Autologous CD22 Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Recurrent or Refractory B Cell Malignancies or Acute Lymphoblastic Leukemia

Status: Active

Description

This phase I / Ib trial studies the side effects and best dose of autologous CD22 CAR T cells and to see how well it works in treating patients with B cell malignancies or acute lymphoblastic leukemia that has come back (recurrent) or does not respond to treatment (refractory). Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient’s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. In this study, some of patients' immune cells (called T cells) will be collected during a procedure called ‘leukapheresis’, and genetically modify them to recognize the antigen (marker) CD22 on cancer cells. CD22 is commonly found on B cell cancers. The CAR is a genetically-engineered receptor made recognize a specific molecule, which in this study is the CD22 protein, and activate or ‘turn on’ immune cells. Doctors use a type of virus to introduce the CAR receptor into patients' T cells to make the CD22 CAR T cells, so they may find and kill those cancer cells in the body.

Eligibility Criteria

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 response (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 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 central nervous system (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 World Health Organization (WHO) 2008: ** Diffuse large B-cell lymphoma (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 (CLL)/small lymphocytic lymphoma (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 stable disease (SD) or recurred with transformed disease after initial treatment for DLBCL
  • 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 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 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 undectable, 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
  • 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
  • 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: * 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 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 < 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
  • Toxicities due to prior therapy must be stable or resolved (except for clinically non-significant toxicities such as alopecia or cytopenias)
  • Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or Karnofsky >= 60%
  • Absolute neutrophil count (ANC) >= 750/uL * 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
  • Platelet count >= 50,000/uL * 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
  • Absolute lymphocyte count (ALC) >= 150/uL * 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
  • Creatinine =< 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 10 x 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 acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI) [performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy (whichever is most recent)]
  • No clinically significant electrocardiography (ECG) findings
  • No clinically significant pleural effusion
  • Baseline oxygen (O2) 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 lymphodepletion regimen
  • Must be able to give informed consent. Legal authorized representative (LAR) is permitted if subject is cognitively able to provide verbal assent

Exclusion Criteria

  • Recurrent or refractory ALL limited to isolated testicular disease
  • 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
  • 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
  • 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), * Hepatitis B (hepatitis B surface antigen [HBsAg] positive) or * Hepatitis C virus (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
  • 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 who are pregnant or breastfeeding
  • 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
  • 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

Locations & Contacts

California

Palo Alto
Stanford Cancer Institute Palo Alto
Status: Active
Contact: Lori Samantha Muffly
Phone: 650-721-2785
Email: lmuffly@stanford.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. 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 acute lymphoblastic leukemia (ALL) or relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL).

II. 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.

III. 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:

I. Assess the clinical activity of CD22-CAR T cells in adults with relapsed/refractory (R/R) CD22 expressing B-cell ALL and R/R aggressive B-cell NHL, including overall survival (OS) and progressive 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), 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 aggressive B-cell NHL and correlate with disease response.

OUTLINE: This is does-escalation study of CD22-CAR T cells.

Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine IV over 30 minutes on days -5 to -3, and CD22 CAR T cells IV over 10-30 minutes on day 0. Treatment continuous in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, every 3 months for 12 months, every 6-12 months for 5 years, and then annually for up to 15 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Stanford Cancer Institute Palo Alto

Principal Investigator
Lori Samantha Muffly

Trial IDs

Primary ID CCT5029
Secondary IDs NCI-2019-06810
Clinicaltrials.gov ID NCT04088890