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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 : February 21, 2022
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) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 133 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 : December 21, 2022
Estimated Study Completion Date : December 21, 2022


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: placebo, Placebo, placebo therapy, PLCB, sham therapy

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.

  2. Levels of CD8+ T cells binding to A2-cytomegalovirus (CMV)-dextramers [ Time Frame: Up to day 365 after hematopoietic cell transplant ]
    The longitudinal cytomegalovirus-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.

  3. CMV reactivation [>= 1,250 IU/mL] or CMV disease in patients who receive standard Prevymis prophylaxis [ Time Frame: Up to 180 days after hematopoietic cell transplant ]

Secondary Outcome Measures :
  1. non-relapse mortality (NRM) [ Time Frame: At 100 days after HCT ]
    Time of death as day post HCT

  2. Severe (grade 3-4) aGVHD [ Time Frame: Within 100 days after HCT ]
    Highest overall grade

  3. Grade 3-4 AEs (CTCAE version 4.0) probably or definitely related to the vaccination [ Time Frame: Within 2 weeks of vaccination ]
    MEDDRA code

  4. Time to viremia [ Time Frame: Between day 56 and 180 days after HCT ]
    Number of days from transplantation to the first date of >= 500 CMV gc/mL (or antiviral therapy)

  5. Duration of viremia [ Time Frame: Up to 365 days after HCT ]
    Duration (days) between the date of first viremia episode (outcome #7) and date of undetectable of viremia

  6. Incidence of late CMV viremia [ Time Frame: From 180 through 360 days after HCT ]
    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

  7. Use of antiviral drugs [ Time Frame: Up to 365 days after HCT ]
    Day post-HCT of first CMV-directed antiviral dose

  8. Cumulative number of CMV specific antiviral treatment days [ Time Frame: Up to 365 days after HCT ]
    Total number of days of treatment during time frame

  9. Time to engraftment [ Time Frame: Up to 365 days after HCT ]
    Day post HCT of first adequate cell count

  10. Incidence of aGVHD [ Time Frame: Within 100 days after HCT ]
    Day of first aGVHD of any grade

  11. Incidence of cGVHD [ Time Frame: Up to 365 days after HCT ]
    Day of first cGVHD

  12. Incidence of relapse [ Time Frame: Up to 365 days after HCT ]
    Day of relapse

  13. All-cause mortality [ Time Frame: Up to 365 days after HCT ]
    Day of death

  14. Incidence of non-CMV infections [ Time Frame: Up to 365 days after HCT ]
    Day of infection

  15. CMV reactivation (>= 1,250 IU/mL) or CMV disease post-HCT [ Time Frame: Up to 180 days after hematopoietic cell transplant ]
    Day of event

  16. 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 ]
    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



Information from the National Library of Medicine

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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)
    • 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
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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
Layout table for investigator information
Principal Investigator: Ryotaro Nakamura, MD City of Hope Medical Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02396134    
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: February 21, 2022
Last Verified: January 2022
Additional relevant MeSH terms:
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Cytomegalovirus Infections
Lymphoma
Leukemia
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Hodgkin Disease
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myeloid, Accelerated Phase
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Leukemia, B-Cell
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Infections