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.
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
- Creatinine =< 2 x ULN or creatinine clearance (CrCl) > 30 ml/min
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to registration; if the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required
- Females of childbearing potential (FOCBP) should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; NOTE: A FOCBP
is any woman (regardless of sexual orientation, having undergone a tubal ligation, or
remaining celibate by choice) who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy
- Has had menses at any time in the preceding 12 consecutive months (and therefore
has not been naturally postmenopausal for > 12 months) NOTE: Abstinence is
acceptable if this is the usual lifestyle and preferred contraception for the
subject
- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy
- Patients must have the ability to understand and the willingness to sign a written
informed consent prior to registration on study
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 gents, 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
- Patients with known human immunodeficiency virus (HIV) infection or active TB
(Bacillus tuberculosis) are not eligible
- Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection are not eligible
- Patients must not have a hypersensitivity to pembrolizumab or any of its excipients
- Patients must not have received a live vaccine within 30 days of registration Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed)
- Patients must not be pregnant or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, starting with the pre-screening
or screening visit through 120 days after the last dose of trial treatment
- Patients who are unwilling or unable to comply with the protocol or have known
psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the trial are not eligible
