This phase I trial tests the safety, side effects, and best dose of genetically engineered cells called EGFRt/19-28z/IL-12 CAR T cells, and to see how they work in treating patients with hematologic malignancies that makes a protein called CD19 (CD19-positive) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric Antigen Receptor (CAR) T-cell Therapy is a type of treatment in which a patient's 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. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (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. To improve the effectiveness of the modified T cells and to help the immune system fight cancer cells better, the modified T cells given in this study will include a gene that makes the T cells produce a cytokine (a molecule involved in signaling within the immune system) called interleukin-12 (IL-12). The researchers think that IL-12 may improve the effectiveness of the modified T cells, and it may also strengthen the immune system to fight cancer. Giving EGFRt/19-28z/IL-12 CAR T cells may be safe and tolerable in treating patients with relapsed or refractory CD19+ hematologic malignancies.
PRIMARY OBJECTIVE: I. To determine the safety, toxicity and maximum tolerated dose (MTD) of EGFRt/19-28z/IL-12 CAR T-lymphocytes (EGFRt/19-28z/IL-12 CAR T cells) in patients with relapsed or refractory CD19+ aggressive hematologic malignancies. SECONDARY OBJECTIVES: I. To assess the anti-tumor efficacy of adoptively transferred EGFRt/19-28z/IL-12 T cells. II. To assess the in vivo persistence of adoptively transferred EGFRt/19-28z/IL-12 T cells. EXPLORATORY OBJECTIVES: I. To describe the cellular and cytokine microenvironment following infusion of adoptively transferred EGFRt/19-28z/IL-12 T cells. II. To characterize endogenous anti-tumor immune responses following infusion of adoptively transferred EGFRt/19-28z/IL-12 T cells. III. To summarize levels of normal B cells and the incidence of B cell aplasia following infusion of adoptively transferred EGFRt/19-28z/IL-12 T cells. IV. To determine the proportion of evaluable patients who achieve minimal residual disease (MRD)-negativity in peripheral blood and/or bone marrow. V. To assess phenotype and in vitro function of end-of-production (EOP) EGFRt/19-28z/IL-12 CAR T cells and phenotype at recovery following CAR T cell administration. OUTLINE: This is a dose-escalation study of EGFRt/19- 28z/IL-12 CAR T cells. Patients are assigned to 1 of 2 cohorts. COHORT A: Patients undergo leukapheresis prior to treatment. Patients receive EGFRt/19- 28z/IL-12 CAR T cells intravenously (IV) over 5 to 30 minutes on day 0. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo computed tomography (CT) or positron emission tomography (PET) as well as bone marrow biopsy and aspiration and blood sample collection throughout the trial. Additionally, patients undergo a tissue biopsy during screening and on the trial. COHORT B: Patients undergo leukapheresis prior to treatment and receive lymphodepletion chemotherapy with cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes on days -5, -4, and -3. Patients then receive EGFRt/19- 28z/IL-12 CAR T cells IV over 5 to 30 minutes on day 0. Patients also undergo ECHO or MUGA during screening. Patients also undergo CT or PET as well as bone marrow biopsy and aspiration and blood sample collection throughout the trial. Additionally, patients undergo a tissue biopsy during screening and on the trial. After completion of study treatment, patients are followed up weekly for 4 weeks, every 4 weeks until 24 months, every 3 months thereafter for 1 year, then annually for up to 5 years, followed by long-term follow up for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Undergo tissue biopsy
Undergo blood sample collection
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo CT
Given IV
Undergo ECHO
Given IV
Given IV
Undergo leukapheresis
Undergo MUGA
Undergo PET
Roswell Park Cancer Institute
Buffalo, New York, United States
Incidence of adverse events
Will be graded on a scale of 1 to 5 as described by the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0).
Time frame: Up to 5 years
Maximal tolerated dose (MTD) of EGFRt/19-28z/IL-12 chimeric antigen receptor T-cells
Will be defined as the highest dose with an observed incidence of dose limiting toxicities in no more than one out of six patients treated at a particular dose level. Will be assessed using NCI CTCAE v 5.0.
Time frame: Within 30 days from the final infusion of the EGFRt/19-28z/IL-12 T cells
Incidence of complete remission (CR)/complete remission with incomplete count recovery (CRi)
Time frame: Within 3 months of CAR T-cell infusion
Incidence of CR/CRi + partial response (PR) (ORR)
Time frame: Within 3 months of CAR T-cell infusion
Event free survival
Will be computed using the Kaplan- Meier method.
Time frame: Up to 5 years
Overall survival
Will be computed using the Kaplan- Meier method.
Time frame: Up to 5 years
Progression-free survival
Time frame: Up to 5 years
Modified T-cell persistence
Will be determined by the presence of detectable CAR T-cells (quantitative polymerase chain reaction or multiparameter flow cytometry).
Time frame: Up to 5 years
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