Clinical Trials /

Pembrolizumab and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

NCT03077828

Description:

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.

Related Conditions:
  • Classical Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma
  • Official Title: Phase II Trial of Pembrolizumab in Combination With ICE Salvage Chemotherapy for Relapsed/Refractory Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NU 16H07
  • SECONDARY ID: NU 16H07
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2016-01439
  • SECONDARY ID: STU00203658
  • NCT ID: NCT03077828

Conditions

  • Lymphocyte-Rich Classical Hodgkin Lymphoma
  • Recurrent Lymphocyte-Depleted Classical Hodgkin Lymphoma
  • Recurrent Mixed Cellularity Classical Hodgkin Lymphoma
  • Recurrent Nodular Sclerosis Classical Hodgkin Lymphoma
  • Refractory Lymphocyte-Depleted Classical Hodgkin Lymphoma
  • Refractory Mixed Cellularity Classical Hodgkin Lymphoma
  • Refractory Nodular Sclerosis Classical Hodgkin Lymphoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, etoposide, carboplatin, ifosfamide)ExperimentalPatients 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.
  • Carboplatin
  • Etoposide
  • Ifosfamide
  • Pembrolizumab

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response Rate
Time Frame:Up to 59 days
Safety Issue:
Description:Determine the complete response rate by evaluating FDG-PET/CT scans prior to Autologous Hematopoietic Stem Cell Transplant (AHSCT) with the combination of pembrolizumab and ICE salvage chemotherapy for relapsed/refractory Hodgkin lymphoma.

Secondary Outcome Measures

Measure:Incidence of Adverse Events
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluate the safety and tolerability of pembrolizumab in combination with ICE salvage high-dose chemotherapy by measuring the frequency and severity of adverse events by type, severity (grade), timing, and attribution to pembrolizumab which will be assessed according the NCI-CTCAE version 4.03.
Measure:Event Free Survival (EFS)
Time Frame:Up to 2 years
Safety Issue:
Description:EFS will be defined as the length of time from treatment on protocol until the first occurrence of disease relapse, progression, re-initiation of cytotoxic chemotherapy, or death due to disease, or until last contact if the patient did not experience any of these, assessed up to 2 years.
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:OS will be defined as time from study enrollment until death, or until last contact if the patient did not die, assessed up to 2 years.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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