evaluate the toxicities of BV-nivo in the study population.

EXPLORATORY OBJECTIVES:

Estimate the second PFS after salvage therapy for patients who progress after study therapy, and for the subset of these patients who proceeded to autologous stem cell transplant (ASCT).
Explore the association between clinical outcomes and pathological tumor characteristics.
Explore the association between clinical outcomes and circulating tumor deoxyribonucleic acid (ctDNA) characteristics (mutation profile, kinetics of clearance).

OUTLINE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and 6, 12, 18, 24, 36, 48, and 60 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

31 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2 Study of Brentuximab Vedotin Plus Nivolumab Without Stem Cell Consolidation in Patients With Relapsed Classical Hodgkin Lymphoma

Actual Study Start Date :

Nov 12, 2021

Anticipated Primary Completion Date :

Oct 15, 2023

Anticipated Study Completion Date :

Oct 15, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (brentuximab vedotin, nivolumab) Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 16 cycles 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: Nivolumab Given IV Other Names: BMS-936558 MDX-1106 NIVO ONO-4538 Opdivo

Arm

Intervention/Treatment

Experimental: Treatment (brentuximab vedotin, nivolumab)

Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 16 cycles 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: Nivolumab

Given IV

Other Names:

BMS-936558

MDX-1106

NIVO

ONO-4538

Opdivo

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) at 24 months in patients who achieve complete metabolic response (CMR) after 4 cycles of treatment [From start of protocol treatment to time of disease relapse/progression or death due to any cause, assessed at 24 months]
Estimated using Kaplan-Meier product limit method.

Secondary Outcome Measures

Complete metabolic response (CMR) rate [After 4 or 8 cycles (each cycle is 21 days)]
Defined as the proportion of response-evaluable participants that achieve a best response of CMR with brentuximab vedotin (BV)-nivolumab (Nivo) therapy. Will be estimated along with the 95% exact binomial confidence interval.
Overall response rate (ORR) [After 4 or 8 cycles (each cycle is 21 days)]
defined as the proportion of response-evaluable participants that achieve a best response of either CMR or partial metabolic remission (PMR) with BV-Nivo therapy. Will be estimated along with the 95% exact binomial confidence interval.
Overall survival (OS) [From start of protocol treatment to time of death due to any cause, assessed up to 5 years (each cycle is 21 days)]
Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation. Median PFS/OS will be estimated when available. PFS and OS will be estimated for the entire cohort, for subgroups defined by response, and for responders who did and did not receive radiotherapy.
PFS [From start of protocol treatment to time of disease relapse/progression or death due to any cause, whichever occurs earlier, assessed up to 5 years(each cycle is 21 days)]
Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation. Median PFS/OS will be estimated when available. PFS and OS will be estimated for the entire cohort, for subgroups defined by response, and for responders who did and did not receive radiotherapy.
Incidence of adverse events [Up to 30 days post-treatment]
Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Observed toxicities of BV-Nivo therapy will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity, and attribution.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Be willing to provide tissue (either from a fresh core or excisional biopsy performed as standard of care, or from archival tissue) of a biopsy that was performed after frontline systemic therapy, and prior to starting protocol therapy
If unavailable, exceptions may be granted with study principal investigator (PI) approval
Eastern Cooperative Oncology Group (ECOG) =< 2
Histologically confirmed diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution
First relapse, defined as:
No more than 1 line of prior therapy (not counting radiotherapy)
No primary refractory disease (i.e. patients cannot have relapsed within 90 days of the end of frontline therapy)
Patients who received BV or an anti-PD-1/PD-L1 agent as part of frontline therapy are eligible if they achieved a CMR with frontline therapy and have not relapsed within 6 months from the end of frontline therapy Relapse must have been confirmed histologically (with hematopathology review at the participating institution)
Not a candidate for ASCT, based on age, co-morbidities, or patient preference. The reason for ASCT non-candidacy must be documented in the Case Report Form and verified by the site PI
Measurable disease (at least one non-bony fludeoxyglucose F-18 [FDG]-avid lesion >= 1.5 cm in long axis)
Absolute neutrophil count (ANC) >= 1,000/mm^3
NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
Platelets >= 50,000/mm^3
NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
Hemoglobin >= 8 g/dL (no transfusion allowed within 3 days prior to screening)
Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< 1.5 x ULN for patients with Gilbert's disease
Aspartate aminotransferase (AST) =< 2.5 x ULN
Alanine aminotransferase (ALT) =< 2.5 x ULN
Creatinine clearance of >= 40 mL/min per 24 hour urine test or the Cockcroft-Gault formula
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Agreement by women and men of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 5 months (women) or 7 months (men) after the last dose of protocol therapy
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

Concomitant investigational therapy
Live vaccine within 30 days prior to day 1 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies, bacillus Calmette-Guerin [BCG], oral polio vaccine, and oral typhoid)
Grade >= 2 peripheral neuropathy
History of prior >= grade 3 hypersensitivity to either brentuximab vedotin or nivolumab
Known active central nervous system (CNS) involvement by lymphoma, including parenchymal and/or lymphomatous meningitis
History of another primary malignancy that has not been in remission for at least 3 years, with the following exceptions:
Non-melanoma skin cancer treated with curative intent
In situ cervical cancer
If the malignancy is expected to not require any treatment for at least 2 years (this exception should be discussed with the study PI)
Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Exceptions are:
Inhaled or topical steroids and
Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active autoimmune disease
History of progressive multifocal leukoencephalopathy (PML)
Prior diagnosis of inherited or acquired immunodeficiency
Active pneumonitis or interstitial lung disease
Active, known or suspected autoimmune disease. The following are exceptions:
Vitiligo
Psoriasis not requiring systemic treatment
Hemolytic anemia associated with the lymphoma
Type I diabetes mellitus, if adequately controlled with therapy
Thyroid disease, if adequately controlled with therapy
Conditions not expected to recur in the absence of an external trigger (such exceptions should be discussed with the study PI)
Active history of:
Hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection. Patients with past HBV infection (defined as negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody [HBcAb]) are eligible if HBV DNA is undetectable. Patients who are positive for HCV antibody are eligible if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
Human immunodeficiency virus (HIV) infection. Subjects who have an undetectable or unquantifiable human immunodeficiency virus (HIV) viral load with CD4 >= 200 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures
History of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to day 1 of protocol therapy
Pregnant or breastfeeding
Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)