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

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02506933

Collaborator

National Cancer Institute (NCI) (NIH), Diavax Biosciences (Other)

102

Enrollment

Locations

Arms

85.3

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

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.

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:

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.
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:

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.
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.
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

Study Type:

Interventional

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

Actual Study Start Date :

Nov 5, 2015

Anticipated Primary Completion Date :

Dec 14, 2022

Anticipated Study Completion Date :

Dec 14, 2022

Arms and Interventions

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 Names: 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

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 Names:

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

Primary Outcome Measures

CMV events encompassing any CMV reactivation >= 500 CMV genome copies gc/mL, low-level reactivation prompting antiviral therapy, or CMV disease [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.
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 [Within 2 weeks of injection]
Will be listed, with incidence compared by Fisher's exact test.
Incidence of severe (grade 3-4) aGVHD [Up to 100 days post-HCT]
Will be summarized by Kaplan-Meier curves, and compared using the log-rank test.
NRM [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

All-cause mortality [Up to 1 year post-HCT]
Cumulative number of CMV specific antiviral treatment days [Up to 1 year post-HCT]
Duration of viremia [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.
Incidence of aGVHD [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.
Incidence of cGVHD [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.
Incidence of infections [Up to 1 year post-HCT]
Incidence of late CMV viremia [Up to 360 days post-HCT]
Assessed between > 100 days and =< 360 days post-HCT.
Levels and kinetics of CMV-specific T cell immunity [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.
NK phenotype and function (cytotoxicity and cytokine production) [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.
NRM [Up to 1 year post-HCT]
Relapse-free survival [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.
Time to engraftment, defined as the first of 3 consecutive days when the peripheral blood absolute neutrophil count is >= 500/mm^3 [Up to 1 year post-HCT]
Time-to viremia, defined as number of days from transplantation to the date of > 500 CMV gc/mL [Up to 1 year post-HCT]
Use of antiviral drugs, triggered by clinically significant viremia >= 1500 CMV gc/mL [Up to 1 year post-HCT]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	M D Anderson Cancer Center	Houston	Texas	United States	77030