Phase II Trial of Pembrolizumab in Combination With ICE Salvage Chemotherapy for Relapsed/Refractory Hodgkin Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Carboplatin
- Conditions
- Lymphocyte-Rich Classical Hodgkin Lymphoma
- Sponsor
- Northwestern University
- Enrollment
- 43
- Locations
- 6
- Primary Endpoint
- Complete Response Rate
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this research study is to evaluate a new drug Pembrolizumab in combination with chemotherapy, for Relapsed/Refractory Hodgkin Lymphoma. The chemotherapy regimen is called "ICE" and includes three drugs: ifosfamide, carboplatin, and etoposide. Pembrolizumab is currently Food and Drug Administration (FDA) approved for the treatment of some patients with melanoma, lung cancer and head and neck cancer, but has not yet been approved for the treatment of Relapsed/Refractory Hodgkin Lymphoma. The 'ICE' regimen of chemotherapy is currently FDA approved for the treatment of Relapsed/Refractory Hodgkin Lymphoma, but has not yet been investigated in combination with pembrolizumab for this disease. For patients who have a relapse of their Hodgkin's lymphoma, retreatment with chemotherapy followed by a stem cell transplant is recommended. We know that obtaining a complete remission (not able to detect any disease on scans) is very important prior to proceeding to the stem cell transplant. Patients with negative scans have a lower chance of the disease coming back and a higher chance of achieving a long-term cure.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the complete response rate by fludeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) prior to autologous hematopoietic stem cell transplant (AHSCT) with the combination of pembrolizumab and ifosfamide, carboplatin, etoposide (ICE) salvage chemotherapy for relapsed/refractory Hodgkin lymphoma. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of pembrolizumab in combination with salvage high-dose chemotherapy according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03. II. To estimate the event free survival (EFS) at 2 years from start of treatment. III. To estimate the overall survival (OS) at 2 years from start of treatment. TERTIARY OBJECTIVES: I. To characterize PD-1 pathway specific expression and correlate with response. II. To characterize serum biomarkers of immune and inflammatory response during treatment. III. To characterize levels of soluble PD-L1 related to treatment with pembrolizumab. IV. To characterize T-lymphocyte subset changes to treatment with pembrolizumab. V. To investigate the prevalence and clinical correlation of chromosome 9p24.1 mutations for this population. VI. To evaluate the effect on stem cell harvest following treatment with pembrolizumab. OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3. After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years.
Investigators
Jane N. Winter
Jane N. Winter, M.D.
Northwestern University
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed diagnosis of classical Hodgkin lymphoma including nodular sclerosis, mixed cellularity, lymphocytic-rich, and lymphocyte depleted subtypes by the 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues published in 2008
- •Patients must have disease with FDG-PET/CT avidity
- •Patients must have relapsed/refractory disease, with at least one line of prior chemotherapy, but =\< 2 prior lines of treatment, for Hodgkin lymphoma; NOTE: Patients must not have had prior immune checkpoint inhibitors; however, there are no other limitations to prior agent or regimen types
- •Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Patients must have adequate organ and bone marrow function within 10 days of registration, as defined below:
- •Absolute neutrophil count \>= 1,000/mcL (in the absence of granulocyte colony stimulating factor (GCSF) for \>= 14 days)
- •Platelets \>= 75,000/mcl (in the absence of platelet transfusion for \>= 14 days)
- •Hemoglobin \>= 7g/dL (transfusion permitted)
- •Total bilirubin =\< 2 x institutional upper limit of normal (ULN); if total bilirubin is \> 2 x ULN, the direct bilirubin must be normal
- •Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SPGT\]) =\< 2.5 x institutional ULN
Exclusion Criteria
- •Patients who have had chemotherapy, radiotherapy, monoclonal antibody (mAb), or targeted small molecule therapy within 4 weeks of study registration are not eligible; those who have not recovered from adverse events (grade 1 or baseline) due to such agents administered more than 4 weeks earlier are not eligible
- •Patients may not be currently receiving any other investigational agents within 4 weeks of study registration
- •Patients must not have had prior exposure to any immune checkpoint inhibitors including anti-PD-1, anti-PD-L1 agents, anti-PD-L2 agents, or anti-CTLA-4 monoclonal antibodies
- •Patients must not have known central nervous system (CNS) involvement
- •Patients must not have had prior stem cell transplantation (autologous or allogeneic)
- •Patients must not have persistent diarrhea greater than National Cancer Institute (NCI) CTCAE grade 2 at the time of study registration, despite medical management
- •Patients must not have a history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, noninfectious pneumonitis
- •Patients with known immunodeficiency, known autoimmune disease, or concurrent use of immunomodulatory agents including systemic steroids within 7 days prior to registration, are ineligible
- •Patients must not have 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; this includes, 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
- •Patients must not have a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
Arms & Interventions
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
Patients receive pembrolizumab IV over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3.
Intervention: Carboplatin
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
Patients receive pembrolizumab IV over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3.
Intervention: Etoposide
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
Patients receive pembrolizumab IV over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3.
Intervention: Ifosfamide
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
Patients receive pembrolizumab IV over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
Patients receive pembrolizumab IV over 30 minutes on day 1, etoposide IV over 60 minutes on days 1-3 of courses 1-2, carboplatin IV over 60 minutes on day 2 of courses 1-2, and ifosfamide IV over 24 hours on day 2 of courses 1-2. Pembrolizumab in combination with ICE chemotherapy repeats every 21 days for 2 courses, patients will then receive pembrolizumab as monotherapy on course 3.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Complete Response Rate
Time Frame: Up to 59 days
To determine the complete response rate by FDG-PET/CT prior to AHSCT with the combination of pembrolizumab and ICE salvage chemotherapy for relapsed/refractory Hodgkin lymphoma. Response was assessed using Lugano criteria 2014. To address the primary aim, the proportion of patients with complete responses was calculated(defined as FDG-PET/CT Deauville score ≤ 3) as (number of responders) / (number of evaluable patients).
Secondary Outcomes
- Incidence of Adverse Events(Up to 2 years)
- Event Free Survival (EFS)(Up to 2 years)
- Overall Survival (OS)(Up to 2 years)