This phase II trial studies the side effects of nivolumab and to see how well it works when given together with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin lymphoma that has come back (relapsed) and does not respond to treatment (refractory). 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. Drugs used in chemotherapy, such as ifosfamide, carboplatin and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab, ifosfamide, carboplatin and etoposide may work better in treating patients with Hodgkin lymphoma.
PRIMARY OBJECTIVES: I. Evaluate the anti-tumor activity of nivolumab as single agent and in combination with ifosfamide, carboplatin, etoposide (ICE) chemotherapy (nivolumab \[N\]ICE) as assessed by complete response (CR) rate prior to autologous hematopoietic cell transplantation. II. To estimate the proportion of patients experiencing unacceptable adverse events. (Cohort B) III. To assess the safety and tolerability of nivolumab + ICE chemotherapy through evaluation of toxicities, including type, frequency, severity, attribution, time course, and duration. (Cohort B) IV. To obtain estimate of overall response rate (ORR), complete response rate, response duration and survival (overall and event-free). (Cohort B) V. Summarize stem cell mobilization outcomes (e.g., total CD34+ cell yield, number of apheresis days, proportion of patients who achieve \>= 2 x 10\^6 CD34+ cells/kg). (Cohort B) VI. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab. (Cohort B) SECONDARY OBJECTIVES: I. Assess the safety and tolerability of nivolumab +/- ICE chemotherapy through evaluation of toxicities, including type, frequency, severity, attribution, time course and duration. II. Obtain estimates of overall response rate (ORR), response duration and survival (overall and event-free). III. Summarize stem cell mobilization outcomes (e.g., total CD34+ cell yield, number of apheresis days, proportion of patients who achieve \>= 2 x 10\^6 CD34+ cells/kg). IV. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab. V. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), estimate the post-AHCT overall/progression free survival (PFS) probability and cumulative incidence of relapse/progression, non-relapse mortality (NRM) at 100-days, 1-year and 2-years. VI. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), characterize post-AHCT toxicities during the first 30- and 100- days post stem cell infusion by type, frequency, severity, attribution, time course and duration. VII. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), evaluate short and long-term post-AHCT complications, including: delayed engraftment (neutrophil and platelet) and infection, graft versus host disease and sinusoidal obstruction syndrome. EXPLORATORY OBJECTIVES: I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and serial plasma samples for future biomarker evaluation. II. Evaluate potential changes in Hodgkin lymphoma biological markers of patients treated with nivolumab. OUTLINE: Patients are sequentially assigned to 1 of 2 cohorts. COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients with CR or partial response (PR) receive nivolumab for an additional 6 weeks. Patients with only stable disease (SD) after 6-week nivolumab treatment receive nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with progressive disease (PD) after 6-week nivolumab treatment or patients with PR, SD, or PD after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. COHORT B: Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day 1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
78
Given IV
Given IV
Given IV
Correlative studies
Given IV
City of Hope Medical Center
Duarte, California, United States
Yale University
New Haven, Connecticut, United States
M D Anderson Cancer Center
Houston, Texas, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
Complete Response Rate by Lugano Classification
Complete response rates were calculated as the percent of evaluable patients that have confirmed complete response by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits were calculated for this estimate.
Time frame: From the initial treatment to the end of the treatment, up to 6 months.
Number of Participants With Unacceptable Adverse Events
Toxicities were assessed and reported using the Bearman (non-hematologic) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scales. Unacceptable toxicity in a given patient is defined as any non-hematologic or hematological grade 3/4 toxicity that did not resolve to a grade 1/2 within 14 days per NCI CTCAE v4.03 toxicity criteria and was considered at least possibly related to nivolumab and/or ICE, or any other regimen-related cause of death.
Time frame: From initial treatment to the end of the study, up to 77 months.
Overall Response Rate
Overall response rate was calculated as the percent of evaluable patients that have confirmed complete response or partial remission by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits were calculated for this estimate.
Time frame: From the initial treatment to the end of the treatment, up to 6 months.
Two-Year Overall Survival (OS) Rate
Overall survival (OS) is defined as the duration of time from start of study treatment to time of death (due to any cause). OS rate was estimated using the product-limit method of Kaplan and Meier. The event is death.
Time frame: 2 years from start of treatment
Two-Year Progression-Free Survival (PFS) Rate
Progression-free survival is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first. PFS rate was estimated using the product-limit method of Kaplan and Meier. The event is progression/relapse or death.
Time frame: 2 years from start of treatment
Two-Year Progression-Free Survival Rate (Post Autologous Transplant)
Progression-free survival (PFS) is defined as the duration of time from start of transplant to time of progression or death, whichever occurs first. PFS rate was estimated using the product-limit method of Kaplan and Meier. The event is post-transplant progression/relapse or death.
Time frame: From start of transplant to time of progression, death (due to any cause), or last contact, whichever comes first, assessed 2 years post-transplant, up to 3 years.
Cumulative Incidence of Relapse/Progression at 2 Years
The cumulative incidence of relapse/progression was calculated as competing risks using the method of Gooley et al. The event is relapse/progression. Deaths without relapse/progression are considered a competing risk.
Time frame: 2 years from start of treatment
Non-relapse Mortality (NRM) at 2 Years
The cumulative incidence of non-relapse mortality was calculated as competing risks using the method of Gooley et al. NRM is defined as death occurring in a patient from causes other than relapse or progression. Deaths from relapse/progression are considered a competing risk.
Time frame: 2 years from start of treatment
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