Summary

This phase I trial studies the side effects of autologous CD19/CD22 chimeric antigen receptor T-cells and to see how well it works in treating patients with CD19 positive B acute lymphoblastic leukemia that has come back (recurrent) or does not respond to treatment (refractory). 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 B acute lymphoblastic leukemia. Giving autologous CD19/CD22 chimeric antigen receptor T-cells may help treat patients with B acute lymphoblastic leukemia.

Objectives

PRIMARY OBJECTIVES:
I. Determine the feasibility of producing autologous CD19/CD22 chimeric antigen receptor T-cells (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 OBJECTIVE:
I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in adults with diffuse large B-Cell lymphoma (DLBCL) and/or adults with acute lymphoblastic leukemia (ALL).

EXPLORATORY 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 correlations between immune responses directed toward the CD19/22-CAR T cells 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 autologous CD19/CD22 chimeric antigen receptor 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 autologous CD19/CD22 chimeric antigen receptor T-cells IV over 10-30 minutes on day 0. Patients that benefited from the first dose of autologous CD19/CD22 chimeric antigen receptor T-cells, had no unacceptable side effects, and have enough cells left over may receive additional doses of autologous CD19/CD22 chimeric antigen receptor T-cells based on the number of additional cells available.

After completion of study treatment, patients are followed up daily until day 14, twice per week until day 28, at 2, 3, 6, 9, and 12 months, every 6-12 months up to year 5, and then annually for years 6-15.

Eligibility

1. For B-ALL * Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the following types: ** Chemotherapy refractory disease in subjects with B-ALL is defined as progression or stable disease after two lines of lines of therapies ** Recurrence of disease after achieving complete remission (CR) * Subjects with persistent or relapsed minimal residual disease (MRD) (by flow cytometry, polymerase chain reaction [PCR], fluorescence in situ hybridization [FISH], or next generation sequencing) require verification of MRD positivity 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) * Subjects with recurrence of isolated central nervous system (CNS) relapse after achieving complete remission (CR); if relapsed with MRD, will require verification of MRD positivity on two occasions at least 4 weeks apart
2. CD19 expression is required at any time since diagnosis; if patient has received anti-CD19 targeted therapy (i.e. blinatumomab or CD19-CAR T cell), the CD19 expression must be subsequently demonstrated; CD19 expression may be detected by immunohistochemistry or 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
3. 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 have no evidence of graft versus host disease (GVHD) and have been without immunosuppressive agents for at least 30 days
4. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be at least 30 days post CAR infusion and have < 5% of CD3+ cells express the previous CAR if a validated assay is available
5. Must have evaluable or measurable disease; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
6. 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 * Exceptions: ** There is no time restriction with regard to prior intrathecal chemotherapy (including [incl.] steroids) provided there is complete recovery from any acute toxic effects ** Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis ** Subjects who are on standard ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy is discontinued at least 1 week or 5 half-lives (whichever is shorter) prior to apheresis ** Subjects receiving steroid therapy at physiologic replacement doses (=< 5 mg/day of prednisone or equivalent doses of other corticosteroids) only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis ** For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to apheresis, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port
7. Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for clinically non-significant toxicities such as alopecia)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; or Karnofsky >= 60%
9. Absolute neutrophil count (ANC) >= 750/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
10. Platelet count >= 50,000/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
11. Absolute lymphocyte count >= 150/uL * A subject will not be excluded because of pancytopenia >= grade 3 if it is felt by the investigator to be due to underlying leukemia/lymphoma
12. Creatinine =< 2 mg/dL or creatinine clearance >= 60 mL/min
13. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 upper limit of normal (ULN) (elevated ALT/AST associated with leukemia or lymphoma involvement of the liver will not disqualify a subject; only one value required for eligibility)
14. Total bilirubin =< 1.5 mg/dl, except in subjects with Gilbert’s syndrome
15. Cardiac ejection fraction >= 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), multigated acquisition (MUGA) or cardiac magnetic resonance imaging (MRI) (performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy [whichever is most recent])
16. No clinically significant electrocardiogram (ECG) findings
17. No clinically significant pleural effusion
18. Baseline oxygen saturation > 92% on room air
19. CNS status * Subjects with CNS involvement are eligible as long as there are no overt signs or symptoms that in the evaluation of the investigator would mask or interfere with the neurological assessment of toxicity
20. 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)
21. 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 lymphodepletion regimen
22. Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study

Treatment Sites in Georgia