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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

Primary Purpose

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
Placebo
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 Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • City of Hope Medical Center
  • Dana-Farber Cancer Institute
  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (multi-peptide CMV-MVA vaccine)

Arm II (placebo)

Arm Description

Patients receive multi-peptide CMV-MVA vaccine IM on days 28 and 56 post-HCT.

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

Outcomes

Primary Outcome Measures

Cytomegalovirus (CMV) Events to Day 100
Cytomegalovirus (CMV) events included CMV reactivation ≥1250 CMV DNA IU/mL, CMV viremia prompting antiviral therapy, or CMV disease before day 100 after HCT.
Incidence of Severe (Grade 3-4) Acute Graft-Versus-Host Disease
Severe acute graft-versus-host disease (aGVHD, grade 3-4) was monitored as every 12th subject on the vaccine arm reaches the 100 day evaluation point. aGVHD was scored using Keystone consensus criteria [Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant, 1995. 15(6): p. 825-8].

Secondary Outcome Measures

All-cause Mortality
Death due to any cause.

Full Information

First Posted
July 21, 2015
Last Updated
March 21, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI), Diavax Biosciences
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1. Study Identification

Unique Protocol Identification Number
NCT02506933
Brief Title
Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant
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 Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 5, 2015 (Actual)
Primary Completion Date
January 25, 2018 (Actual)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
102 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (multi-peptide CMV-MVA vaccine)
Arm Type
Experimental
Arm Description
Patients receive multi-peptide CMV-MVA vaccine IM on days 28 and 56 post-HCT.
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo 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
Intervention Description
Given IM
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
placebo therapy, PLCB, sham therapy
Intervention Description
Given IM
Primary Outcome Measure Information:
Title
Cytomegalovirus (CMV) Events to Day 100
Description
Cytomegalovirus (CMV) events included CMV reactivation ≥1250 CMV DNA IU/mL, CMV viremia prompting antiviral therapy, or CMV disease before day 100 after HCT.
Time Frame
Prior to day 100 post-HCT
Title
Incidence of Severe (Grade 3-4) Acute Graft-Versus-Host Disease
Description
Severe acute graft-versus-host disease (aGVHD, grade 3-4) was monitored as every 12th subject on the vaccine arm reaches the 100 day evaluation point. aGVHD was scored using Keystone consensus criteria [Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant, 1995. 15(6): p. 825-8].
Time Frame
Up to 100 days post-transplant
Secondary Outcome Measure Information:
Title
All-cause Mortality
Description
Death due to any cause.
Time Frame
Up to 1 year post-HCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ryotaro Nakamura, MD
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
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32040960
Citation
Aldoss I, La Rosa C, Baden LR, Longmate J, Ariza-Heredia EJ, Rida WN, Lingaraju CR, Zhou Q, Martinez J, Kaltcheva T, Dagis A, Hardwick N, Issa NC, Farol L, Nademanee A, Al Malki MM, Forman S, Nakamura R, Diamond DJ; TRIPLEX VACCINE Study Group. Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Ann Intern Med. 2020 Mar 3;172(5):306-316. doi: 10.7326/M19-2511. Epub 2020 Feb 11.
Results Reference
derived
PubMed Identifier
27760761
Citation
La Rosa C, Longmate J, Martinez J, Zhou Q, Kaltcheva TI, Tsai W, Drake J, Carroll M, Wussow F, Chiuppesi F, Hardwick N, Dadwal S, Aldoss I, Nakamura R, Zaia JA, Diamond DJ. MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. Blood. 2017 Jan 5;129(1):114-125. doi: 10.1182/blood-2016-07-729756. Epub 2016 Oct 19.
Results Reference
derived

Learn more about this trial

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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