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Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT02396134
Recruitment Status : Active, not recruiting
First Posted : March 24, 2015
Last Update Posted : December 19, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This randomized phase II trial studies how well vaccine therapy works in reducing the frequency of cytomegalovirus severe infections (events) in patients with hematologic malignancies undergoing donor stem cell transplant. Vaccines made from a peptide may help the body build an effective immune response and may reduce cytomegalovirus events after donor stem cell transplant.

Condition or disease Intervention/treatment Phase
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Adult Acute Lymphoblastic Leukemia in Remission Adult Acute Myeloid Leukemia in Remission Adult Hodgkin Lymphoma Adult Non-Hodgkin Lymphoma Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Cytomegaloviral Infection Hematopoietic and Lymphoid Cell Neoplasm HLA-A*0201 Positive Cells Present Myelodysplastic Syndrome Adult Lymphoblastic Lymphoma Chronic Lymphocytic Leukemia Myelofibrosis Myeloproliferative Neoplasm Biological: CMVpp65-A*0201 peptide vaccine Other: Placebo Other: Laboratory Biomarker Analysis Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine if cytomegalovirus (CMV)peptide(Pep)vaccine(Vax) (CMVpp65-A*0201 peptide vaccine) reduces the frequency of CMV events defined as reactivation or CMV disease in human leukocyte antigen (HLA) A*0201 allogeneic CMV positive hematopoietic stem cell transplant (HCT) recipients (HCT-R+).

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of CMVPepVax by assessing the following: non-relapse mortality (NRM) at 100 days post HCT, severe (grade 3-4) acute graft versus host disease (GVHD) (aGVHD), and grade 3-4 adverse events (AEs) (Common Terminology Criteria for Adverse Events [CTCAE] 4.0) probably or definitely related to the vaccination within 2 weeks from each vaccination.

II. To characterize CMV reactivation and CMV disease in recipients of CMVPepVax compared to placebo by assessing time-to viremia (defined as number of days from transplantation to the date of >= 500 CMV genome copies [gc]/mL) , duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (> 100 and =< 360 days post HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV specific antiviral treatment days.

III. To evaluate the impact of CMVPepVax on transplant related outcomes by assessing the incidence of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, non-relapse mortality, all-cause mortality, infections.

IV. To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated HLA A*0201, CMV seropositive HCT-recipients.

V. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells.

VI. To explore GVHD biomarkers and compare between the vaccine and placebo groups.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive CMVpp65-A*0201 peptide vaccine subcutaneously (SC) on days 28 and 56 after HCT.

ARM II: Patients receive placebo SC on days 28 and 56 after HCT.

After completion of study treatment, patients are followed up to day 365 after HCT.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Supportive Care
Official Title: A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate Protective Function of an Optimized Dose of CMVPepVax in Recipients of an Allogeneic Hematopoietic Stem Cell Transplant
Actual Study Start Date : May 21, 2015
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019


Arm Intervention/treatment
Experimental: Arm I (CMVpp65-A*0201 peptide vaccine)
Patients receive CMVpp65-A*0201 peptide vaccine SC on days 28 and 56 after HCT.
Biological: CMVpp65-A*0201 peptide vaccine
Given SC

Other: Laboratory Biomarker Analysis
Correlative studies

Placebo Comparator: Arm II (placebo)
Patients receive placebo SC on days 28 and 56 after HCT.
Other: Placebo
Given SC
Other Name: PLCB

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. CMV events encompassing any CMV reactivation defined as >= 500 CMV gc/mL or CMV disease [ Time Frame: Up to day 100 after HCT ]
    Each randomized study subject will be followed according to the study calendar for the occurrence of CMV reactivation events, which are defined in terms of either viremia, low-level viremia treated with antivirals, or CMV disease. Both initial and recurrent events will be recorded, with patients considered at risk for recurrent events after completion of a full planned course of a full course of anti-viral therapy. Vaccine and placebo groups will be compared with regard to the hazard of CMV events, using the Anderson-Gill approach to repeated events.


Secondary Outcome Measures :
  1. non-relapse mortality (NRM) [ Time Frame: At 100 days after HCT ]
  2. Severe (grade 3-4) aGVHD probably or definitely related to the vaccination [ Time Frame: Within 100 days after HCT ]
  3. Grade 3-4 AEs graded by CTCAE version 4.0 probably or definitely related to the vaccination [ Time Frame: Within 2 weeks of vaccination ]
  4. Time to viremia [ Time Frame: Up to 365 days after HCT ]
    Defined as the number of days from transplantation to the date of >= 500 CMV gc/mL

  5. Duration of viremia [ Time Frame: Up to 365 days after HCT ]
  6. Incidence of late CMV viremia [ Time Frame: Up to 360 days after HCT ]
  7. Use of antiviral drugs triggered by clinically significant viremia >= 1,500 CMV gc/mL [ Time Frame: Up to 365 days after HCT ]
  8. Cumulative number of CMV specific antiviral treatment days [ Time Frame: Up to 365 days after HCT ]
  9. Time to engraftment [ Time Frame: Up to 365 days after HCT ]
  10. Incidence of aGVHD [ Time Frame: Within 100 days after HCT ]
  11. Incidence of cGVHD [ Time Frame: Up to 365 days after HCT ]
  12. Incidence of relapse [ Time Frame: Up to 365 days after HCT ]
  13. All-cause mortality [ Time Frame: Up to 365 days after HCT ]
  14. Incidence of infections [ Time Frame: Up to 365 days after HCT ]
  15. PD-1 expression [ Time Frame: Up to day 365 after HCT ]
  16. NK phenotype assessed by change in cytotoxicity [ Time Frame: From day 28 to day 365 after HCT ]
  17. NK function assessed by change in cytokine production [ Time Frame: From day 28 to day 365 after HCT ]
  18. Levels of CD8+ T cells binding to A2-CMV-dextramers [ Time Frame: Up to day 365 after HCT ]
    The longitudinal CMV-specific cellular assay data will be modeled on a logarithmic scale, using a generalized estimating equation approach to accommodate the stochastic dependence through time. This produces an estimated multiplicative effect of vaccination, qualified by a valid estimate of variability.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All subjects must have the ability to understand and the willingness to sign a written informed consent
  • Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT
  • Planned HCT for the treatment of the following hematologic malignancies:

    • Lymphoma (Hodgkin and non-Hodgkin)
    • Myelodysplastic syndrome
    • Acute lymphoblastic leukemia in first or second remission (for acute lymphoblastic leukemia/lymphoblastic lymphoma, the disease status needs to be in hematologic remission by bone marrow and peripheral blood; persistent lymphadenopathy on computed tomography [CT] or CT/positron emission tomography [PET] scan without progression is allowed)
    • Acute myeloid leukemia in first or second remission
    • Chronic myelogenous leukemia in first chronic or accelerated phase, or in second chronic phase
    • Other hematologic malignancies including chronic lymphocytic leukemia, myeloproliferative disorders and myelofibrosis; patients with multiple myeloma and those with non-malignant disease such as aplastic anemia are excluded
  • HLA A*0201 High resolution, 4-digit typing is required at HLA-A2 to ensure A*0201 status.
  • CMV seropositive (recipient)
  • Planned related or unrelated HCT, with HLA donor allele matching; related donor must be an 8/8 match for HLA-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid (DNA)-based typing; unrelated donor must be an 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing; patients undergoing a second allo HCT are not eligible (patients who have undergone a previous autologous HCT are eligible)
  • Planned HCT with no ex-vivo T cell depletion of graft; conditioning and immunosuppressive regimens according to institutional guidelines are permitted
  • Negative serum or urine beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) within two weeks of registration
  • Seronegative for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and active hepatitis B virus (HBV) (surface antigen negative) within 2 months of registration
  • Agreement by females of childbearing potential and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for up to 90 days post-HCT; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

Exclusion Criteria:

  • Any prior investigational CMV vaccine
  • Experimental anti-CMV chemotherapy in the last 6 months
  • Planned medications from the time of HCT to day 70 post-HCT:

    • Live attenuated vaccines
    • Medically indicated subunit (Engerix-B for HBV; Gardasil for human papilloma virus [HPV]) or killed vaccines (e.g. influenza, pneumococcal, or allergy treatment with antigen injections)
    • Allergy treatment with antigens injections
    • Alemtuzumab or any equivalent in vivo T-cell depleting agent; this includes anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide
    • Antiviral medications with known therapeutic effects against CMV such as ganciclovir (GCV)/valine (VAL), foscarnet (FOS), cidofovir, hexadecyloxypropyl-cidofovir (CMX-001) and maribavir; acyclovir has no therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV)
    • Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment
    • Other investigational product - concurrent enrollment in other clinical trials using an investigational product is prohibited
    • Other medications that might interfere with the evaluation of the investigational product
  • Patients with active autoimmune conditions requiring systemic immunosuppressive therapy within the previous 5 years are not eligible
  • Pregnant women and women who are lactating; breastfeeding should be discontinued if the mother is enrolled on this study
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., social/psychological issues, etc
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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): NCT02396134


Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
United States, Georgia
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Minnesota
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, United States, 55455
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Ryotaro Nakamura, MD City of Hope Medical Center

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02396134     History of Changes
Other Study ID Numbers: 13494
NCI-2015-00283 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
13494 ( Other Identifier: City of Hope Medical Center )
R01CA181045 ( U.S. NIH Grant/Contract )
First Posted: March 24, 2015    Key Record Dates
Last Update Posted: December 19, 2017
Last Verified: December 2017

Additional relevant MeSH terms:
Lymphoma
Leukemia
Neoplasms
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid
Hodgkin Disease
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Primary Myelofibrosis
Myeloproliferative Disorders
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myeloid, Accelerated Phase
Hematologic Neoplasms
Cytomegalovirus Infections
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, B-Cell
Neoplasms by Site
Herpesviridae Infections