Autologous CD19 / CD22 Chimeric Antigen Receptor T-cells and Chemotherapy in Treating Patients with Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

Status: Active

Description

This phase I trial studies the side effects of autologous CD19 / CD22 chimeric antigen receptor 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 autologous CD19 / CD22 chimeric antigen receptor T-cells and chemotherapy may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.

Eligibility Criteria

Inclusion Criteria

  • For 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, marginal zone lymphoma or chronic lymphocytic leukemia 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-ALL * 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
  • CD19 expression is required at any time since diagnosis; if patient has received anti-CD19 targeted therapy (i.e. blinatumomab or CD19-CAR T cells), then CD19 expression must be subsequently demonstrated; CD19 expression 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
  • Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy will be eligible if < 5% of circulating levels of CD3+ cells express the previous CAR by flow cytometry
  • Must have evaluable or measurable disease; subjects with lymphoma 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 * 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 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 enrollment, 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
  • 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 * If these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
  • Platelet count >= 50,000/uL * If these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
  • Absolute lymphocyte count >= 150/uL * If these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
  • Creatinine =< 2 mg/dL or creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 upper limit of normal (ULN) (unless elevated ALT/AST is associated with leukemia or lymphoma involvement of the liver, in which case this criterion will be waived and not disqualify a patient)
  • 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
  • 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 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 no detectable evidence of CNS disease on magnetic resonance imaging (MRI) at the time of screening; subjects who have been previously treated for CNS disease and who have the following CNS status will be eligible: *** CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of 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 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
  • 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 because of the potentially dangerous/unknown effects on the fetus
  • 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
  • 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 PCR and/or nucleic acid testing
  • CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement that in the judgment of the investigator may impair the ability to evaluate neurotoxicity
  • 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 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 because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant; 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

Locations & Contacts

California

Palo Alto
Stanford Cancer Institute Palo Alto
Status: Active
Contact: David B. Miklos
Phone: 650-452-8155
Email: dmiklos@stanford.edu

Trial Objectives and Outline

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 OBJECTIVES:

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 10-20 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 2 or 3 additional doses of autologous CD19/CD22 chimeric antigen receptor 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.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Stanford Cancer Institute Palo Alto

Principal Investigator
David B. Miklos

Trial IDs

Primary ID CCT5001
Secondary IDs NCI-2017-01291
Clinicaltrials.gov ID NCT03233854