Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02396134

Collaborator

National Cancer Institute (NCI) (NIH)

133

Enrollment

Locations

Arms

Anticipated Duration (Months)

26.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well vaccine therapy works in reducing the frequency of cytomegalovirus severe infections (events) in patients with hematologic malignancies undergoing donor stem cell transplant. Vaccines made from a peptide may help the body build an effective immune response and may reduce cytomegalovirus events after donor stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Adult Acute Lymphoblastic Leukemia in Remission Adult Acute Myeloid Leukemia in Remission Adult Hodgkin Lymphoma Adult Non-Hodgkin Lymphoma Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Cytomegaloviral Infection Hematopoietic and Lymphoid Cell Neoplasm HLA-A*0201 Positive Cells Present Myelodysplastic Syndrome Adult Lymphoblastic Lymphoma Chronic Lymphocytic Leukemia Myelofibrosis Myeloproliferative Neoplasm	Biological: CMVpp65-A*0201 peptide vaccine Other: Placebo Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To determine if cytomegalovirus (CMV) peptide(Pep)vaccine(Vax) (CMVpp65-A0201 peptide vaccine) increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated human leukocyte antigen (HLA) A0201 allogeneic CMV positive hematopoietic stem cell transplant (HCT) recipients (HCT-R+). (Entire cohort) II. To provide a preliminary evaluation of the incidence of CMV reactivation between day 56 and day 180 in patients who receive standard letermovir (Prevymis) prophylaxis (from day 14 through day 100), comparable to the evaluation of an expansion cohort in a pilot study, or the futility stage of a phase II trial. (Letermovir combination cohort) III. To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated HCT patients who receive standard Prevymis prophylaxis. (Letermovir combination cohort)

SECONDARY OBJECTIVES:

To determine, within the constraints of a pilot cohort, if CMVPepVax reduces the frequency of CMV events alone or in combination with Prevymis defined as reactivation or CMV disease in HLA A*0201 allogeneic HCT-R+.

II. To evaluate the safety and tolerability of CMVPepVax 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 characterize CMV reactivation and CMV disease in recipients of CMVPepVax 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), cumulative number of CMV specific antiviral treatment days.
To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells.
To determine the impact of CMVPepVax on CMV immune reconstitution in patients who undergo treatment with antiviral agent Prevymis.
To explore GVHD biomarkers and compare between the vaccine and placebo groups.
To characterize CMV reactivation after day 180

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive CMVpp65-A*0201 peptide vaccine subcutaneously (SC) on days 28 and 56 after HCT.

ARM II: Patients receive placebo SC on days 28 and 56 after HCT.

After completion of study treatment, patients are followed up to day 365 after HCT.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

133 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Supportive Care

Official Title:

A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate Protective Function of an Optimized Dose of CMVPepVax in Recipients of an Allogeneic Hematopoietic Stem Cell Transplant

Actual Study Start Date :

May 21, 2015

Anticipated Primary Completion Date :

Dec 21, 2022

Anticipated Study Completion Date :

Dec 21, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (CMVpp65-A0201 peptide vaccine) Patients receive CMVpp65-A0201 peptide vaccine SC on days 28 and 56 after HCT.	Biological: *CMVpp65-A0201 peptide vaccine Given SC Other: Laboratory Biomarker Analysis** Correlative studies
Placebo Comparator: Arm II (placebo) Patients receive placebo SC on days 28 and 56 after HCT.	Other: Placebo Given SC Other Names: placebo, Placebo, placebo therapy, PLCB, sham therapy Other: Laboratory Biomarker Analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Arm I (CMVpp65-A*0201 peptide vaccine)

Patients receive CMVpp65-A*0201 peptide vaccine SC on days 28 and 56 after HCT.

Biological: CMVpp65-A*0201 peptide vaccine

Given SC

Other: Laboratory Biomarker Analysis

Correlative studies

Placebo Comparator: Arm II (placebo)

Patients receive placebo SC on days 28 and 56 after HCT.

Other: Placebo

Given SC

Other Names:

placebo, Placebo, placebo therapy, PLCB, sham therapy

Other: Laboratory Biomarker Analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

CMV events encompassing any CMV reactivation defined as >= 500 CMV gc/mL or CMV disease [Up to day 100 after HCT]
Each randomized study subject will be followed according to the study calendar for the occurrence of CMV reactivation events, which are defined in terms of either viremia, low-level viremia treated with antivirals, or CMV disease. Both initial and recurrent events will be recorded, with patients considered at risk for recurrent events after completion of a full planned course of a full course of anti-viral therapy. Vaccine and placebo groups will be compared with regard to the hazard of CMV events, using the Anderson-Gill approach to repeated events.
Levels of CD8+ T cells binding to A2-cytomegalovirus (CMV)-dextramers [Up to day 365 after hematopoietic cell transplant]
The longitudinal cytomegalovirus-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.
CMV reactivation [>= 1,250 IU/mL] or CMV disease in patients who receive standard Prevymis prophylaxis [Up to 180 days after hematopoietic cell transplant]

Secondary Outcome Measures

non-relapse mortality (NRM) [At 100 days after HCT]
Time of death as day post HCT
Severe (grade 3-4) aGVHD [Within 100 days after HCT]
Highest overall grade
Grade 3-4 AEs (CTCAE version 4.0) probably or definitely related to the vaccination [Within 2 weeks of vaccination]
MEDDRA code
Time to viremia [Between day 56 and 180 days after HCT]
Number of days from transplantation to the first date of >= 500 CMV gc/mL (or antiviral therapy)
Duration of viremia [Up to 365 days after HCT]
Duration (days) between the date of first viremia episode (outcome #7) and date of undetectable of viremia
Incidence of late CMV viremia [From 180 through 360 days after HCT]
Number of days from transplantation to the first date of >= 500 CMV gc/mL (or antiviral therapy) after day 180, either as a first event or a recurrence after earlier viremia became non-detectable
Use of antiviral drugs [Up to 365 days after HCT]
Day post-HCT of first CMV-directed antiviral dose
Cumulative number of CMV specific antiviral treatment days [Up to 365 days after HCT]
Total number of days of treatment during time frame
Time to engraftment [Up to 365 days after HCT]
Day post HCT of first adequate cell count
Incidence of aGVHD [Within 100 days after HCT]
Day of first aGVHD of any grade
Incidence of cGVHD [Up to 365 days after HCT]
Day of first cGVHD
Incidence of relapse [Up to 365 days after HCT]
Day of relapse
All-cause mortality [Up to 365 days after HCT]
Day of death
Incidence of non-CMV infections [Up to 365 days after HCT]
Day of infection
CMV reactivation (>= 1,250 IU/mL) or CMV disease post-HCT [Up to 180 days after hematopoietic cell transplant]
Day of event
Immune reconstitution measured as levels, function and kinetics of CMV-specific T cells through day 365 post-HCT in patients who receive standard Prevymis prophylaxis (day 14 through day 100). [at days 28, 42, 56, 70, 84, 100, 140, 180, 270 and 365 after hematopoietic cell transplant]
The measurement of function is determined by "dextramer-binding CD8 T cells/microliter, and "kinetics" will be determined as "% change" from the baseline (day 28) value at each time point below

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 needs to 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
HLA A0201 High resolution, 4-digit typing is required at HLA-A2 to ensure A0201 status.
CMV seropositive (recipient)
Planned related or unrelated HCT, with HLA donor allele matching; related donor must be an 8/8 match for HLA-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid (DNA)-based typing; unrelated donor must be an 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing; patients undergoing a second allo HCT are not eligible (patients who have undergone a previous autologous HCT are eligible)
Planned HCT with no ex-vivo 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
Planned medications from the time of HCT to day 70 post-HCT:
Live attenuated vaccines
Medically indicated subunit (Engerix-B for HBV; Gardasil for human papilloma virus [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; this includes anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide
Antiviral medications with known therapeutic effects against CMV such as ganciclovir (GCV)/valine (VAL), foscarnet (FOS), cidofovir, hexadecyloxypropyl-cidofovir (CMX-001) and maribavir; acyclovir has no therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV)
Other investigational product - concurrent enrollment in other clinical trials using an investigational product 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	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
3	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
4	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
5	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109