CD19/CD22 Chimeric Antigen Receptor(CAR) T Cells in Adults With Recurrent/Refractory B Cell Malignancies

• ClinicalTrials.gov Identifier: NCT03233854
• Recruitment Status: Recruiting
• First Posted: July 31, 2017
• Last Update Posted: November 13, 2020
• Sponsor: Crystal Mackall, MD
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Crystal Mackall, MD, Stanford University

Tracking Information

• First Submitted Date: July 26, 2017
• First Posted Date: July 31, 2017
• Last Update Posted Date: November 13, 2020
• Actual Study Start Date: September 9, 2017
• Estimated Primary Completion Date: September 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2017)

• Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 28 days ]
  Safety data will be analyzed per standard methods and interpreted descriptively for each dose cohort. Safety data will be summarized for each dose cohort separately and for all dose cohorts combined. Adverse events will be assessed using the CTCAE version 4.03 for type and severity of event. Serious Adverse Events will be summarized for each dose cohort and for all dose cohorts combined. Reasons for discontinuation of study therapy will be tabulated.
• Maximum tolerated dose of CD19/CD22 chimeric antigen receptor (CAR) T cells defined as the dose level immediately below the level at which the enrollment is stopped due to a dose limiting toxicity [ Time Frame: Up to 28 days ]
  Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
• Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis [ Time Frame: Up to 15 years ]
  In addition to aiming to evaluate up to 6 subjects at a given dose level with respect to toxicity, the number of subjects which can successfully manufacture the targeted dose number will be determined.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 26, 2017)

• Overall survival [ Time Frame: From the start of the preparative regimen until death, assessed for up to 15 years ]
  Will be assessed by dose cohort.
• Progression free survival [ Time Frame: From the start of the preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed for up to 15 years ]
  Will be assessed by dose cohort.
• The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 15 years ]
  Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 26, 2017)

• Alterations in early B cell development induced by immune pressure exerted via CD19/CD22 chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 15 years ]
  Will be evaluated.
• CD19/CD22 chimeric antigen receptor (CAR) T cell properties [ Time Frame: Up to 15 years ]
  Will explore correlations with CAR T cell efficacy and persistence.
• Establish the utility of chromatin structure and epigenomic technology to characterize chimeric antigen receptor (CAR) T cell therapies [ Time Frame: Up to 15 years ]
  Investigators will attempt to establish parameters for how best to utilize the technology in CAR research to: establish basis for blood therapeutic monitoring; derive blood biomarkers for prediction of the safety and efficacy of CAR cell therapy; and develop metrics for CAR T product release criteria that can be used during the manufacturing of the product.
• Frequency of CD22+ expression on lymphoma cells [ Time Frame: Up to 15 years ]
  Will correlate with clinical response to CAR T cells.
• Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid [ Time Frame: Up to 15 years ]
  Will be assessed by flow cytometry. Will be analyzed and reported as time from T cell infusion.
• Relapse with loss or diminished expression of CD19 and/or CD22 [ Time Frame: Up to 15 years ]
  Will be evaluated.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: CD19/CD22 Chimeric Antigen Receptor(CAR) T Cells in Adults With Recurrent/Refractory B Cell Malignancies
• Official Title: Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults With Recurrent or Refractory B Cell Malignancies
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• B Acute Lymphoblastic Leukemia
• CD19 Positive
• Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation
• Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
• Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly
• Minimal Residual Disease
• Philadelphia Chromosome Positive
• Recurrent Diffuse Large B-Cell Lymphoma
• Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma
• Refractory Diffuse Large B-Cell Lymphoma
• Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma
• T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Intervention

• Biological: Chimeric Antigen Receptor T-Cell Therapy
  Given CD19/CD22 CAR T cells IV
  Other Name: CAR T-cell therapy
• Drug: Cyclophosphamide
  Given IV
  Other Names:

  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
• Drug: Fludarabine Phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

Experimental: Treatment (CD19/CD22 CAR T cells, chemotherapy)

Patients receive cyclophosphamide 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.

Interventions:

• Biological: Chimeric Antigen Receptor T-Cell Therapy
• Drug: Cyclophosphamide
• Drug: Fludarabine Phosphate
• Other: Laboratory Biomarker Analysis
• Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 26, 2017): 57
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 1, 2035
• Estimated Primary Completion Date: September 1, 2025 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Juliana Craig; 650-736-0912; jkcraig@stanford.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03233854
• Other Study ID Numbers: IRB-41382; 41382 ( Other Identifier: Stanford IRB ); CCT5001 ( Other Identifier: OnCore )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Crystal Mackall, MD, Stanford University
• Study Sponsor: Crystal Mackall, MD
• Collaborators: California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: David Miklos; Stanford University

• PRS Account: Stanford University
• Verification Date: November 2020