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

Study Overview
=================
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.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine if cytomegalovirus (CMV) peptide(Pep)vaccine(Vax) (CMVpp65-A*0201 peptide vaccine) increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated human leukocyte antigen (HLA) A*0201 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: I. 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. III. 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. IV. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells. V. To determine the impact of CMVPepVax on CMV immune reconstitution in patients who undergo treatment with antiviral agent Prevymis. VI. To explore GVHD biomarkers and compare between the vaccine and placebo groups. VII. 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.

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

Conditions
-----------------
Myelofibrosis, 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, Myeloproliferative Neoplasm

Intervention / Treatment
-----------------
* Biological: CMVpp65-A*0201 peptide vaccine
* Other: Placebo
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
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 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 A*0201 High resolution, 4-digit typing is required at HLA-A2 to ensure A*0201 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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (CMVpp65-A*0201 peptide vaccine)<br>Patients receive CMVpp65-A*0201 peptide vaccine SC on days 28 and 56 after HCT. | Biological: CMVpp65-A*0201 peptide vaccine<br>* Given SC<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo SC on days 28 and 56 after HCT. | Other: Placebo<br>* Given SC<br>* Other names: placebo, Placebo, placebo therapy, PLCB, sham therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of CMV at 100 Days | The primary endpoint was CMV event. A CMV event encompasses detection of CMV by either qPCR (termed reactivation: DNAemia at ≥500 gc/ml = 1250iu/ml) or by tissue histology (end-organ disease). The cumulative incidence was calculated as competing risks using the method of Gooley with death viewed as a competing risk. | Up to day 100 after HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-Relapse Mortality (NRM) at 100 Days | NRM was defined as death without recurrent or progressive disease after transplant. Probabilities of NRM were calculated as competing risks using the method of Gooley with relapse viewed as a competing risk. | Up to 100 days after transplant | 
| Cumulative Incidence of Relapse at One Year | Probabilities of relapse were calculated as competing risks using the method of Gooley with death viewed as a competing risk. | Up to 365 days after HCT |