Classic Hodgkin Lymphoma, Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma
Conditions
Brief summary
This phase II trial studies how well nivolumab and brentuximab vedotin work after stem cell transplant in treating patients with high-risk classical Hodgkin lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as nivolumab and brentuximab, 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 OBJECTIVE: I. Assess the efficacy of nivolumab plus brentuximab vedotin consolidation after autologous stem cell transplantation (ASCT) in participants with relapsed/refractory Hodgkin lymphoma (HL), as assessed by 18-month progression-free survival (PFS). SECONDARY OBJECTIVES: I. Estimate the overall survival (OS), the cumulative incidence of relapse/progression, the cumulative incidence of non-relapse mortality (TRM) in participants with relapsed/ refractory HL who receive nivolumab plus brentuximab vedotin consolidation after ASCT. II. Estimate the overall response rate to nivolumab plus brentuximab vedotin therapy in participants with measurable disease after ASCT. III. Establish the safety and tolerability of nivolumab plus brentuximab vedotin when used as consolidation after ASCT in participants with relapsed/ refractory HL. EXPLORATORY OBJECTIVES: I. Evaluate the Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) definition of indeterminate response to guide the management of patients regarding treatment past progressive disease. II. Explore the impact of nivolumab plus brentuximab vedotin therapy on immune reconstitution after ASCT. III. Explore the prognostic impact of and temporal dynamics of minimal residual disease (MRD) in the peripheral blood as assessed by the next-generation sequencing-based ClonoSEQ platform. IV. Explore the prognostic impact of 9p24.1 abnormalities in tumor tissue assessed by fluorescence in situ hybridization (FISH) on outcomes after ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. V. Explore the relationship between immune cells and Hodgkin and Reed/Sternberg (HRS) in tumor samples by 6-color quantitative spatial image analysis using the Vectra system, and correlate with outcome after ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. VI. Explore whether genetic alterations (e.g. gene expression profiles or genetic mutations) in HL tumor samples are associated with outcome after ASCT and nivolumab plus brentuximab vedotin post-ASCT consolidation therapy. OUTLINE: Beginning 30-60 days post-ASCT, patients receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 100 days, at 3, 6, 12, and 18 months from start of treatment, and then biannually thereafter.
Interventions
DRUGBrentuximab Vedotin
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALNivolumab
Given IV
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented informed consent * Agreement to allow the use of archival tissue from pre-ASCT tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval * Eastern Cooperative Oncology Group (ECOG) performance status =\< 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 * Have high-risk relapsed or refractory Hodgkin lymphoma (HL), defined as at least one of the following: * Primary refractory disease to front-line therapy * Relapse within 1 year of completing front-line therapy * Extranodal involvement at the time of pre-ASCT relapse * B symptoms at pre-ASCT relapse * More than one type of pre-ASCT salvage therapy required * Planning to receive or have received autologous stem cell transplantation (ACST) per institutional standards as part of standard of care * Pre-ASCT participants may consent but will not be eligible to begin treatment until after ASCT, and will have to fulfill all inclusion and
Exclusion criteria
before starting protocol * All participants must initiate day 1 of protocol therapy within 30-60 days post stem cell reinfusion; study PI can grant exception for a patient to start as late as 75 days post stem cell reinfusion with a reasonable justification for a delay (e.g. recovery from post -ASCT toxicity) and this will not be a protocol deviation, nor require an exception to be filled * Recovery from ASCT toxicity as defined as outpatient status, able to drink, eat normally, and do not need intravenous hydration prior to day 1 of therapy * Achieved at least stable disease to salvage treatment determined by positron emission tomography (PET)/computed tomography (CT) using 2014 Lugano Classification prior to ASCT * Brentuximab vedotin naive OR had at least stable disease by Lugano Classification to prior brentuximab vedotin treatment * Absolute neutrophil count (ANC) \>= 1000/mm\^3 * Platelets \>= 50,000/mm\^3 * Hemoglobin \>= 8 g/dL * Total bilirubin =\< 1.5 x upper limit of normal (ULN) or 3 x ULN for Gilbert's disease * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN * Creatinine clearance \>= 40 mL/min per 24 hour urine collection or the Cockcroft-Gault formula * Calculated per institutional standard * Forced expiratory volume in one second (FEV1) and carbon monoxide diffusion capacity (DLCO) (adjusted for hemoglobin \[Hb\]) \>= 50% adjusted * Women of childbearing potential (WOCBP) only: Negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Woman of childbearing potential (WOCBP): use two effective methods of contraception (hormonal or barrier method) or be surgically sterile, or abstain from heterosexual activity for the course of the study through 7 months post last dose of nivolumab * WOCBP defined as not being surgically sterilized or have not been free from menses for \> 1 year * Male: use two effective methods of contraception (barrier method) or abstain from heterosexual activity with the first dose of study therapy through 7 months post last dose of nivolumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival at 18 Months | From the first dose of study treatment to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed at 18 months. | Progression-free survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error. When there is no censoring in progression-free survival prior to 18 months after the first dose of study treatment, the observed 18-month progression-free survival will be compared to the baseline of 65% by one-sided exact test of binomial proportion. In case of censoring in progression-free survival prior to 18 months after the first dose of study treatment, the Kaplan-Meier estimate for 18-month progression-free survival along with the Greenwood standard error estimator will be used for the testing of null hypothesis at 65%. Hodgkin Lymphoma(HL) response/progression was evaluated using 2014 Lugano Classification \[Cheson, Journal of Clinical Oncology 2014 Sep 20;32(27):3059-68\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 18 Months | From the first dose of study treatment to death from any cause, assessed up to 18 months | Overall survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAlex Herrera
City of Hope Medical Center
Participant flow
Pre-assignment details
Three subjects consented but did not participate in the study. Two subjects withdrew consent and one subject became ineligible due to developmental of interstitial pneumonia after consent before screening.
Participants by arm
| Arm | Count |
|---|---|
| Brentuximab Vedotin 1.8 mg/kg + Nivolumab 3 mg/kg Q21 Days Beginning 30-60 days post-ASCT, patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Brentuximab Vedotin: Given IV Nivolumab: Given IV | 59 |
| Total | 59 |
Baseline characteristics
| Characteristic | Brentuximab Vedotin 1.8 mg/kg + Nivolumab 3 mg/kg Q21 Days |
|---|---|
| Age, Continuous | 30 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Region of Enrollment United States | 59 participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 59 |
| other Total, other adverse events | 59 / 59 |
| serious Total, serious adverse events | 19 / 59 |
Outcome results
Primary
Progression-free Survival at 18 Months
Progression-free survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error. When there is no censoring in progression-free survival prior to 18 months after the first dose of study treatment, the observed 18-month progression-free survival will be compared to the baseline of 65% by one-sided exact test of binomial proportion. In case of censoring in progression-free survival prior to 18 months after the first dose of study treatment, the Kaplan-Meier estimate for 18-month progression-free survival along with the Greenwood standard error estimator will be used for the testing of null hypothesis at 65%. Hodgkin Lymphoma(HL) response/progression was evaluated using 2014 Lugano Classification \[Cheson, Journal of Clinical Oncology 2014 Sep 20;32(27):3059-68\].
Time frame: From the first dose of study treatment to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed at 18 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brentuximab Vedotin 1.8 mg/kg + Nivolumab 3 mg/kg Q21 Days | Progression-free Survival at 18 Months | 94 percentage of survival probability |
Secondary
Overall Survival at 18 Months
Overall survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error.
Time frame: From the first dose of study treatment to death from any cause, assessed up to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brentuximab Vedotin 1.8 mg/kg + Nivolumab 3 mg/kg Q21 Days | Overall Survival at 18 Months | 98 percentage of survival probability |