Clinical trial NCT02396134: Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2015-03-24
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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)

Primary outcomes:
measure: Cumulative Incidence of CMV at 100 Days
timeFrame: Up to day 100 after HCT
Secondary outcomes:
measure: Non-Relapse Mortality (NRM) at 100 Days
timeFrame: Up to 100 days after transplant
measure: Cumulative Incidence of Relapse at One Year
timeFrame: Up to 365 days after HCT
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: City of Hope Medical Center
name: Ryotaro Nakamura, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999 Mar 30;18(6):695-706. doi: 10.1002/(sici)1097-0258(19990330)18:63.0.co;2-o.