Clinical Trials /

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

NCT02396134

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
  • Myelofibrosis
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 13494
  • SECONDARY ID: NCI-2015-00283
  • SECONDARY ID: 13494
  • SECONDARY ID: R01CA181045
  • NCT ID: NCT02396134

Conditions

  • 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

Interventions

DrugSynonymsArms
CMVpp65-A*0201 peptide vaccineArm I (CMVpp65-A*0201 peptide vaccine)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if cytomegalovirus (CMV) peptide(Pep)vaccine(Vax) (CMVpp65-A*0201 peptide
      vaccine) increases levels, function and kinetics of CMV-specific T cell immunity in
      vaccinated compared to placebo treated human leukocyte antigen (HLA) A*0201 allogeneic CMV
      positive hematopoietic stem cell transplant (HCT) recipients (HCT-R+). (Entire cohort) II. To
      provide a preliminary evaluation of the incidence of CMV reactivation between day 56 and day
      180 in patients who receive standard letermovir (Prevymis) prophylaxis (from day 14 through
      day 100), comparable to the evaluation of an expansion cohort in a pilot study, or the
      futility stage of a phase II trial. (Letermovir combination cohort) III. To determine if
      CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity in
      vaccinated HCT patients who receive standard Prevymis prophylaxis. (Letermovir combination
      cohort)

      SECONDARY OBJECTIVES:

      I. To determine, within the constraints of a pilot cohort, if CMVPepVax reduces the frequency
      of CMV events alone or in combination with Prevymis defined as reactivation or CMV disease in
      HLA A*0201 allogeneic HCT-R+.

      II. 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.

      III. 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 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.

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

      V. To determine the impact of CMVPepVax on CMV immune reconstitution in patients who undergo
      treatment with antiviral agent Prevymis.

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

      VII. To characterize CMV reactivation after day 180

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (CMVpp65-A*0201 peptide vaccine)ExperimentalPatients receive CMVpp65-A*0201 peptide vaccine SC on days 28 and 56 after HCT.
  • CMVpp65-A*0201 peptide vaccine
Arm II (placebo)Placebo ComparatorPatients receive placebo SC on days 28 and 56 after HCT.

    Eligibility 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)
    
                   -  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)
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:CMV events encompassing any CMV reactivation defined as >= 500 CMV gc/mL or CMV disease
    Time Frame:Up to day 100 after HCT
    Safety Issue:
    Description: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

    Measure:non-relapse mortality (NRM)
    Time Frame:At 100 days after HCT
    Safety Issue:
    Description:Time of death as day post HCT
    Measure:Severe (grade 3-4) aGVHD
    Time Frame:Within 100 days after HCT
    Safety Issue:
    Description:Highest overall grade
    Measure:Grade 3-4 AEs (CTCAE version 4.0) probably or definitely related to the vaccination
    Time Frame:Within 2 weeks of vaccination
    Safety Issue:
    Description:MEDDRA code
    Measure:Time to viremia
    Time Frame:Between day 56 and 180 days after HCT
    Safety Issue:
    Description:Number of days from transplantation to the first date of >= 500 CMV gc/mL (or antiviral therapy)
    Measure:Duration of viremia
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Duration (days) between the date of first viremia episode (outcome #7) and date of undetectable of viremia
    Measure:Incidence of late CMV viremia
    Time Frame:From 180 through 360 days after HCT
    Safety Issue:
    Description:Number of days from transplantation to the first date of >= 500 CMV gc/mL (or antiviral therapy) after day 180, either as a first event or a recurrence after earlier viremia became non-detectable
    Measure:Use of antiviral drugs
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day post-HCT of first CMV-directed antiviral dose
    Measure:Cumulative number of CMV specific antiviral treatment days
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Total number of days of treatment during time frame
    Measure:Time to engraftment
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day post HCT of first adequate cell count
    Measure:Incidence of aGVHD
    Time Frame:Within 100 days after HCT
    Safety Issue:
    Description:Day of first aGVHD of any grade
    Measure:Incidence of cGVHD
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day of first cGVHD
    Measure:Incidence of relapse
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day of relapse
    Measure:All-cause mortality
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day of death
    Measure:Incidence of non-CMV infections
    Time Frame:Up to 365 days after HCT
    Safety Issue:
    Description:Day of infection
    Measure:CMV reactivation (>= 1,250 IU/mL) or CMV disease post-HCT
    Time Frame:Up to 180 days after hematopoietic cell transplant
    Safety Issue:
    Description:Day of event
    Measure:Immune reconstitution measured as levels, function and kinetics of CMV-specific T cells through day 365 post-HCT in patients who receive standard Prevymis prophylaxis (day 14 through day 100).
    Time Frame:at days 28, 42, 56, 70, 84, 100, 140, 180, 270 and 365 after hematopoietic cell transplant
    Safety Issue:
    Description:The measurement of function is determined by "dextramer-binding CD8 T cells/microliter, and "kinetics" will be determined as "% change" from the baseline (day 28) value at each time point below

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:City of Hope Medical Center

    Last Updated

    July 12, 2019