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

• ClinicalTrials.gov Identifier: NCT02506933
• Recruitment Status: Active, not recruiting
• First Posted: July 23, 2015
• Last Update Posted: January 27, 2021
• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI); Diavax Biosciences
• Information provided by (Responsible Party): City of Hope Medical Center

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:

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

• 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
• Actual Study Start Date: November 5, 2015
• Estimated Primary Completion Date: December 14, 2021
• Estimated Study Completion Date: December 14, 2021

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 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

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

• 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

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT02506933
• 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
• Last Update Posted: January 27, 2021
• Last Verified: January 2021

Additional relevant MeSH terms:

Cytomegalovirus Infections; Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Leukemia, Myeloid, Accelerated Phase; Myelodysplastic Syndromes; Myeloproliferative Disorders; Lymphadenopathy; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Leukemia, B-Cell; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs