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Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant

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ClinicalTrials.gov Identifier: NCT02506933
Recruitment Status : Active, not recruiting
First Posted : July 23, 2015
Last Update Posted : May 8, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Diavax Biosciences
Information provided by (Responsible Party):
City of Hope Medical Center

Study Description
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Brief Summary:
This randomized phase II trial studies the safety and how well multi-peptide cytomegalovirus (CMV)-modified vaccinia Ankara (MVA) vaccine works in reducing CMV complications in patients previously infected with CMV and are undergoing a donor hematopoietic cell transplant. CMV is a virus that may reproduce and cause disease and even death in patients with lowered immune systems, such as those undergoing a hematopoietic cell transplant. By placing 3 small pieces of CMV deoxyribonucleic acid (DNA) (the chemical form of genes) into a very safe, weakened virus called MVA, the multi-peptide CMV-MVA vaccine may be able to induce immunity (the ability to recognize and respond to an infection) to CMV. This may help to reduce both CMV complications and reduce the need for antiviral drugs in patients undergoing a donor hematopoietic cell transplant.

Condition or disease Intervention/treatment Phase
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Acute Lymphoblastic Leukemia in Remission Acute Myeloid Leukemia in Remission Chronic Lymphocytic Leukemia Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Cytomegaloviral Infection Hodgkin Lymphoma Lymphadenopathy Lymphoblastic Lymphoma Myelodysplastic Syndrome Myelofibrosis Myeloproliferative Neoplasm Non-Hodgkin Lymphoma Other: Laboratory Biomarker Analysis Biological: Multi-peptide CMV-Modified Vaccinia Ankara Vaccine Other: Placebo Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of CMV-MVA Triplex (multi-peptide CMV-MVA vaccine) in vaccinated hematopoietic cell transplant (HCT) recipients 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 determine if CMV-MVA Triplex reduces the frequency of CMV events defined as reactivation or CMV disease in allogeneic CMV positive HCT recipients (HCT-R+).

SECONDARY OBJECTIVES:

I. To characterize CMV reactivation and CMV disease in recipients of CMV-MVA Triplex 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 of >= 1500 CMV gc/mL), cumulative number of CMV specific antiviral treatment days.

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

III. To determine 1) if CMV-MVA Triplex increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated human leukocyte antigen (HLA) A*0201, CMV seropositive HCT-recipients, 2) to determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory killer cell lectin-like receptor subfamily C, member 2 (NKG2C)+ NK cells, and 3) 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 multi-peptide CMV-MVA vaccine intramuscularly (IM) on days 28 and 56 post-HCT.

ARM II: Patients receive placebo IM on days 28 and 56 post-HCT.

After completion of study, patients are followed up for 1 year post-HCT.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Supportive Care
Official Title: A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate the Protective Function of a CMV-MVA Triplex Vaccine in Recipients of an Allogeneic Hematopoietic Stem Cell Transplant
Study Start Date : November 5, 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (multi-peptide CMV-MVA vaccine)
Patients receive multi-peptide CMV-MVA vaccine IM on days 28 and 56 post-HCT.
 Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
Given IM
Other Name: CMV-MVA Triplex Vaccine
Placebo Comparator: Arm II (placebo)
Patients receive placebo IM on days 28 and 56 post-HCT.
 Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given IM
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy


Outcome Measures
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Primary Outcome Measures :
  1. CMV events encompassing any CMV reactivation >= 500 CMV genome copies gc/mL, low-level reactivation prompting antiviral therapy, or CMV disease [ Time Frame: Prior to day 100 post-HCT ]
    Vaccine and placebo groups will be compared with regard to the hazard of CMV events, using the Anderson-Gill approach to repeated events, as implemented in the R survival package. Power calculations are conservatively based only on binomial incident event rates.

  2. Incidence of grade 3-4 severe adverse events (SAE) that are at least possibly attributed to the injection by the (masked) treating physician, assessed by CTCAE version 4.0 [ Time Frame: Within 2 weeks of injection ]
    Will be listed, with incidence compared by Fisher's exact test.

  3. Incidence of severe (grade 3-4) aGVHD [ Time Frame: Up to 100 days post-HCT ]
    Will be summarized by Kaplan-Meier curves, and compared using the log-rank test.

  4. NRM [ Time Frame: At 100 days post-HCT ]
    Will be summarized by arm as percentages, with exact binomial confidence bounds, and compared across arms using Fishers exact test.


Secondary Outcome Measures :
  1. All-cause mortality [ Time Frame: Up to 1 year post-HCT ]
  2. Cumulative number of CMV specific antiviral treatment days [ Time Frame: Up to 1 year post-HCT ]
  3. Duration of viremia [ Time Frame: Up to 1 year post-HCT ]
    The total days on antivirals for CMV reactivation (induction, maintenance, and total) will be assessed for each individual, with arms compared using Wilcoxon's rank-sum test. Other characterizations of the duration of viremia and response to therapy will be descriptive in nature.

  4. Incidence of aGVHD [ Time Frame: Up to 1 year post-HCT ]
    The cumulative incidence of aGVHD will be estimated using Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test, or the corresponding subdistribution test due to Gray.

  5. Incidence of cGVHD [ Time Frame: Up to 1 year post-HCT ]
    The cumulative incidence of cGVHD will be estimated using Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test, or the corresponding subdistribution test due to Gray.

  6. Incidence of infections [ Time Frame: Up to 1 year post-HCT ]
  7. Incidence of late CMV viremia [ Time Frame: Up to 360 days post-HCT ]
    Assessed between > 100 days and =< 360 days post-HCT.

  8. Levels and kinetics of CMV-specific T cell immunity [ Time Frame: Up to 1 year post-HCT ]
    Will be combined with immunophenotyping and functional studies. The data analysis for estimating the effect of vaccination on cellular immunity will necessarily be more exploratory in nature. 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.

  9. NK phenotype and function (cytotoxicity and cytokine production) [ Time Frame: Up to 1 year post-HCT ]
    The data analysis for estimating the effect of vaccination on cellular immunity will necessarily be more exploratory in nature. 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.

  10. NRM [ Time Frame: Up to 1 year post-HCT ]
  11. Relapse-free survival [ Time Frame: Up to 1 year post-HCT ]
    The cumulative incidence of relapse-free survival will be estimated using Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test, or the corresponding subdistribution test due to Gray.

  12. Time to engraftment, defined as the first of 3 consecutive days when the peripheral blood absolute neutrophil count is >= 500/mm^3 [ Time Frame: Up to 1 year post-HCT ]
  13. Time-to viremia, defined as number of days from transplantation to the date of > 500 CMV gc/mL [ Time Frame: Up to 1 year post-HCT ]
  14. Use of antiviral drugs, triggered by clinically significant viremia >= 1500 CMV gc/mL [ Time Frame: Up to 1 year post-HCT ]

Eligibility Criteria
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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 must 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
    • Patients undergoing a second allogeneic (allo) HCT are not eligible (patients who have undergone a previous autologous HCT are eligible)
  • CMV seropositive (recipient)
  • Planned related or unrelated HCT, with 8/8 (A,B,C,DRB1) high/intermediate resolution HLA donor allele matching
  • Planned HCT with minimal to no-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
  • Live attenuated vaccines
  • Medically indicated subunit (Engerix-B for HBV; Gardasil for human papillomavirus [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
  • Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valganciclovir (VAL), foscarnet (FOS), Cidofovir, CMX-001, maribavir; acyclovir has no known 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 any investigational new drug (IND) drugs with unknown effects on CMV or with unknown toxicity profiles 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)
Contacts and Locations
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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): NCT02506933


Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Diavax Biosciences
Investigators
Principal Investigator: Ryotaro Nakamura, MD City of Hope Medical Center
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02506933     History of Changes
Other Study ID Numbers: 14295
NCI-2015-01228 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
14295 ( Other Identifier: City of Hope Medical Center )
R01CA077544 ( U.S. NIH Grant/Contract )
First Posted: July 23, 2015    Key Record Dates
Last Update Posted: May 8, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
Lymphoma
Leukemia
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
Lymphadenopathy
Cytomegalovirus Infections
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, B-Cell
Herpesviridae Infections
DNA Virus Infections