Phase I Study of Anti-CD22 Chimeric Receptor T Cells in Patients With Relapsed/Refractory Hairy Cell Leukemia and Variant

Background

• Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias. Most cases of HCL respond well to purine analog chemotherapy and harbor BRAF V600E mutation that can be considered for targeted treatment at the time of relapse. However, there are patients with high-risk HCL such as patients with BRAF wild type IGHV4-34 unmutated HCL who respond poorly to chemotherapy and have poor survival.
• HCL variant (HCLv), also brightly CD22+, resembles HCL morphologically but is more aggressive and responds poorly to standard purine analog chemotherapy. Patients have fewer options of targeted treatment partly due to wild type BRAF. We showed that the overall survival in patients progressed after cladribine-rituximab is less than three years.
• Moxetumomab pasudotox-tdfk is an anti-CD22 recombinant immunotoxin which in 2018 was FDA-approved for adult patients with relapsed/refractory HCL. However, there are patients with HCL and HCLv who progress after treatments with standard purine analog chemotherapy and moxetumomab pasudotox-tdfk, and in the case of classic HCL, even after BRAF +/- MEK inhibition. There is still an unmet need for new treatment options for those with relapsed/refractory disease.
• Adoptive cellular therapy with T-cells genetically modified using viral-based vectors to express chimeric antigen receptors (CAR) targeting the CD22 molecule have demonstrated dramatic clinical responses in patients with CD22+ acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL).
• Moxetumomab pasudotox-tdfk proved that CD22 is a potent target for HCL due to its ubiquitous expression in HCL and HCLv, and cellular therapy represents a promising target for those patients that have progressed after other treatments options with chemotherapy, immunotherapy and targeted therapy. This will be the first trial of anti-CD22 CAR T-cell therapy in the treatment of relapsed/refractory HCL and HCLv.

Objectives

• To assess the safety and feasibility of administering escalating doses of autologous anti-CD22-CAR (M971BBz) engineered T-cells in participants with HCL/HCLv following a cyclophosphamide/fludarabine lymphodepletion regimen.
• Explore whether the administration of anti-CD22-CAR engineered T-cells can mediate antitumor effects in HCL/HCLv.

Eligibility

• HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1) Rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab pasudotox-tdft, and 3) BRAF-inhibition.
• Need for treatment, either 1) absolute neutrophil count (ANC) <1/nL, 2) hemoglobin (Hgb) <10g/dL, 3) Platelets <100/nL, 4) HCL mass with short axis > 2 cm outside or >0.5 cm inside the central nervous system (CNS), 5) HCL/HCLv count >5/nL in blood or >25/mm^3 in cerebrospinal fluid (CSF), 6) HCL/HCLv count doubling time <6 months and increasing lytic or blastic bone lesions, 7) symptomatic splenomegaly.

->= 18 years of age.

• CD22 expression must be detected on greater than 80% of the malignant cells by flow cytometry
• No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment.
• No chemotherapy, immunotherapy, or radiation therapy less than or equal to 2 weeks prior to apheresis.

Design

• Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis, CD3+ cells enriched and cultured in the presence of anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22 (M971BBz) CAR.
• On Day -5 (cell infusion is Day 0), participants will begin lymphodepleting chemotherapy comprising fludarabine 30 mg/m2 on Days -5, -4, -3, and -2, and cyclophosphamide 500 mg/m2 on days -3 and -2.
• The CD22-CAR T-cells will be infused on Day 0, with up to a 7 day delay if cells are cryopreserved, if needed for resolution of clinical toxicities, to generate adequate cell numbers, or to facilitate scheduling.
• A Phase I cell dose escalation scheme will be performed primarily using 4 dose levels (1 x 10^5; 3 x 10^5, 1 x 10^6, and 3 x 10^6 transduced T-cells/kg.
• After 2 participants are enrolled at dose level 1 without dose limiting toxicity (DLT) or response, subsequent participants will each be enrolled at increasing dose levels until either DLT or complete response (CR) is observed, after which that dose level will be expanded. Once the maximum tolerated dose (or highest level evaluated) is reached, with 0-1 out of 6 having DLT, an additional 4 participants will be enrolled to provide further assessment of DLTs and for determining a preliminary assessment of the efficacy of the therapy in this participant population.
• Participants will be monitored for toxicity, response and T-cell persistence as well as other biologic correlates.
• Participants who achieve inadequate engraftment of transduced T-cells may receive a 2nd dose of CAR T-cells at a same or higher dose level, with the same or lower dose of lymphodepleting chemotherapy, with results not to affect the primary endpoint of the study.
• Accrual ceiling will be set at 27 to allow for a few inevaluable participants and screen failures.

• INCLUSION CRITERIA
• Histologically confirmed diagnosis of HCL or HCLv according to morphological and immunophenotypic criteria of WHO classification [WHO, 2008 revised 2016] of lymphoid neoplasm.
• Participants should have any of the following indications for therapy:

• ANC <1/nL,
• Hemoglobin <10g/dL,
• Platelets<100/nL,
• Symptomatic splenomegaly,
• HCL mass with short axis > 2 cm outside or >0.5 cm inside the CNS,
• HCL/HCLv count >5/nL in blood or >25/mm^3 in CSF,
• HCL/HCLv count doubling time <6 months and increasing lytic or blastic bone lesions

Participants who have eligible blood counts within 4 weeks from the initiation of study will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.

• HCL/HCLv, after prior treatment with, ineligible for, refusal of, or inability to obtain 1)rituximab given concurrently with or sequentially after purine analog, 2) moxetumomab pasudotox-tdft, and 3) BRAF-inhibition.
• CD22 expression must be detected on greater than 80% of malignant cells by flow cytometry.
• Participants must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease (MRD) detected by flow cytometry or immunohistochemistry.
• Age >=18 years
• ECOG performance <=2 (Karnofsky >=60%, see Appendix A), participants are exempt from this criterion if poor performance status is related to HCL.
• Participants must have adequate organ function as defined below: Participants must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. If participants exhibit minor lab abnormalities that are determined to be related to HCL (not therapy-related), then those participants will be allowed to participate

• Total bilirubin <= 3 ULN, unless consistent with Gilbert s (ratio between total and direct bilirubin > 5)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x upper limit of normal (ULN)
• Alkaline phosphatase < 2.5 ULN
• Serum creatinine <= 1.5 mg/dL or creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal calculated using eGFR or measured
• Serum albumin > 2 g/dL
• Prothrombin time (PT)/International Normalized Ratio (INR) < 2.5x ULN (if on warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, PT < 2.5x ULN
• Fibrinogen >= 0.5x lower limit of normal
• Participants with CNS disease are eligible, with exceptions
• Participants with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active graft-versus-host disease (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to initiation of study intervention.
• Women of childbearing potential (WOCBP) must agree to use effective contraception (barrier, hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy or 4 months after cells infusion, whichever is later.

Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drug.

• Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 4 months after the last dose of study drug.
• Ability of participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Pregnancy
• Systemic chemotherapy, immunotherapy, or radiation therapy <= 2 weeks prior to apheresis with the following exception:

• Participants receiving steroids may be enrolled, provided there has been no increase in dose for at least 1 week prior to starting apheresis;
• For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment (including CNS radiation), with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the participant has measurable/evaluable disease outside the radiation port.
• Other anti-neoplastic investigational agents, or antibody-based therapies currently or within 2 weeks prior to apheresis
• Participants taking warfarin
• Prior CAR therapy within 30 days prior to apheresis or prior CAR therapy at any time with evidence for persistence of CAR T cells in blood samples (circulating levels of genetically modified cells of >= 5% by flow cytometry)
• Seropositive for human immunodeficiency virus (HIV) antibody. (Participants with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy in the future should study results indicate effectiveness.)
• Seropositive for hepatitis C virus (HCV) or positive for hepatitis B surface antigen (HbsAG). Participants who convert to negative will not be excluded for history of positive test.
• Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, asthma, chronic obstructive pulmonary disease, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject
• History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e., gentamicin)