Clinical Trials /

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

NCT04088890

Description:

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).

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma Associated with Chronic Inflammation
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Primary Mediastinal B-Cell Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Autologous CD22 CAR T Cells in Adults w/ Recurrent or Refractory B Cell Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IRB-50836
  • SECONDARY ID: CCT5029
  • SECONDARY ID: IRB-50836
  • NCT ID: NCT04088890

Conditions

  • B-ALL
  • B-cell Non Hodgkin Lymphoma
  • DLBCL

Interventions

DrugSynonymsArms
FludarabineR/R ALL
CyclophosphamideR/R ALL
CD22 CARR/R ALL

Purpose

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).

Detailed Description

      Primary Objective:

        -  Determine the feasibility of manufacturing CD22 CAR T cells using the Miltenyi CliniMACS
           Prodigy® system for administration to adults with relapsed/refractory CD22 expressing
           B-cell ALL or relapsed/refractory aggressive B-cell non hodgkins lymphoma (NHL).

        -  Establish the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of CD22 CAR T
           cells in adults with relapsed/refractory aggressive B-cell NHL.

        -  Determine the safety of an established dose of CD22-CAR T cells in adults with
           relapsed/refractory CD22 expressing B-cell ALL and the safety of the MTD/RP2D of
           CD22-CAR T cells in adults with relapsed/refractory aggressive B-cell NHL.

      Secondary Objective:

      - Assess the clinical activity of CD22-CAR T cells in adults with R/R CD22 expressing B-cell
      ALL and R/R aggressive B-cell NHL, including overall survival (OS) and progressive free
      survival (PFS).
    

Trial Arms

NameTypeDescriptionInterventions
R/R ALLExperimentalRelapsed/refractory ALL Lymphodepletion prior to CD22 CAR T cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m2 per day IV for days 5, 4, 3 Cyclophosphamide 500 mg/m2 per day IV for days 5, 4, 3 Autologous CD22 CAR T cells will be administered intravenously at Dose1: 3 x 10^5cells/kg (± 20%) 10
  • Fludarabine
  • Cyclophosphamide
  • CD22 CAR
R/R aggressive B-cell NHLExperimentalRelapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Lymphodepletion prior to CD22 CAR T cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m2 per day IV for days 5, 4, 3 Cyclophosphamide 500 mg/m2 per day IV for days 5, 4, 3 Autologous CD22-CAR T cells will be administered in 3 escalating doses (Dose Level 1, 2, and 3) to determine MTD/RP2D. Dose1: 1 x 10^6 cells/kg (± 20%) Dose2: 3 x 10^6 cells/kg (± 20%) Dose3: 1 x 10^7 cells/kg (± 20%)
  • Fludarabine
  • Cyclophosphamide
  • CD22 CAR

Eligibility Criteria

        Inclusion Criteria:

          1. Disease Status 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 CR.

               -  Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
                  cytometry, polymerase chain reaction (PCR), Fluorescence in in situ hybridization
                  (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.

             Disease Status of aggressive B-cell NHL

               -  Histologically confirmed aggressive B cell NHL including the following types
                  defined by 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; OR
                  transformation of follicular lymphoma, marginal zone lymphoma or chronic
                  lymphocytic leukemia/small lymphocytic lymphoma to DLBCL

               -  Subjects with DLBCL or subjects with transformed follicular lymphoma (FL),
                  marginal zone lymphoma (MZL), or chronic lymphocytic leukemia/small lymphocytic
                  lymphoma (CLL/SLL) who have not received chemotherapy prior to transformation:

                  - Must 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:

                    -  Must 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, next-generation sequencing (NGS), or PCR is acceptable).

               -  Subjects with aggressive B-cell NHL: must have evaluable or measurable disease
                  according to the revised International Working Group (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 ozogamicin) 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 stem
             cell transplant (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.

          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.

             Subjects with ALL may not have received inotuzumab ozogamicin therapy within the past
             3 months.

             Exceptions:

               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
                  apheresis.

               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 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 or the site of radiation
                  has documented progression.

          6. Prior CAR Therapy Subjects who have undergone prior CAR therapy will be eligible if <
             5% of circulating levels of CD3+ cells express the previous CAR by flow cytometry; 30
             days must have elapsed post CAR infusion prior to apheresis.

          7. Toxicities due to prior therapy must be stable or resolved (except for clinically non
             significant toxicities such as alopecia or cytopenias

          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%

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

               -  Absolute neutrophil count (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 (as estimated by Cockcroft Gault
                  Equation) ≥ 60 mL/min

               -  Serum alanine or aspartate aminotransferase (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 echocardiogram (ECHO), multigated
                  radionuclide angiography (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 * 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. 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
             (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
             therapy.

          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 fungal, bacterial, viral, or other infection that is uncontrolled. Simple
             urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if
             responding to active treatment.

          5. Ongoing infection with :

               -  HIV,

               -  Hepatitis B (HBsAg positive) or

               -  Hepatitis C virus (HCV) (anti 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.

          6. 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.

          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 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.

         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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of successful manufacture of CD22 CAR T cells
Time Frame:7-11 days from start of manufacturing
Safety Issue:
Description:The percentage of apheresis samples (fresh or frozen) that are successfully processed and expanded to manufacture CD22 CAR T cells will be determined for each dose cohort.

Secondary Outcome Measures

Measure:Clinical activity of CD22-CAR T cells in adults with relapsed/refractory CD22-expressing B-cell ALL at target dose
Time Frame:28 months after infusion of CD22-CAR T cells
Safety Issue:
Description:Clinical activity will be assessed by modified International Working Group response criteria for acute lymphoblastic leukemia. Results will be reported as best response (i.e. complete response (CR), partial response (PR), stable disease )SD), or progressive disease [PR]) at Day 28 for adult subjects with ALL treated at the target dose.
Measure:Clinical activity of CD22-CAR T cells in adults with relapsed/refractory aggressive B-cell NHL at MTD/RP2D
Time Frame:3 months after infusion of CD22-CAR T cells
Safety Issue:
Description:Clinical activity will be assessed by Lugano response criteria for lymphoma (see Appendix 13.3.2). Results will be reported as best response (i.e. complete response [CR], partial response [PR], stable disease [SD], or progressive disease [PR]) at Month 3 for adult aggressive B-cell NHL subjects treated at MTD/RP2D.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stanford University

Trial Keywords

  • CD22
  • CAR T cells

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