This early phase I trial tests the safety and side effects of allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine and how well it works in treating patients with high-risk acute lymphoblastic leukemia after a matched related donor (allogeneic) hematopoietic stem cell transplant (alloHSCT). Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood, in this study, the T cells are cytomegalovirus (CMV) specific. Then the gene for a special receptor that binds to a certain protein, CD19, on the patient's cancer cells is added to the CMV-specific T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Vaccines made from three CMV tumor associated antigens, may help the body build an effective immune response to kill cancer cells. Giving allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine after matched related alloHSCT may be safe, tolerable, and/or effective in treating patients with high-risk acute lymphoblastic leukemia.
PRIMARY OBJECTIVE: I. Assess the safety and describe the toxicity profile of allogeneic anti-CD19-CAR CMV-specific T-lymphocytes (CMV-specific CD19-CAR T cells) (allo CMV-specific CD19-CAR T cells) alone and when given in combination with multi-peptide CMV-modified vaccinia ankara vaccine (CMV-MVA) triplex vaccine following allogeneic hematopoietic cell transplantation (alloHSCT) to treat participants with high-risk acute lymphoblastic leukemia (ALL). SECONDARY OBJECTIVES: I. Determine the feasibility of allo CMV-specific CD19-CAR T cell manufacturing, as assessed by the ability to meet the required cell dose and product release requirements. II. Estimate the rate of CMV reactivation after CAR T cell infusion with 100 days of HSCT. III. Estimate the incidence of secondary graft failure. IV. Estimate the incidence and severity of acute graft versus host disease (GVHD) at 100 days and chronic GVHD at 1 year after transplant. V. Estimate the rate of 100 day non-relapse mortality. VI. Estimate disease-free and overall survival (DFS/OS) rate at 12 months post alloHSCT. EXPLORATORY OBJECTIVES: I. Determine short and longer-term allo CMV-specific CD19-CAR T cell expansion and persistence; II. Assess whether the allo CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine III. Assess whether the allo CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine when administered to participants that received CAR T cells only in the safety lead-in portion in the expansion phased of the study (i.e., once safety of the CMV-MVA triplex vaccine is established in the feasibility portion of the study). OUTLINE: DONORS: Donors undergo leukapheresis over 2-4 hours. PART 1: Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells intravenously (IV) over 10-15 minutes on day 0. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), blood and optional cerebrospinal fluid (CSF) sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per principal investigator (PI) discretion and positron emission tomography (PET)/computed tomography (CT) or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study. PART 2: This is a dose-escalation study of followed by a dose-expansion study. Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells IV over 10-15 minutes on day 0. Patients receive CMV-MVA triplex vaccine intramuscularly (IM) on day 28 in the absence of DLTs and may receive an additional CMV-MVA triplex vaccine IM on day 56 in the absence of DLTs during the second evaluation period. Patients undergo ECHO or MUGA, blood and optional CSF sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per PI discretion and PET/CT or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study. After completion of study treatment, patients are followed up monthly for the first year, then at 18, 24, 30 and 36 months after CAR T cell infusion. Patients are then followed up yearly for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Undergo alloHSCT
Given IV
Undergo blood and optional CSF sample collection
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo CT or PET/CT
Undergo ECHO
Undergo leukapheresis
Undergo lumbar puncture
Undergo MRI
Given IM
Undergo MUGA
Undergo PET/CT
Given HSCT conditioning regimen
Undergo chest x-ray
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of adverse events (AEs)
Will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. AEs will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 30 days after last dose of study treatment
Dose-limiting toxicities (DLT)
Will be graded according to NCI CTCAE v 5.0, and the revised American Society for Transplantation and Cellular Therapy Cytokine Release Syndrome Cytokine Release Syndrome grading system.
Time frame: Up to 28 days after T cell infusion
Achieving required cell dose and product release requirements
Time frame: Up to first segment of the trial (6 weeks)
Disease status
Will be evaluated based on grading of tumor responses according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for acute lymphoblastic leukemia. Will be assessed using linear mixed effects modeling. The overall fit of the model will be evaluated graphically by taking a scatter plot of data for the chimeric antigen receptor (CAR) T cells and applying an overlay of the line generated by the model. To assess changes over time, functional regression modeling will be used. Similar modeling techniques will be used to assess the impact of combination treatment (CAR T cells and vaccine) on clinical events (e.g., disease response). Swimmer plots will be generated to show response status after infusion of CAR T cells, vaccination, DLTs, and other clinical outcomes such as disease progression or death of each participant.
Time frame: At days 0 and 72 and months 5 and 11
Secondary graft failure
Will be defined as loss of donor cells after initial engraftment. Graft failure is defined as \> 95% recipient CD3+ or CD34+ cells at any single time after engraftment in the absence of leukemia relapse.
Time frame: Up to 15 years
Cytomegalovirus reactivation requiring antiviral treatment
Will be assessed using polymerase chain reaction.
Time frame: Up to 100 days after transplant
Acute graft versus host disease (GVHD)
Will assessed and graded according to the Mount Sinai Acute GVHD International Consortium grading. Cumulative incidence will be estimated.
Time frame: From date of stem cell infusion to documented/biopsy proven acute GVHD onset date, assessed up 100 days
Chronic GVHD
Will be scored according to the National Institute of Health Consensus staging. Cumulative incidence will be estimated.
Time frame: From approximately 80-100 days post-transplant to the documented/biopsy proven chronic GVHD onset date, assessed at 1 year
Non-relapse mortality (NRM)
NRM is calculated using the Fine and Gray method as a competing risk with disease relapse.
Time frame: From start of protocol therapy until non-disease related death, or last follow up, whichever comes first, assessed at 100 days
Disease-free survival
Will be estimated using the product-limit method of Kaplan-Meier.
Time frame: From the start of protocol therapy to the date of death, disease relapse, or last follow-up whichever occurs first, assessed at 1 year
Overall survival
Will be estimated using the product-limit method of Kaplan-Meier.
Time frame: From start of protocol therapy to death, or last follow-up, whichever occurs first, assessed at 1 year
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