Clinical Trials /

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

NCT04815356

Description:

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). 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 subjects 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) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL, 5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass > 2cm in short axis, 8) increasing lytic or blastic bone lesions. > 18 years of age. CD22 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 80% by flow cytometry No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment. No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to apheresis. Design 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 -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising fludarabine 25 mg/m2 on Days 4, 3 and 2 and cyclophosphamide 900 mg/m2 on day 2. The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of fresh cells or 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 2 dose levels (1 x 105 transduced T-cells/kg; 3 x 105 transduced T-cells/kg). If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated dose of 3 x 104 transduced T-cells/kg (plus minus 20%). 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. Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen failures.

Related Conditions:
  • Hairy Cell Leukemia
  • Hairy Cell Leukemia Variant
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 210019
  • SECONDARY ID: 21-C-0019
  • NCT ID: NCT04815356

Conditions

  • Hairy Cell Leukemia
  • Hairy Cell Leukemia Variant

Interventions

DrugSynonymsArms
CD22CART cell infusionExperimental therapy: Dose Escalation

Purpose

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). 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 subjects 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) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL, 5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass > 2cm in short axis, 8) increasing lytic or blastic bone lesions. > 18 years of age. CD22 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 80% by flow cytometry No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment. No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to apheresis. Design 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 -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising fludarabine 25 mg/m2 on Days 4, 3 and 2 and cyclophosphamide 900 mg/m2 on day 2. The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of fresh cells or 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 2 dose levels (1 x 105 transduced T-cells/kg; 3 x 105 transduced T-cells/kg). If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated dose of 3 x 104 transduced T-cells/kg (plus minus 20%). 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. Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen failures.

Detailed Description

      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).

      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 subjects 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) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) HCL count >5/nL,
      5) HCLv count doubling time <3 months, 6) symptomatic splenomegaly, 7) enlarging HCL mass >
      2cm in short axis, 8) increasing lytic or blastic bone lesions.

      >= 18 years of age.

      CD22 expression must be detected on greater than 15% of the malignant cells by
      immunohistochemistry or greater than 80% by flow cytometry

      No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring
      treatment.

      No chemotherapy, immunotherapy, or radiation therapy less than or equal to 3 weeks prior to
      apheresis.

      Design

      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 -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising
      fludarabine 25 mg/m2 on Days -4, -3 and -2 and cyclophosphamide 900 mg/m^2 on day -2.

      The CD22-CAR T-cells will be infused on Day 0, with up to a 72h delay allowed for infusion of
      fresh cells or 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 2 dose levels (1 x
      10^5 transduced T-cells/kg; 3 x 10^5 transduced T-cells/kg).

      If 2 of 2-6 participants at dose level 1 have DLT, safety will be evaluated in a de-escalated
      dose of 3 x 10^4 transduced T-cells/kg (plus minus 20%). 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.

      Accrual ceiling will be set at 23 to allow for a few unevaluable participants and screen
      failures.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental therapy: Dose EscalationExperimentalEscalating doses of autologous anti-CD22-CAR T-cells in subjects to determine the MTD
  • CD22CART cell infusion
Experimental therapy: Dose ExpansionExperimentalAutologous anti-CD22-CAR T-cells at the MTD
  • CD22CART cell infusion

Eligibility Criteria

        -  INCLUSION CRITERIA:

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

                    -  Absolute neutrophil count (ANC) <1/nL,

                    -  Hemoglobin <10g/dL,

                    -  Platelets<100/nL,

                    -  Symptomatic splenomegaly,

                    -  Enlarging HCL mass or bone lesion > 2cm in short axis,

                    -  HCL count >5/nL,

                    -  HCLv count doubling time <3 months,

                    -  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

               2. 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.

               3. CD22 expression must be detected on greater than 80% of malignant cells by flow
                  cytometry.

               4. Patients must have measurable or evaluable disease at the time of enrollment,
                  which may include any evidence of disease including minimal residual disease
                  detected by flow cytometry or immunohistochemistry

               5. Age >18 years

               6. ECOG performance <2 (Karnofsky >60%), participants are exempt from this criteria
                  if poor performance status is related to HCL

               7. Participants must have adequate organ function as defined below: Subjects 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 less than or equal to 3 ULN, unless consistent with Gilbert
                       s (ratio between total and direct bilirubin > 5)

                    -  AST and ALT less than or equal to 3x upper limit of normal (ULN)

                    -  Alkaline phosphatase < 2.5 ULN

                    -  Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance
                       greater than or equal to 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 < 2.5x ULN (If on
                       warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, Prothrombin
                       time (PT) < 2.5x ULN

                    -  Fibrinogen greater than or equal to 0.5x lower limit of normal

               8. Subjects with CNS disease are eligible, with exceptions

               9. Participants with history of allogeneic stem cell transplantation are eligible if
                  at least 100 days post-transplant, if there is no evidence of active GVHD and no
                  longer taking immunosuppressive agents for at least 30 days prior to enrollment

              10. Participants of child-bearing or child-fathering potential must use effective
                  contraception from the time of enrollment on this study and for four months after
                  receiving the preparative regimen as agents used in this study are teratogenic.

              11. Ability of subject to understand and the willingness to sign a written informed
                  consent document.

        EXCLUSION CRITERIA:

          1. Pregnant or breast-feeding females

          2. Systemic chemotherapy, immunotherapy, or radiation therapy less than or equal to 3
             weeks prior to apheresis; with the following exception:

               -  Subjects 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 subject has measurable/evaluable disease outside the radiation
                  port.

          3. Other anti-neoplastic investigational agents, or antibody based therapies currently or
             within 2 weeks prior to apheresis

          4. Subjects taking warfarin

          5. 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 greater than or equal to 5% by flow cytometry)

          6. HIV/HBV/HCV Infection:

               -  Seropositive for HIV antibody. (Patients 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 or positive for Hepatitis B surface antigen (HbsAG).
                  Participants who convert to negative will not be excluded for history of positive
                  test.

          7. 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

          8. Second malignancy other than in situ carcinoma of the cervix, unless the tumor was
             treated with curative intent at least two years previously and subject is in remission

          9. 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety and feasibility
Time Frame:end of treatment
Safety Issue:
Description:Fraction of participants at each dose level who experience a toxicity along with the grades and types of toxicity and which can successfully manufacture the targeted dose number

Secondary Outcome Measures

Measure:expansion and persistence
Time Frame:every year for 5 years
Safety Issue:
Description:Measure expansion and persistence of adoptively-transferred anti-CD22-CAR-transduced T-cells in the blood and, where possible, the bone marrow
Measure:MRD negative CR
Time Frame:every year for 15 years
Safety Issue:
Description:Fraction of HCL patients who achieve MRD negative CR following treatment with anti-CD22-CAR engineered T-cells
Measure:duration of response
Time Frame:every year for 15 years
Safety Issue:
Description:The time between the initial response to therapy and subsequent disease progression or relapse
Measure:progression free-survival
Time Frame:every year for 15 years
Safety Issue:
Description:Duration of time from the start of treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first
Measure:event free survival
Time Frame:every year for 15 years
Safety Issue:
Description:Duration of time from the start of treatment until time of disease relapse, disease progression, alternative therapy given (such as radiation), or death, whichever occurs first.
Measure:overall survival
Time Frame:every year for for 15 years or until death
Safety Issue:
Description:Overall survival (OS) will be determined as the time from the start of the CD22CART infusion until death
Measure:time to next treatment
Time Frame:every year for 15 years
Safety Issue:
Description:Duration of time from the start of administration of anti-CD22-CAR engineered T-cells to next line of treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • CD-22 Expressing Tumor
  • Chimeric Antigen Receptor
  • Adoptive Immunotherapy

Last Updated

August 27, 2021