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Genetically Engineered Cells (CD22-CAR T Cells) for the Treatment of Recurrent or Refractory B Cell Malignancies

Trial Status: Approved

This phase Ib trial studies the side effects and how well cell therapy (CD22-CAR T cells) works for the treatment of B cell malignancies that have come back (recurrent) and does not respond to treatment (refractory). The antigen CD22 is commonly found on B cell cancers. In this study, a CD22 gene and a type of virus (lentivirus; a virus similar to HIV) are used in making the cells (CD22-CAR T cells). The chimeric antigen receptor (CAR) is a genetically-engineered receptor made so that immune cells can recognize and respond to a specific molecule, such as CD22 protein. This uses a portion of an antibody to CD22 and part of a molecule that activates or ‘turns on’ the immune cell. Together, the CAR may help these T cells find the cancer in the body. Giving chemotherapy (fludarabine and cyclophosphamide) before CD22-CAR T cells may help prepare the immune system to accept the CD22-CAR T cells.

Inclusion Criteria

  • 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 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 minimal residual disease (MRD) on two occasions at least 2 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)
  • 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/small lymphocytic 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 with transformed follicular lymphoma (FL), marginal zone lymphoma (MZL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) must have progressed, had SD, or recurred with transformed disease after initial treatment for DLBCL. Subjects who relapse >= 12 months after therapy should have progressed after autologous transplant or been ineligible for autologous transplant
  • Subjects with ALL 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
  • Subjects with ALL: CD22 positive expression on malignant cells is required and must be detected by immunohistochemistry or 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. 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 lymphoma: must have archival tissue available for analysis of CD22 expression, or must be willing to undergo a biopsy of easily accessible disease
  • 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
  • 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 * At least 5 half-lives must have elapsed since prior therapy with inotuzumab ozogamicin * Exceptions: ** There is no time restriction with regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such ** 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 or 5 half-lives, whichever is shorter, 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 or the site of radiation has documented progression
  • Subjects who have undergone prior CAR therapy will be eligible if at least 30 days has elapsed prior to apheresis
  • Toxicities due to prior therapy must be stable (except for clinically non-significant toxicities such as alopecia)
  • Subjects > 10 years of age: Karnofsky >= 70% OR Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Subjects =< 10 years of age: Lansky scale >= 70%
  • 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 within institutional norms for age (i.e. =< 2 mg/dL in adults or according to table below in children < 18 years) OR creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min * Age (years): =< 5; maximum serum creatinine (mg/dL): 0.8 * Age (years): 5 < age =< 10; maximum serum creatinine (mg/dL): 1.0 * Age (years): > 10-18; maximum serum creatinine (mg/dL): 1.2 * Age (years): > 18; maximum serum creatinine (mg/dL): 2.0
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 x ULN (unless elevated ALT/AST is associated with leukemia 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 echocardiography (ECHO)
  • No clinically significant electrocardiography (ECG) findings
  • No clinically significant pleural effusion
  • Baseline oxygen saturation > 92% on room air
  • 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
  • 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 or for as long as CD19/CD22-CAR T cells are detectable in peripheral blood
  • All subjects >= 18 years of age must be able to give informed consent. For subjects < 18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate. If a minor becomes of age during participation of this study, he/she will be asked to reconsent as an adult

Exclusion Criteria

  • Recurrent or refractory ALL limited to isolated testicular disease
  • Hyperleukocytosis (>= 50,000 blasts/uL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy
  • 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. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
  • Ongoing infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will pose unacceptable risk. 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
  • 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 because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant
  • 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
  • Has 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

California

Palo Alto
Stanford Cancer Institute Palo Alto
Status: APPROVED
Contact: Liora Michal Schultz
Phone: 650-497-8953

PRIMARY OBJECTIVES:

I. Determine the feasibility of manufacturing anti-CD22 CAR-expressing T lymphocytes (CD22-CAR T cells) for administration to children and young adults with relapsed/refractory (R/R) CD22 expressing B-cell acute lymphoblastic leukemia (ALL) or lymphoma using the Miltenyi CliniMACS Prodigy system.

II. Determine the safety of an established dose of CD22-CAR T cells in children and young adults with R/R CD22 expressing B-cell malignancies.

SECONDARY OBJECTIVE:

I. Assess the clinical activity of CD22-CAR T cells in children and young adults with R/R CD22 expressing B-cell malignancies, including overall survival (OS) and progression free survival (PFS).

EXPLORATORY OBJECTIVES:

I. Analyze alterations in early B cell development induced by immune pressure exerted via CD22-CAR T cells.

II. Evaluate whether subjects receiving CD22-CAR T cells relapse with loss or diminished expression of CD22, when feasible.

III. Measure persistence of CD22-CAR T cells in the blood, bone marrow and cerebrospinal fluid (CSF) (when feasible), and explore correlations between CD22-CAR T cell properties and CAR T cell efficacy and persistence.

IV. Establish the utility of chromatin structure and epigenomic technology to characterize CAR T cell therapies.

V. Analyze CD22 expression in lymphoma/diffuse large B-cell lymphoma (DLBCL) and correlate with disease response.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD22-CAR T cells IV over 10-30 minutes on day 0.

After completion of study treatment, patients are followed up monthly for 3 months, every 3 months for 9 months, every 6-12 months for 4 years, and then annually for up to 15 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Stanford Cancer Institute Palo Alto

Principal Investigator
Liora Michal Schultz

  • Primary ID CCT6003
  • Secondary IDs NCI-2019-07285, IRB-50878
  • Clinicaltrials.gov ID NCT04088864