Palo Alto, California 94304

  • Minim

Purpose:

This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating patients with CD19 positive diffuse large B-cell lymphoma or B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.


Study summary:

PRIMARY OBJECTIVES: I. Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria. II. Assess the safety of administering escalating doses of autologous CD19/CD22-CAR T cells that meet established release specifications in adults with hematologic malignancies following a cyclophosphamide/fludarabine phosphate (fludarabine) conditioning regimen. SECONDARY OBJECTIVES: I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in adults with B cell malignancies. TERTIARY OBJECTIVES: I. Evaluate the frequency of CD22+ expression on lymphoma cells, and determine site density when possible. II. Analyze alterations in early B cell development induced by immune pressure exerted via CD19/CD22-CAR T cells. III. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or diminished expression of CD19 and/or CD22, when feasible. IV. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebrospinal fluid (CSF), and explore correlations between anti CD19/CD22-CAR T cell properties and CAR T cell efficacy and persistence. V. Establish the utility of chromatin structure and epigenomic technology to characterize CAR T cell therapies. OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells. Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells. After completion of study treatment, patients are followed up daily until day 14, twice per week until day 28, at 2 months, at 3 months, every 3 months until month 12, every 6-12 months up to year 5, and then annually for years 6-15.


Criteria:

Inclusion Criteria: - For diffuse large B-cell lymphoma (DLBCL) - Histologically confirmed aggressive B cell non-Hodgkin lymphoma (NHL) including the following types defined by World Health Organization (WHO) 2008: - DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein Barr virus (EBV)+ DLBCL of the elderly; OR - Primary mediastinal (thymic) large B cell lymphoma - Transformation of follicular lymphoma to DLBCL will also be included - Subjects with DLBCL must have progressed, had stable disease (SD), or recurred after initial treatment regimens that include an anthracycline and an anti CD20 monoclonal antibody; subjects who relapse >= 12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant - For B acute lymphoblastic leukemia (ALL) - Chemotherapy refractory disease in subjects with B-ALL is defined as progression or stable disease after two lines of standard therapies (two induction regimens), or relapsed disease after 2 established induction regimens - Subjects with persistent or relapsed minimal residual disease (MRD) / next generation sequencing (NGS) relapse require verification of relapse on two occasions at least 4 weeks apart - Subjects with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed after two lines of therapy, including tyrosine kinase inhibitors (TKIs) - CD19 expression is required and must be detected on greater than 50% of the malignant cells by immunohistochemistry or >= 90% by flow cytometry; the choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each subject; in general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples - Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse following SCT are eligible; subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they are at least 100 days post transplant, they have no evidence of graft versus host disease (GVHD) and have been without immunosuppressive agents for at least 30 days - Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy - At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives - Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for clinically non significant toxicities such as alopecia) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or Karnofsky >= 80% - Absolute neutrophil count (ANC) >= 750/uL - Platelet count >= 50,000/uL - Absolute lymphocyte count >= 150/uL - Creatinine =< 2 mg/dL or creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min - Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 upper limit of normal (ULN) - Total bilirubin =< 1.5 mg/dl, except in subjects with Gilbert?s syndrome - Cardiac ejection fraction >= 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings - No clinically significant pleural effusion - Baseline oxygen saturation > 92% on room air - Central nervous system (CNS) status - Subjects with ALL - Subjects with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy: - CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of white blood cells (WBCs); - CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: - CNS 2a: < 10/uL red blood cells (RBCs); < 5/uL WBCs and cytospin positive for blasts; - CNS 2b: >= 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts; - CNS 2c: >= 10/uL RBCs; >= 5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm - Subjects with DLBCL - Subjects must have no signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at the time of screening; subjects who have been previously treated for CNS disease but have no evidence of disease at screening are eligible - Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential) - Subjects of child bearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen; females of child bearing potential must have a negative pregnancy test - Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study Exclusion Criteria: - History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years - History of Richter?s transformation of chronic lymphocytic leukemia (CLL) - Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment; known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C virus (anti hepatitis C virus [HCV] positive); a history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing - History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement - History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment, or have cardiac atrial or cardiac ventricular lymphoma involvement - Subjects receiving anticoagulation therapy - Any medical condition that in the judgement of the sponsor investigator is likely to interfere with assessment of safety or efficacy of study treatment - History of severe immediate hypersensitivity reaction to any of the agents used in this study - Women of child bearing potential who are pregnant or breastfeeding; females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential - In the investigators judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation - May not have primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years


NCT ID:

NCT03233854


Primary Contact:

Principal Investigator
David Miklos
Stanford University

Juliana Craig
Phone: 650-736-0912
Email: jkcraig@stanford.edu


Backup Contact:

N/A


Location Contact:

Palo Alto, California 94304
United States

Juliana Craig
Phone: 650-736-0912
Email: jkcraig@stanford.edu

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: September 18, 2021

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