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

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ClinicalTrials.gov Identifier: NCT03077828
Recruitment Status : Recruiting
First Posted : March 13, 2017
Last Update Posted : November 15, 2018
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Jane N. Winter, Northwestern University

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.

Condition or disease Intervention/treatment Phase
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 Drug: Carboplatin Drug: Etoposide Drug: Ifosfamide Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Pembrolizumab in Combination With ICE Salvage Chemotherapy for Relapsed/Refractory Hodgkin Lymphoma
Actual Study Start Date : April 21, 2017
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : February 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplat
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213

Drug: Ifosfamide
Given IV
Other Names:
  • Asta 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-4942

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Complete Response Rate [ Time Frame: Up to 59 days ]
    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 :
  1. Incidence of Adverse Events [ Time Frame: Up to 2 years ]
    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.

  2. Event Free Survival (EFS) [ Time Frame: Up to 2 years ]
    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.

  3. Overall Survival (OS) [ Time Frame: Up to 2 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03077828


Contacts
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Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
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United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Pamela Allen, MD, MSc    404-778-1900      
Principal Investigator: Pamela Allen, MD, MSc         
Augusta University Medical Center Recruiting
Augusta, Georgia, United States, 30912
Contact: Locke J. Bryan, M.D.    706-721-2505    lbryan@augusta.edu   
Principal Investigator: Locke J. Bryan, M.D.         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Jane N. Winter, M.D.    312-695-4538      
Principal Investigator: Jane N. Winter, M.D.         
Sub-Investigator: Leo I. Gordon, M.D.         
Sub-Investigator: Shuo Ma, M.D., Ph.D.         
Sub-Investigator: Barbara Pro, M.D.         
Sub-Investigator: Jason Kaplan, M.D.         
Loyola University Medical Center Recruiting
Maywood, Illinois, United States, 60153
Contact: Scott E. Smith, M.D.,Ph.D.    708-216-9000      
Principal Investigator: Scott E. Smith, M.D.,Ph.D.         
United States, New Jersey
Hackensack University Medical Center Not yet recruiting
Hackensack, New Jersey, United States, 07601
Contact: Andre H. Goy, M.D., M.S    210-996-4469    agoy@hackensackumc.org   
Principal Investigator: Andre H. Goy, M.D., M.S         
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14642
Contact: Carla Casulo, M.D.    585-273-3258    carla_casulo@urmc.rochester.edu   
Principal Investigator: Carla Casulo, M.D.         
Sponsors and Collaborators
Northwestern University
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jane N. Winter, M.D. Northwestern University

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Responsible Party: Jane N. Winter, Jane N. Winter, M.D., Northwestern University
ClinicalTrials.gov Identifier: NCT03077828     History of Changes
Other Study ID Numbers: NU 16H07
NU 16H07 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
NCI-2016-01439 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STU00203658 ( Other Identifier: Northwestern University IRB# )
First Posted: March 13, 2017    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Sclerosis
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Carboplatin
Pembrolizumab
Etoposide
Etoposide phosphate
Ifosfamide
Isophosphamide mustard
Podophyllotoxin
Antineoplastic Agents
Antineoplastic Agents, Immunological
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Keratolytic Agents
Dermatologic Agents
Tubulin Modulators
Antimitotic Agents