Clinical trial NCT01588015: Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant
Official title: A Phase I Trial to Evaluate Safety and Immunogenicity of a Cytomegalovirus Peptide Vaccine Co-Injected With PF-03512676 Adjuvant in Recipients of Allogeneic Hematopoietic Stem Cell Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Promyelocytic Leukemia (M3)
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma
Anaplastic Large Cell Lymphoma
B-cell Adult Acute Lymphoblastic Leukemia
Chronic Eosinophilic Leukemia
Chronic Myelomonocytic Leukemia
Chronic Phase Chronic Myelogenous Leukemia
Contiguous Stage II Adult Burkitt Lymphoma
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Contiguous Stage II Adult Lymphoblastic Lymphoma
Contiguous Stage II Grade 1 Follicular Lymphoma
Contiguous Stage II Grade 2 Follicular Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Contiguous Stage II Mantle Cell Lymphoma
Contiguous Stage II Small Lymphocytic Lymphoma
Cytomegalovirus Infection
de Novo Myelodysplastic Syndromes
Essential Thrombocythemia
Extramedullary Plasmacytoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Isolated Plasmacytoma of Bone
Monoclonal Gammopathy of Undetermined Significance
Nodal Marginal Zone B-cell Lymphoma
Noncontiguous Stage II Adult Burkitt Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Lymphoblastic Lymphoma
Noncontiguous Stage II Grade 1 Follicular Lymphoma
Noncontiguous Stage II Grade 2 Follicular Lymphoma
Noncontiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Noncontiguous Stage II Small Lymphocytic Lymphoma
Peripheral T-cell Lymphoma
Polycythemia Vera
Post-transplant Lymphoproliferative Disorder
Previously Treated Myelodysplastic Syndromes
Primary Central Nervous System Hodgkin Lymphoma
Primary Central Nervous System Non-Hodgkin Lymphoma
Primary Myelofibrosis
Progressive Hairy Cell Leukemia, Initial Treatment
Prolymphocytic Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Adult T-cell Leukemia/Lymphoma
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
Refractory Multiple Myeloma
Relapsing Chronic Myelogenous Leukemia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Stage I Adult Burkitt Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Hodgkin Lymphoma
Stage I Adult Lymphoblastic Lymphoma
Stage I Adult T-cell Leukemia/Lymphoma
Stage I Chronic Lymphocytic Leukemia
Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
Stage I Grade 1 Follicular Lymphoma
Stage I Grade 2 Follicular Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Multiple Myeloma
Stage I Small Lymphocytic Lymphoma
Stage IA Mycosis Fungoides/Sezary Syndrome
Stage IB Mycosis Fungoides/Sezary Syndrome
Stage II Adult Hodgkin Lymphoma
Stage II Adult T-cell Leukemia/Lymphoma
Stage II Chronic Lymphocytic Leukemia
Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
Stage II Multiple Myeloma
Stage IIA Mycosis Fungoides/Sezary Syndrome
Stage IIB Mycosis Fungoides/Sezary Syndrome
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Hodgkin Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Adult T-cell Leukemia/Lymphoma
Stage III Chronic Lymphocytic Leukemia
Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Multiple Myeloma
Stage III Small Lymphocytic Lymphoma
Stage IIIA Mycosis Fungoides/Sezary Syndrome
Stage IIIB Mycosis Fungoides/Sezary Syndrome
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Hodgkin Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Adult T-cell Leukemia/Lymphoma
Stage IV Chronic Lymphocytic Leukemia
Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Small Lymphocytic Lymphoma
Stage IVA Mycosis Fungoides/Sezary Syndrome
Stage IVB Mycosis Fungoides/Sezary Syndrome
T-cell Adult Acute Lymphoblastic Leukemia
T-cell Large Granular Lymphocyte Leukemia
Untreated Adult Acute Myeloid Leukemia
Untreated Hairy Cell Leukemia
Waldenström Macroglobulinemia
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2012-04-30
Enrollment: 36
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 I trial studies the side effects of vaccine therapy in preventing cytomegalovirus (CMV) infection in patients with hematological malignancies undergoing donor stem cell transplant. Vaccines made from a tetanus-CMV peptide or antigen may help the body build an effective immune response and prevent or delay the recurrence of CMV infection in patients undergoing donor stem cell transplant for hematological malignancies.

Detailed description: PRIMARY OBJECTIVES: I. To discover whether two administrations of 2.5 mg tetanus (Tet)-CMV peptide co-injected with 1 mg of PF-03512676 (tetanus-CMV fusion peptide vaccine), by subcutaneous (SC) route on days 28 and 56 post-hematopoietic cell transplantation (HCT) are safe and well tolerated in human leukocyte antigen (HLA) A\*0201 CMV-positive recipients of allogeneic HCT.

SECONDARY OBJECTIVES:

I. To measure levels of CMV-specific T cells in vaccinated compared to unvaccinated HCT recipients (control arm).

II. To assess whether vaccination of HCT recipients with Tet-CMV co-injected with PF03512676 reduces expression of programmed death 1 (PD-1) on CMV-specific T cells.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive Tet-CMV + PF03512675 SC on days 28 and 56 post-HCT.

ARM II: Patients undergo immune monitoring only.

After completion of study treatment, patients are followed up at days 70, 84, 100, 130, 160, and 180.

Eligibility criteria: Inclusion Criteria:

* HLA A\*0201 subtype
* CMV seropositive
* Able and willing to sign the informed consent form (ICF)
* Willingness to be followed for the planned duration of the trial (6 months post-HCT)
* Seronegative for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and active hepatitis B virus (HBV) (surface antigen negative)
* Planned related or unrelated HCT, with 8/8 or 7/8 (A, B, C, DRB1) high resolution HLA donor allele matching
* HCT for the treatment of hematologic cancers including, but not limited to:

  * 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/peripheral blood; persistent lymphadenopathy on computed tomography \[CT\] or CT/positron emission tomography \[PET\] scan without progression is allowed)
  * Chronic myelogenous leukemia in first chronic or accelerated phase, or in second chronic phase
  * Hodgkin and non-Hodgkin lymphoma
  * Myelodysplastic syndrome
* Planned HCT with minimal to no-T cell depletion of graft
* Use of contraception up to 90 days post-HCT
* Negative pregnancy test for female recipient
* DISEASE STATUS: Recipients to be enrolled are patients eligible for allogeneic HCT, who were diagnosed with hematologic cancers including:
* Acute lymphoblastic leukemia (ALL); B-precursor ALL; T cell ALL
* Acute myeloid leukemia (AML), acute promyelocytic leukemia; treatment related AML
* Chronic lymphoid leukemia; adult T cell leukemia/lymphoma, chronic lymphocytic leukemia not otherwise specified (NOS), hairy cell leukemia; prolymphocytic leukemia (B or T); T cell large granular (gran.) lymphocytic (lymph.) leukemia (leuk)
* Chronic myeloproliferative disease (CML); chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome; chronic idiopathic myelofibrosis; CML - Philadelphia chromosome; essential thrombocythemia; polycythemia vera
* Leukemia, not otherwise specified (NOS)
* Myelodysplastic syndrome, NOS; chronic myelomonocytic leukemia
* Hodgkin lymphoma, NOS; Hodgkin lymphoma nodular lymphocyte predominant (LP), NOS; Hodgkin lymphoma - like post-transplant lymphoproliferative disorder (PTLD)
* Lymphoma, NOS
* Non-Hodgkin lymphoma (NHL); anaplastic large-cell lymphoma (ALCL), cutaneous, ALCL, systemic; Burkitt lymphoma/leukemia; cutaneous T-cell lymphoma (CTCL)/mycosis fungoides; CTCL/Sezary syndrome; diffuse large B-cell lymphoma; mucosa associated lymphoid tissue (MALT)-lymphoma; extranodal natural killer (NK)/T cell lymphoma, extranodal NK/T lymphoma nasal; follicular lymphoma; lymphoplasmacytic lymphoma mantle cell lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (lymph.); NHL aggressive, NOS; NHL indolent, NOS; NHL, NOS; peripheral T cell lymphoma, NOS; PTLD (monoclonal); PTLD (polyclonal); precursor (precur.) B-lymphoblastic lymphoma; precur T-lymphoblastic lymphoma; primary central nervous system (CNS) lymphoma; primary effusion lymphoma; small lymphocytic lymphoma, NOS
* Myeloma, NOS; monoclonal gammopathy of undetermined significance (MGUS); solitary plasmacytoma
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
* All medications, supportive care, blood products or radiation therapy taken or administered during the trial will be documented in the subject's clinical/hospital and case report form (CRF), using City of Hope (COH) guidelines; the subject's clinical information will be recorded on the appropriate CRF
* Concurrent enrollment in other clinical trials using an investigational product is prohibited
* The use of alemtuzumab for immunosuppression is not permitted in this study
* Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment is not allowed
* Medications that might interfere with the evaluation of the investigational product should not be administered, from 30 days prior to participation on the trial and up to 14 days after the second vaccination (day 70 post-HCT); medications in this category include, but are not limited to:

  * Live attenuated vaccines
  * Medically indicated subunit (Engerix-B for HBV; Gardasil for HPV) or killed vaccines (e.g. influenza, pneumococcal, or allergy treatment with antigen injections)
* Antiviral treatment for herpes simplex virus (HSV), human herpes virus 6 (HHV6), Epstein-Barr virus (EBV) and adenovirus including the use of GVC/VAL, FOS, Cidofovir, CMX-001 may also suppress reactivation of CMV, thus it will not be allowed in this study; patients requiring such treatment before randomization (day 28) will be removed from the study and replaced; reasons for removal will be reported in the patient's CRF
* All enrolled recipients who will require anti-CMV therapy before day 28 will be replaced, treated and monitored as required by COH standard of care; GVC/VAL, FOS, Cidofovir, CMX-001 may be used according to COH standard of care (SOC) for preemptive management of CMV viremia; should antiviral treatment be required after day 28, the planned 2nd vaccine injection at day 56 will not be administered (vaccine arm only)
* All subjects must have the ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

* A poor-risk patient, as defined by any of the following:

  * Chronic myelogenous leukemia in blast crisis
  * Acute myeloid leukemia beyond second remission
  * Multiple myeloma
  * Aplastic anemia
* Planned immunosuppression with alemtuzumab or any equivalent in vivo T-cell depleting agent
* In vitro T cell depleted graft
* Planned prophylactic therapy with CMV immunoglobulin
* Planned CMV prophylactic therapy
* Experimental anti-CMV chemotherapy in the last 6 months
* Diagnosed with autoimmune disease
* Receipt of the following substances:

  * Any prior investigational CMV vaccine
  * Live attenuated vaccines, medically indicated subunit or killed vaccines from 30 days prior to participation in the trial and up to 14 days after the second vaccination (day 70 post-HCT)
  * Investigational research products or allergy treatment with antigens injections from 30 days prior to participation in the trial and up to 14 days after the second vaccination (day 70 post-HCT)
* Pregnant and/or breast feeding if a female recipient
* Refusing to use contraception up to 90 days post-HCT
* POST-HCT STUDY-SPECIFIC EXCLUSIONS:
* On days 28 and 56 post-HCT (immunization day for the vaccine arm) all study recipients (vaccine and observation arms) will be reviewed for eligibility and ruled ineligible to initiate or continue in the study and receive vaccination (for the vaccine arm) if:

  * Diagnosed with \> grade 2 graft-versus-host disease (GVHD) before day 28 post-HCT, and diagnosed with \> grade 2 GVHD between day 28 post-HCT and administration of the 2nd vaccine at day 56
  * Received steroid therapy with prednisone \> 1 mg/kg/day, less than 7 days prior to injection
  * Had relapse
  * Experience graft failure (absolute neutrophil count \< 500/mm\^3)
  * Received antiviral treatment with GVC/VAL, FOS, Cidofovir, CMX-001 at any point during the 28 day period
  * There are ongoing non-hematological post-HCT toxicities \>= grade 3 non-hematological (hem) adverse events (AE's), with exception of grade 3 glucose intolerance and grade 3 non-hem labs; cholesterol, triglyceride, and hyperglycemia

Primary outcomes:
measure: Safety based on assessment of GVHD, graded according to the Keystone Consensus system and adverse events (AEs) based on National Cancer Institute (NCI) CTCAE version 4.03
timeFrame: Up to day 180
Secondary outcomes:
measure: Immunogenicity evaluated by monitoring CMV-specific CD8+ T cells by multi color flow cytometric analyses
timeFrame: Up to day 180
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Ryotaro Nakamura
role: PRINCIPAL_INVESTIGATOR
References:
citation: La Rosa C, Longmate J, Lingaraju CR, Zhou Q, Kaltcheva T, Hardwick N, Aldoss I, Nakamura R, Diamond DJ. Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax. Biol Blood Marrow Transplant. 2019 Apr;25(4):771-784. doi: 10.1016/j.bbmt.2018.12.070. Epub 2018 Dec 16.
citation: Nakamura R, La Rosa C, Longmate J, Drake J, Slape C, Zhou Q, Lampa MG, O'Donnell M, Cai JL, Farol L, Salhotra A, Snyder DS, Aldoss I, Forman SJ, Miller JS, Zaia JA, Diamond DJ. Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol. 2016 Feb;3(2):e87-98. doi: 10.1016/S2352-3026(15)00246-X. Epub 2015 Dec 24.