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Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Reducing CMV Related Complications in Patients With Blood Cancer Undergoing Donor Stem Cell Transplant

Primary Purpose

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

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Multi-antigen CMV-Modified Vaccinia Ankara Vaccine
Laboratory Biomarker Analysis
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 - undefined (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 peripheral blood stem cell (PBSC) or bone marrow (BM) 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 judged appropriate by the clinical principal investigators (PIs), including chronic lymphocytic leukemia, myeloproliferative disorders and myelofibrosis; patients with multiple myeloma and those with non-malignant disease such as aplastic anemia are excluded

      • Adult cases of multiple myeloma (MM) are excluded; adults with aplastic anemia are excluded; patients undergoing a second haploHCT are not eligible (patients who have undergone a previous autologous HCT are eligible)
  • Patients receiving myeloablation (MA) or reduced intensity conditioning (RIC) are allowed
  • CMV seropositive (recipient)
  • Planned related HCT with molecular 3/6 (haploidentical) intermediate/high resolution human leukocyte antigen (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 and no history of disseminated cutaneous human papillomavirus (HPV) related disease
  • 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 HPV) or killed vaccine (e.g. influenza, pneumococcal, or allergy treatment with antigen injections)
  • Allergy treatment with antigen injections
  • Alemtuzumab or any equivalent in vivo T-cell depleting agent (or CD34+ selection)
  • Antiviral medications with known therapeutic effects on CMV such as ganciclovir/valganciclovir (GCV/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
  • Conditioning regimens 30 days (d) prior to trial participation and up to d28 post-HCT
  • Disease-based radiation therapy (not total body irradiation)
  • 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 requiting systemic immunosuppressive therapy within the previous 5 years at not eligible
  • Patients considered by PIs/protocol team to have a complicated prior therapy or HCT regimen, or who have a low survival probability (e.g., refractory leukemia and/or undergoing 2nd HCT)
  • Poor risk disease/disease status including: chronic myeloid leukemia (CML) in blast crisis, acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) beyond 2nd remission, multiple myeloma, and aplastic anemia
  • 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
  • Northside Hospital
  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (CMV-MVA triplex vaccine)

Arm II (placebo)

Arm Description

Patients receive multi-antigen CMV-modified vaccinia Ankara vaccine via injection on days 28 and 56 post-HCT.

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

Outcomes

Primary Outcome Measures

Cytomegalovirus (CMV) events
Will include any CMV reactivation (detection of >= 1250 U/mL plasma), low-level reactivation prompting antiviral therapy, or CMV disease (defined by histology) prior to day 100 post-hematopoietic cell transplantation (HCT).

Secondary Outcome Measures

Non-relapse mortality (NRM)
Severe (grade 3-4) acute graft versus host disease (GVHD)
Grade 3-4 adverse events probably/definitely related to the vaccination and modified vaccinia Ankara vector persistence
Duration of viremia
The primary statistical analyses will compare vaccine and placebo regarding hazards of CMV events from injection to day 100. Events prior to injection will inform Kaplan Meier estimates for both arms to obtain unbiased estimates of reactivation rates applicable to all transplanted subjects on each arm.
Duration of anti-CMV therapy
Peak CMV polymerase chain reaction value
Recurrence of CMV viremia
Incidence of late CMV reactivation or disease
Time to engraftment
Incidence of acute GVHD
Will be scored using Keystone consensus criteria. Whenever possible, acute GVHD will be confirmed histologically with microscopic review.
Incidence of chronic GVHD
Relapse
Non-relapse mortality
All-cause mortality
Infections
Overall survival
Levels of CMV-specific T cell immunity
Will also assess immunophenotyping and function.
Natural killer cell function
Will assess cytotoxicity of NK cells against K562 target cell line compared with control (% killing) and cytokine production using flow-cytometry with intra-cellular staining of gamma-interferon and other cytokines (% of NK cells producing these cytokines).

Full Information

First Posted
December 29, 2017
Last Updated
November 19, 2018
Sponsor
City of Hope Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03438344
Brief Title
Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Reducing CMV Related Complications in Patients With Blood Cancer Undergoing Donor Stem 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 a Haploidentical Hematopoietic Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Withdrawn
Why Stopped
PI Withdrawal
Study Start Date
December 2018 (Anticipated)
Primary Completion Date
December 2021 (Anticipated)
Study Completion Date
December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomized phase II trial studies how well multi-antigen cytomegalovirus (CMV)-modified vaccinia Ankara vaccine works in reducing CMV related complications in patients with blood cancer who are undergoing donor stem cell transplant. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine if multi-antigen CMV-modified vaccinia Ankara vaccine (CMV-modified vaccinia Ankara [MVA] triplex) reduces the frequency of CMV events, defined as reactivation or CMV disease in CMV+, haploidentical hematopoietic cell transplantation (haploHCT) recipients. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of CMV-MVA triplex in vaccinated, haploHCT recipients by assessing the following: non-relapse mortality (NRM) at 100 days post hematopoietic cell transplantation (HCT), severe (grade 3-4) acute graft versus host disease (GVHD), and grade 3-4 adverse events (AEs) probably or definitely related to the vaccination within 2 weeks from each vaccination. II. To characterize CMV related events in recipients of CMV-MVA triplex compared to placebo, by assessing time to viremia (number of days from transplantation to the date of >= 1250 IU/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 >= 1250 IU/mL), cumulative number of CMV specific antiviral treatment days. III. To evaluate the impact of CMV-MVA triplex on transplant related outcomes by assessing the incidence of acute graft versus host disease (aGVHD), chronic GVHD, relapse, non-relapse mortality, all-cause mortality, infections. IV. To determine if CMV-MVA triplex increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated, CMV seropositive HCT-recipients. V. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cell. VI. To compare GVHD biomarkers between the vaccine and placebo groups. OUTLINE: Patients are randomized into 1 of 2 arms. ARM I: Patients receive multi-antigen CMV-modified vaccinia Ankara 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 treatment, patients are followed up at 100, 140, 180, 270, and 365 days, and then periodically for 3 years.

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, Bone Marrow Transplantation Recipient, Chronic Lymphocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematopoietic Cell Transplantation Recipient, Hodgkin 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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (CMV-MVA triplex vaccine)
Arm Type
Experimental
Arm Description
Patients receive multi-antigen CMV-modified vaccinia Ankara vaccine via injection on days 28 and 56 post-HCT.
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo via injection on days 28 and 56 post-HCT.
Intervention Type
Biological
Intervention Name(s)
Multi-antigen CMV-Modified Vaccinia Ankara Vaccine
Other Intervention Name(s)
CMV-MVA Triplex Vaccine
Intervention Description
Given IM
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
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
Description
Will include any CMV reactivation (detection of >= 1250 U/mL plasma), low-level reactivation prompting antiviral therapy, or CMV disease (defined by histology) prior to day 100 post-hematopoietic cell transplantation (HCT).
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Non-relapse mortality (NRM)
Time Frame
At 100 days post HCT
Title
Severe (grade 3-4) acute graft versus host disease (GVHD)
Time Frame
Up to 3 years
Title
Grade 3-4 adverse events probably/definitely related to the vaccination and modified vaccinia Ankara vector persistence
Time Frame
Up to 3 years
Title
Duration of viremia
Description
The primary statistical analyses will compare vaccine and placebo regarding hazards of CMV events from injection to day 100. Events prior to injection will inform Kaplan Meier estimates for both arms to obtain unbiased estimates of reactivation rates applicable to all transplanted subjects on each arm.
Time Frame
Up to 3 years
Title
Duration of anti-CMV therapy
Time Frame
Up to 3 years
Title
Peak CMV polymerase chain reaction value
Time Frame
Up to 3 years
Title
Recurrence of CMV viremia
Time Frame
Up to 3 years
Title
Incidence of late CMV reactivation or disease
Time Frame
Up to 3 years
Title
Time to engraftment
Time Frame
Up to 3 years
Title
Incidence of acute GVHD
Description
Will be scored using Keystone consensus criteria. Whenever possible, acute GVHD will be confirmed histologically with microscopic review.
Time Frame
Up to 3 years
Title
Incidence of chronic GVHD
Time Frame
Up to 3 years
Title
Relapse
Time Frame
Up to 3 years
Title
Non-relapse mortality
Time Frame
Up to 3 years
Title
All-cause mortality
Time Frame
Up to 3 years
Title
Infections
Time Frame
Up to 3 years
Title
Overall survival
Time Frame
Up to 3 years
Title
Levels of CMV-specific T cell immunity
Description
Will also assess immunophenotyping and function.
Time Frame
Up to 3 years
Title
Natural killer cell function
Description
Will assess cytotoxicity of NK cells against K562 target cell line compared with control (% killing) and cytokine production using flow-cytometry with intra-cellular staining of gamma-interferon and other cytokines (% of NK cells producing these cytokines).
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 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 peripheral blood stem cell (PBSC) or bone marrow (BM) 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 judged appropriate by the clinical principal investigators (PIs), including chronic lymphocytic leukemia, myeloproliferative disorders and myelofibrosis; patients with multiple myeloma and those with non-malignant disease such as aplastic anemia are excluded Adult cases of multiple myeloma (MM) are excluded; adults with aplastic anemia are excluded; patients undergoing a second haploHCT are not eligible (patients who have undergone a previous autologous HCT are eligible) Patients receiving myeloablation (MA) or reduced intensity conditioning (RIC) are allowed CMV seropositive (recipient) Planned related HCT with molecular 3/6 (haploidentical) intermediate/high resolution human leukocyte antigen (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 and no history of disseminated cutaneous human papillomavirus (HPV) related disease 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 HPV) or killed vaccine (e.g. influenza, pneumococcal, or allergy treatment with antigen injections) Allergy treatment with antigen injections Alemtuzumab or any equivalent in vivo T-cell depleting agent (or CD34+ selection) Antiviral medications with known therapeutic effects on CMV such as ganciclovir/valganciclovir (GCV/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 Conditioning regimens 30 days (d) prior to trial participation and up to d28 post-HCT Disease-based radiation therapy (not total body irradiation) 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 requiting systemic immunosuppressive therapy within the previous 5 years at not eligible Patients considered by PIs/protocol team to have a complicated prior therapy or HCT regimen, or who have a low survival probability (e.g., refractory leukemia and/or undergoing 2nd HCT) Poor risk disease/disease status including: chronic myeloid leukemia (CML) in blast crisis, acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) beyond 2nd remission, multiple myeloma, and aplastic anemia 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
Northside Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Reducing CMV Related Complications in Patients With Blood Cancer Undergoing Donor Stem Cell Transplant

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