CD19-Directed CAR-T Cell Therapy for the Treatment of Relapsed/Refractory B Cell Malignancies

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Brief Title

CD19-Directed CAR-T Cell Therapy for the Treatment of Relapsed/Refractory B Cell Malignancies

Official Title

Phase I Dose Escalation Trial of CD19 Directed Chimeric Antigen Receptor T Cell Therapy in the Treatment of Relapsed/Refractory B Cell Malignancies

Brief Summary

      This phase I trial studies the effects of CD-19 directed chimeric antigen receptor (CAR)-T
      cell therapy for the treatment of patients with B cell malignancies that have come back
      (recurrent) or have not responded to treatment (refractory). CD-19 CAR-T cells use some of a
      patient's own immune cells, called T cells, to kill cancer. T cells fight infections and, in
      some cases, can also kill cancer cells. Some T cells are removed from the blood, and then
      laboratory, researchers will put a new gene into the T cells. This gene allows the T cells to
      recognize and possibly treat cancer. The new modified T cells are called the IC19/1563
      treatment. IC19/1563 may help treat patients with relapsed/refractory B cell malignancies.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the maximum tolerated dose of in-house, point of care manufactured autologous
      anti-CD19 CAR-expressing T-lymphocytes IC19/1563 (IC19/1563) in patient with
      relapsed/refractory B cell malignancies.

      SECONDARY OBJECTIVES:

      I. Assess the feasibility of in-house, point of care manufactured IC19/1563 cells.

      II. Evaluate safety, including all grades of neurotoxicity (ICANS) and cytokine release
      syndrome as determined by the American Society for Transplantation and Cellular Therapy
      (ASTCT) criteria, by monitoring adverse events, laboratory abnormalities, vital signs, and
      other safety parameters.

      III. Estimate the incidence of Grade 3 or higher of neurotoxicity and cytokine release
      syndrome by grade 3 or higher neurotoxicity (ICANS) or CRS per the ASTCT criteria.

      IV. Assess efficacy of a single dose of IC19/1563 cells:

      IVa. Overall response rate (ORR); IVb. Duration of response (DOR); IVc. Progression-free
      survival (PFS); IVd. Minimal residual disease (MRD) negative bone marrow disease in patients
      with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), based on one month
      post evaluation.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. Characterize the in vivo cellular kinetics profile (levels, persistence, trafficking) of
      CAR19 transgene and CD3+CAR+ cells into blood.

      II. Characterize the changes in cytokine levels over time. III. Assess hospital resource
      utilization and health economics.

      OUTLINE: This is a dose-escalation study of IC19/1563.

      Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine IV over
      30 minutes on days -5, -4, -3 and IC19/1563 IV on day 0.

      After completion of study treatment, patients are followed up on days 60, every 3 months up
      to year 3, every 6 months from years 3-5, and then annually for up to 15.5 years.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum tolerated dose (MTD)

Secondary Outcome

 Proportion of patients who achieve a successful infusion without manufacturing failure or out of spec products

Condition

Recurrent B-Cell Non-Hodgkin Lymphoma

Intervention

Autologous Anti-CD19 CAR-expressing T-lymphocytes IC19/1563

Study Arms / Comparison Groups

 Treatment (cyclophosphamide, fludarabine, IC19/1563)
Description:  Patients receive cyclophosphamide IV over 60 minutes and fludarabine IV over 30 minutes on days -5, -4, -3 and IC19/1563 IV on day 0.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

18

Start Date

June 27, 2022

Completion Date

December 15, 2025

Primary Completion Date

December 15, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Age >= 18 years

          -  Relapsed or refractory CD19+ B cell malignancies of the one of the following
             histopathology:

               -  Biopsy proven B-cell non-Hodgkin lymphoma (NHL) of any histopathology (including
                  Richter Transformation of CLL); relapsed or refractory disease defined as:

                    -  Two or more prior lines of therapy, at least one anthracycline containing
                       regimen, unless intolerable. Exception: Patients with Richter transformation
                       of CLL are eligible if they had >= one prior treatment, including prior BTK
                       inhibition

                    -  Demonstration of progressive or stable disease by positron emission
                       tomography/computed tomography (PET/CT) or CT criteria as the best response
                       to the most recent chemotherapy regimen according to the revised Lugano
                       Response Criteria for Malignant Lymphoma.

                    -  Measurable disease defined as measurable by CT portion of a PET/CT: To be
                       considered measurable, the must be at least one lesion that has a single
                       diameter of (>1.5 cm Note: Lesions that have been previously irradiated will
                       be considered measurable only if progression has been documented following
                       completion of radiation therapy

               -  Biopsy proven SLL or flow cytometry proven CLL; relapsed disease defined as:

                    -  >= two prior lines of therapy, and/or >= 6 months of second line prior BTK
                       inhibition (e.g. venetoclax and ibrutinib). Exception: Patients in stable
                       disease (SD) or partial response (PR) with a known ibrutinib resistance
                       mutation (BTK or phospholipase Cgamma2) may be included even if on ibrutinib
                       therapy for less than 6 months.

                    -  Demonstration of progressive or stable disease by PET/CT or CT criteria
                       according to the International Workshop on Chronic Lymphocytic Leukemia
                       (iwCLL2018) criteria

                    -  Measurable disease by CT portion of a PET/CT where at least one lesion has a
                       single diameter of >1.5 cm or peripheral blood absolute blood lymphocyte
                       count (ALC) of > 5000. Note: Lesions that have been previously irradiated
                       will be considered measurable only if progression has been documented
                       following completion of radiation therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Hemoglobin >= 8.0 g/dL (=< 14 days prior to registration)

          -  Absolute neutrophil count (ANC) >= 500/mm^3 (=< 14 days prior to registration)

          -  Platelet count >= 30,000/mm^3 (=< 14 days prior to registration)

          -  Total bilirubin =< 2.0 mg/dL (with the exception of subjects with Gilbert's syndrome.
             Subjects with Gilbert's syndrome may be included if their total bilirubin is =< 3.0 x
             upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN) (=< 14 days prior to
             registration)

          -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 14 days
             prior to registration)

          -  Prothrombin time (PT) / international normalized ratio (INR) and/or activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant
             therapy and INR or aPTT is within target range of therapy (for patients receiving
             anticoagulation, there should be no prior history of bleeding, and no recent deep
             venous thrombosis/pulmonary embolism (DVT/PE) within the last 6 months of enrollment)
             (=< 14 days prior to registration)

          -  Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (=< 14
             days prior to registration)

          -  Cardiac ejection fraction >= 50% and no evidence of clinically significant pericardial
             effusion as determined by an echocardiogram (ECHO) or multigated acquisition scan
             (MUGA) scan

          -  Baseline oxygen saturation >= 92% on room air

          -  Negative serum pregnancy test done =< 7 days prior to registration, for persons of
             childbearing potential only

          -  Women patients of child bearing potential, including women with tubal ligations, must
             commit to using use 2 highly effective forms of birth control (defined as the use of
             an intrauterine device, a barrier method with spermicide, condoms, any form of
             hormonal contraceptives) for the duration of the study and for 12 months following
             IC19/1563 therapy

          -  Provide written informed consent

          -  Willingness to provide mandatory blood specimens for correlative research

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

        Exclusion Criteria:

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant persons

               -  Nursing persons

               -  Women of childbearing potential who are unwilling to employ highly effective
                  contraception

          -  Sexually active males who are not willing to use contraception during the study and
             for >= 12 months after IC19/1563 therapy

          -  Patients who are able to obtain market approved CD19 CAR T-cell therapies

          -  Live vaccine =< 6 weeks prior to start of registration

          -  Autologous stem cell transplant =< 6 weeks of registration

          -  History of allogenic stem cell transplant if was performed less than 100 days prior to
             registration, if patients have active graft-versus host disease (GVHD) or are if
             patients are on chronic immunosuppression. Patients with allogeneic transplantation
             more than 100 days prior to registration, with no active GVHD and who are not on
             immunosuppression are eligible

          -  History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
             cerebellar disease, or any autoimmune disease with central nervous system (CNS)
             involvement

          -  Any form of primary immunodeficiency such as severe combined immunodeficiency disease

          -  Current need of systemic corticosteroid therapy, in doses over 20 mg /day of
             prednisone or equivalent forms of steroids

          -  History of severe immediate hypersensitivity reaction to CART19, stem cell infusion
             dimethyl sulfoxide (DMSO) or any of the CAR-T cryopreservation ingredients

          -  History of malignancy other than non-melanoma skin cancer, carcinoma in situ (e.g.
             cervix, bladder, breast), unless disease free for >= 2 years

          -  Clinically significant active infection (e.g. simple urinary tract infection [UTI],
             bacterial pharyngitis allowed) or currently receiving IV antibiotics or have received
             IV antibiotics =< 7 days prior to registration. Note: prophylactic antibiotics,
             antivirals and antifungals are permitted

          -  Known history of human immunodeficiency virus (HIV) infection or acute or chronic
             hepatitis B or hepatitis C infection. Subjects with a history of hepatitis infection
             must have cleared their infection as determined by standard serological and genetic
             testing per current Infectious Diseases Society of America (IDSA) guidelines.
             Prophylactic antiviral therapy should be considered per institutional guidelines

          -  History of any of the following cardiovascular conditions =< 6 months:

               -  Class III or IV heart failure as defined by the New York Heart Association (NYHA)

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Or other clinically significant cardiac disease

          -  Any other acute or chronic medical or psychiatric condition that may increase the risk
             associated with study participation or investigational product administration or that,
             in the judgment of the investigator, would make the subject inappropriate for entry
             into the study

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary disease
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Saad J Kenderian, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04892277

Organization ID

MC198A

Secondary IDs

NCI-2021-03969

Responsible Party

Sponsor

Study Sponsor

Mayo Clinic

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Saad J Kenderian, Principal Investigator, Mayo Clinic in Rochester


Verification Date

May 2022