Autologous CD22 CAR T Cells in Adults w/ Recurrent or Refractory B Cell Malignancies


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Trial ID: NCT04088890


The primary purpose of this study is to test whether CD22-CAR T cells can be successfully made from immune cells collected from adults with relapsed/refractory B-cell malignancies (leukemia and lymphoma).

Official Title

Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults With Recurrent or Refractory B Cell Malignancies

Stanford Investigator(s)

Matthew Frank

Assistant Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)

Surbhi Sidana, MD
Surbhi Sidana, MD

Assistant Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)

Andrew Rezvani, M.D.
Andrew Rezvani, M.D.

Associate Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)

Robert Negrin
Robert Negrin

Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)

David Miklos
David Miklos

Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)

Lori Muffly
Lori Muffly

Associate Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy)


Inclusion criteria.

   1. Disease Status

      1. Disease Status of ALL

         - Must have chemotherapy refractory disease defined as progression or stable
         disease after two lines of therapies, or relapsed disease after achieving

         - Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
         cytometry, PCR, FISH, or next generation sequencing) require verification of
         MRD on two occasions at least 2 weeks apart.

         - Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia
         (Ph+ALL) 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 CNS relapse after achieving complete
         remission (CR) are eligible.

      2. Disease Status of aggressive B-cell NHL •Histologically confirmed aggressive B
      cell NHL including the following types defined by WHO 2008: oDLBCL 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 oprimary
      mediastinal (thymic) large B cell lymphoma; OR otransformation of follicular
      lymphoma, marginal zone lymphoma or chronic lymphocytic leukemia/small
      lymphocytic lymphoma to DLBCL; OR oFollicular Lymphoma Grade 3B •Subjects with
      DLBCL, Follicular Lymphoma Grade 3B -or-

   Subjects with transformed FL, MZL, or CLL/SLL who HAVE NOT received chemotherapy prior
   to transformation:

   oMust have received an anthracycline regimen and an anti CD20 monoclonal antibody
   (unless documented CD20-negative) and be refractory or relapsed after second line of
   DLBCL treatment. Subjects with a partial response to second line therapy must be
   ineligible for autologous transplant.

   •Subjects with transformed FL, MZL, or CLL/SLL who HAVE received
   anthracycline-containing chemotherapy prior to transformation: oMust have progressed,
   had SD or recurred with transformed disease after initial treatment for DLBCL.

   2. Measureable Disease

      - Subjects with ALL: must have evaluable or measurable disease (MRD positive by
      flow cytometry, NGS, or PCR is acceptable).

      - Subjects with aggressive B-cell NHL: must have evaluable or measurable disease
      according to the revised IWG Response Criteria for Malignant Lymphoma[38].
      Lesions that have been previously irradiated will be considered measurable only
      if progression has been documented following completion of radiation therapy.

   3. CD22 expression

   •Subjects with ALL: CD22 positive expression on malignant cells is required and must
   be detected by immunohistochemistry or 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.

   CD22 expression must be demonstrated subsequent to any anti-CD22 targeted therapy
   (e.g. Moxetumomab pasudotox or inotuzumab ogozamicin) in subjects with ALL.

   •Subjects with aggressive B-cell NHL: CD22 expression at any level, including
   undetectable, will be acceptable. Subjects must have archival tissue available for
   analysis of CD22 expression or must be willing to undergo a biopsy of easily
   accessible disease.

   4. Prior Bone Marrow-Stem Cell Transplant Subjects who have undergone autologous 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 GVHD and have been without immunosuppressive agents for at
   least 30 days.

   5. Prior Therapy Wash-out 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.


      1. There is no time restriction with regard to prior intrathecal chemotherapy
      provided there is complete recovery from any acute toxic effects of such;

      2. Subjects receiving hydroxyurea may be enrolled provided there has been no
      increase in dose for at least 2 weeks prior to starting apheresis;

      3. 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

      4. Subjects receiving steroid therapy at physiologic replacement doses only are
      allowed provided there has been no increase in dose for at least 2 weeks prior to
      starting apheresis;

      5. 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 or the site of radiation
      has documented progression.

   6. Prior CAR Therapy Subjects who have undergone prior CAR therapy must be at least 30
   day post CAR infusion and have < 5% of CD3+ cells express the previous CAR if a
   validated assay is available.

   7. Toxicities due to prior therapy must be stable or resolved (except for clinically non
   significant toxicities such as alopecia or cytopenias covered in *footnote to #10)

   8. Age greater than or equal to 18 years of age

   9. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or
   Karnofsky ≥ 60% (See section 13.1, Appendix A)

10. Normal Organ and Marrow Function (supportive care is allowed per institutional
   standards, i.e. filgrastim, transfusion)

      - ANC ≥ 750/uL*

      - Platelet count ≥ 50,000/uL*

      - Absolute lymphocyte count (ALC) ≥ 150/uL*

   Adequate renal, hepatic, pulmonary and cardiac function defined as:

      - Creatinine ≤ 2 mg/dL OR creatinine clearance ≥ 60 mL/min

      - Serum ALT/AST ≤ 10x Upper limit of normal (ULN) (Elevated ALT/AST related to
      leukemia involvement of the liver will not disqualify a subject).

      - 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 ECHO, MUGA or Cardiac MRI [performed
      within 180 days or after most recent anthracycline based treatment or mediastinal
      radiation therapy (whichever is most recent)]

      - No clinically significant ECG findings

      - No clinically significant pleural effusion

      - Baseline O2 saturation > 92% on room air * ALL subjects will not be excluded
      because of pancytopenia ≥ Grade 3 if it is felt by the investigator to be due to
      underlying leukemia.

11. 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.

12. Females of childbearing potential must have a negative serum or urine pregnancy test
   within 7 days prior to leukapheresis(females who have undergone surgical sterilization
   or who have been postmenopausal for at least 2 years are not considered to be of
   childbearing potential)

13. Contraception 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.

14. Ability to give informed consent. Must be able to give informed consent. Legal
   authorized representative (LAR) is permitted if subject is cognitively able to provide
   verbal assent.

Exclusion criteria.

   1. Recurrent or refractory ALL limited to isolated testicular disease.

   2. Hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly progressive disease that in the
   estimation of the investigator and sponsor would compromise ability to complete study

   3. History of other malignancy, unless disease free for at least 3 years. At the
   discretion of the Principal Investigator, subjects in remission for 1-2 years prior to
   enrollment may be deemed eligible after considering the nature of other malignancy,
   likelihood of recurrence during one year following CAR therapy, and impact of prior
   treatment on risk of CD22-CAR T cells. Subjects in remission <1 year are not eligible.

      - Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder,
      breast) is eligible.

      - Hormonal therapy in subjects in remission > 1 year will be allowed.

   4. Presence of active fungal, bacterial, viral, or other infection requiring intravenous
   antimicrobials. Simple UTI and uncomplicated bacterial pharyngitis are permitted if
   responding to active treatment.

   5. No knowledge of:

      - HIV,

      - Hepatitis B (HBsAg positive) or

      - Hepatitis C virus (anti HCV positive) infection. A history of hepatitis B or
      hepatitis C is permitted if the viral load is undetectable per quantitative PCR
      and/or nucleic acid testing.

   6. Presence of 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.

   7. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
   other clinically significant cardiac disease within 12 months of enrollment.

   8. Any medical condition that in the judgement of the sponsor investigator is likely to
   interfere with assessment of safety or efficacy of study treatment.

   9. History of severe immediate hypersensitivity reaction to any of the agents used in
   this study.

10. Women who are pregnant or breastfeeding.

11. In the investigator's 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.

12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid
   arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease
   modifying agents within the last 2 years.


drug: Fludarabine

drug: Cyclophosphamide

drug: CD22 CAR


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Juliana Craig

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