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Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Treating Pediatric Patients With Positive Cytomegalovirus Undergoing Donor Stem Cell Transplant

Primary Purpose

Cytomegaloviral Infection, Hematopoietic Cell Transplant Recipient

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Cytomegaloviral Infection

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • All subjects (or their guardians) must have the ability to understand and the willingness to sign a written informed consent; age appropriate assent will be obtained per institutional guidelines; to allow non-English patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible
  • Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT
  • Planned allogenic (allo)-HCT, with 9/10 or 10/10 (A, B, C, DRB1, DQB1) high/intermediate resolution HLA donor allele matching and with no T-cell depletion of graft
  • Planned related HCT with molecular 3/6 HLA donor allele matching (haploidentical) (for phase I only)
  • CMV seropositive at the time of HCT
  • 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); if hepatitis B virus (HBV) core seropositive, absence of HBV deoxyribonucleic acid (DNA) 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:

  • TRANSPLANT RELATED CRITERIA: Patients undergoing cord blood transplant (CB-HCT)
  • Any prior investigational CMV vaccine
  • Anti-CMV therapy in the last 6 months
  • Live attenuated vaccines
  • Medically indicated subunit (Engerix-B for HBV; Gardasil for human papillomavirus [HPV]) or killed vaccine (e.g. influenza, pneumococcal)
  • Allergy treatment with antigens injections
  • Alemtuzumab, cyclophosphamide, ATG or any equivalent in vivo T-cell depleting agent; Note: Pre-transplant ATG is permitted
  • Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valine (VAL), 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; intravenous immunoglobulin therapy (IVIG) is allowed
  • 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 congenital immune deficiency
  • Patients with active autoimmune conditions requiring systemic immunosuppressive therapy within the previous 5 years are not eligible, the exception to this is patients with aplastic anemia, who are eligible
  • Pregnant women and women who are lactating; CMV-MVA Triplex risks to pregnant women are unknown; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the administered vaccine, also 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 issue related to feasibility/logistics)

Sites / Locations

  • City of Hope Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Supportive Care (multi-antigen CMV-modified vaccinia ankara)

Arm Description

Patients receive multi-antigen CMV-modified vaccinia ankara vaccine IM on days 28 and 56 post-HCT.

Outcomes

Primary Outcome Measures

Optimal dose (Phase I)
Incidence of adverse events (Phase I)
Adverse events will be characterized using the descriptions and grading scales according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Cytomegalovirus (CMV) events (reactivation >= 1250 IU/mL), or viremia treated by anti-viral therapy, or detection of CMV by histology (Phase II)
Will be assessed with exact 90% confidence bounds.
Non-relapse mortality
Will be compared to historical controls at the final analysis, and a 90% lower confidence bound on the difference in 12-month event free survival will be produced.
Severe (grade 3-4) acute graft versus host disease (aGVHD)
Incidence of grade 3-4 adverse events
Will be graded per CTCAE version 4.0.

Secondary Outcome Measures

Time-to viremia
Duration of viremia
Incidence of late CMV viremia
Use of antiviral drugs (triggered by rising CMV viremia or viremia >= 3,750 IU/ml)
Cumulative number of CMV specific antiviral treatment days
Time to engraftment
Incidence of acute graft versus host disease (aGVHD)
Chronic GVHD (cGVHD)
Relapse defined by bone marrow and/or imaging studies
Non-relapse mortality
All-cause mortality
Infections
Levels of CMV-specific T cell immunity
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.
Kinetics of CMV-specific T cell immunity
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.
Natural killer (NK) phenotype
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.
NK function (cytotoxicity and cytokine production)
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.

Full Information

First Posted
November 6, 2017
Last Updated
September 25, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03354728
Brief Title
Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Treating Pediatric Patients With Positive Cytomegalovirus Undergoing Donor Stem Cell Transplant
Official Title
A Phase 1/2 Clinical Study to Evaluate the Optimal Dose and the Protective Effect of CMV-MVA Triplex Vaccine in Pediatric Patients Receiving an Allogeneic Hematopoietic Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 11, 2018 (Actual)
Primary Completion Date
November 11, 2024 (Anticipated)
Study Completion Date
November 11, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and best dose of multi-antigen cytomegalovirus (CMV)-modified vaccinia ankara vaccine and to see how well it works in treating pediatric patients with positive cytomegalovirus who are undergoing donor stem cell transplant. Multi-antigen CMV-modified vaccinia ankara vaccine may help people resist CMV life-threatening complications.
Detailed Description
PRIMARY OBJECTIVES: I. To investigate the optimal dose of multi-antigen CMV-modified vaccinia ankara vaccine (Triplex) in CMV-positive pediatric patients receiving human leukocyte antigen (HLA) matched, mismatched, or haploid-identical hematopoietic cell transplantation (HCT). (Phase I) II. To evaluate the safety profile of Triplex in this patient population. (Phase I) III. To determine if Triplex reduces the frequency of CMV events when compared to historical data. (Phase II) SECONDARY OBJECTIVES: I. To characterize CMV reactivation and disease by assessing: time to CMV reactivation, duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (defined as > 100 days and =< 365 days post HCT), use of anti-viral drugs triggered by rising CMV viremia or viremia >= 3750 IU/mL, cumulative number of CMV specific antiviral treatment days. II. To evaluate the impact of Triplex on transplant related outcomes by assessing the incidence of acute and chronic graft versus host disease (GVHD), relapse, non-relapse mortality (NRM), all-cause mortality, infections. III. To investigate the impact of Triplex on cellular immunity by investigating: the level, function and kinetics of CMV-specific T-cell immunity, the changes in adaptive natural killer (NK) cell population and highly cytotoxic memory NKG2C+ NK cells, and changes in GVHD biomarkers. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive multi-antigen CMV-modified vaccinia ankara vaccine intramuscularly (IM) on days 28 and 56 post-HCT. After completion of study treatment, patients are followed up for up to 270 or 365 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cytomegaloviral Infection, Hematopoietic Cell Transplant Recipient

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Supportive Care (multi-antigen CMV-modified vaccinia ankara)
Arm Type
Experimental
Arm Description
Patients receive multi-antigen CMV-modified vaccinia ankara vaccine IM on days 28 and 56 post-HCT.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Biological
Intervention Name(s)
Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
Other Intervention Name(s)
CMV-MVA Triplex Vaccine, Multi-antigen CMV-Modified Vaccinia Ankara Vaccine
Intervention Description
Given IM
Primary Outcome Measure Information:
Title
Optimal dose (Phase I)
Time Frame
Up to 1 year
Title
Incidence of adverse events (Phase I)
Description
Adverse events will be characterized using the descriptions and grading scales according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame
Up to 1 year
Title
Cytomegalovirus (CMV) events (reactivation >= 1250 IU/mL), or viremia treated by anti-viral therapy, or detection of CMV by histology (Phase II)
Description
Will be assessed with exact 90% confidence bounds.
Time Frame
Prior to day 100 post-hematopoietic cell transplantation (HCT) or viremia treated by anti-viral therapy, or detection of CMV by histology
Title
Non-relapse mortality
Description
Will be compared to historical controls at the final analysis, and a 90% lower confidence bound on the difference in 12-month event free survival will be produced.
Time Frame
At 100 days post-HCT
Title
Severe (grade 3-4) acute graft versus host disease (aGVHD)
Time Frame
Within 2 weeks from each vaccination
Title
Incidence of grade 3-4 adverse events
Description
Will be graded per CTCAE version 4.0.
Time Frame
Within 2 weeks from each vaccination
Secondary Outcome Measure Information:
Title
Time-to viremia
Time Frame
Number of days from transplant to the date of > 1250 IU/mL, assessed up to 1 year
Title
Duration of viremia
Time Frame
Up to 1 year
Title
Incidence of late CMV viremia
Time Frame
> 100 and =< 365 days post-HCT
Title
Use of antiviral drugs (triggered by rising CMV viremia or viremia >= 3,750 IU/ml)
Time Frame
Up to 1 year, rising CMV viremia or viremia >= 3,705
Title
Cumulative number of CMV specific antiviral treatment days
Time Frame
Up to 1 year
Title
Time to engraftment
Time Frame
Up to 1 year
Title
Incidence of acute graft versus host disease (aGVHD)
Time Frame
Up to 1 year
Title
Chronic GVHD (cGVHD)
Time Frame
Up to 1 year
Title
Relapse defined by bone marrow and/or imaging studies
Time Frame
Up to 1 year
Title
Non-relapse mortality
Time Frame
Up to 1 year
Title
All-cause mortality
Time Frame
Up to 1 year
Title
Infections
Time Frame
Up to 1 year
Title
Levels of CMV-specific T cell immunity
Description
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.
Time Frame
Up to 1 year post-HCT
Title
Kinetics of CMV-specific T cell immunity
Description
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.
Time Frame
Up to 1 year post-HCT
Title
Natural killer (NK) phenotype
Description
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.
Time Frame
Up to 1 year post-HCT
Title
NK function (cytotoxicity and cytokine production)
Description
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.
Time Frame
Up to 1 year post-HCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: All subjects (or their guardians) must have the ability to understand and the willingness to sign a written informed consent; age appropriate assent will be obtained per institutional guidelines; to allow non-English patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT Planned allogenic (allo)-HCT, with 9/10 or 10/10 (A, B, C, DRB1, DQB1) high/intermediate resolution HLA donor allele matching and with no T-cell depletion of graft Planned related HCT with molecular 3/6 HLA donor allele matching (haploidentical) (for phase I only) CMV seropositive at the time of HCT 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); if hepatitis B virus (HBV) core seropositive, absence of HBV deoxyribonucleic acid (DNA) 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: TRANSPLANT RELATED CRITERIA: Patients undergoing cord blood transplant (CB-HCT) Any prior investigational CMV vaccine Anti-CMV therapy in the last 6 months Live attenuated vaccines Medically indicated subunit (Engerix-B for HBV; Gardasil for human papillomavirus [HPV]) or killed vaccine (e.g. influenza, pneumococcal) Allergy treatment with antigens injections Alemtuzumab, cyclophosphamide, ATG or any equivalent in vivo T-cell depleting agent; Note: Pre-transplant ATG is permitted Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valine (VAL), 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; intravenous immunoglobulin therapy (IVIG) is allowed 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 congenital immune deficiency Patients with active autoimmune conditions requiring systemic immunosuppressive therapy within the previous 5 years are not eligible, the exception to this is patients with aplastic anemia, who are eligible Pregnant women and women who are lactating; CMV-MVA Triplex risks to pregnant women are unknown; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the administered vaccine, also 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 issue related to feasibility/logistics)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna Pawlowska
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna B. Pawlowska
Phone
626-301-8442
Email
apawlows@coh.org
First Name & Middle Initial & Last Name & Degree
Anna B. Pawlowska

12. IPD Sharing Statement

Learn more about this trial

Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Treating Pediatric Patients With Positive Cytomegalovirus Undergoing Donor Stem Cell Transplant

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