Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

• ClinicalTrials.gov Identifier: NCT03331198
• Recruitment Status: Active, not recruiting
• First Posted: November 6, 2017
• Last Update Posted: September 26, 2022
• Sponsor: Juno Therapeutics, a Subsidiary of Celgene
• Information provided by (Responsible Party): Juno Therapeutics, a Subsidiary of Celgene

Tracking Information

• First Submitted Date: October 29, 2017
• First Posted Date: November 6, 2017
• Last Update Posted Date: September 26, 2022
• Actual Study Start Date: November 27, 2017
• Estimated Primary Completion Date: September 15, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2021)

• Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
  Proportion of subjects experiencing adverse events
• Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
  Proportion of subjects who have CR after treatment with JCAR017 + ibrutinib using iwCLL 2018 guidelines
• Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm [ Time Frame: Through post treatment Day 90 ]
  Recommended dose of venetoclax in combination with JCAR017 based on assessment of data from each dose level of venetoclax
• Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: adverse events [ Time Frame: Through post treatment Day 90 ]
  Proportion of subjects experiencing adverse events
• Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: laboratory abnormalities [ Time Frame: Through post treatment Day 90 ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm [ Time Frame: Through post treatment up to Month 48 ]
  Proportion of subjects who have CR after treatment with JCAR017 + venetoclax using iwCLL 2018 guidelines

Original Primary Outcome Measures (submitted: November 2, 2017)

• Phase 1 monotherapy arm: recommended dose [ Time Frame: 28 days ]
  Recommended dose based on assessment of data from each dose level
• Phase 1 combination therapy arm: adverse events [ Time Frame: 30 days ]
  Proportion of subjects experiencing adverse events
• Phase 1 combination therapy arm: laboratory abnormalities [ Time Frame: 30 days ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 2: antitumor activity [ Time Frame: through post-randomization Month 24 ]
  Complete response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines

Current Secondary Outcome Measures (submitted: May 4, 2021)

• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: ORR [ Time Frame: Up to 48 months post treatment ]
  Defined as the rate of CR (including CRi)
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects experiencing adverse events
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: laboratory abnormalities [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects who achieve MRD CR
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects who achieve MRD CR
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from JCAR017 infusion to the date of death due to any cause
• Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the interval from JCAR017 infusion to the first documentation of CR
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: ORR [ Time Frame: Through post treatment Day 90 ]
  Defined as the rate of CR (including CRi)
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: adverse events [ Time Frame: Up to 48 months post treatment ]
  Proportion of subject experiencing adverse events
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: lab abnormalities [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: MRD-negative response rate in peripheral blood [ Time Frame: Up to 48 months post treatment ]
  Proportion of subjects who achieve MRD CR
• Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: MRD-negative CR rate in peripheral blood [ Time Frame: Through post treatment Day 90 ]
  Proportion of subjects who achieve MRD CR
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of response (DOR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of complete response (DoCR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to response (TTR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to complete response (TTCR) [ Time Frame: Up to 48 months post treatment ]
  Defined as the interval from JCAR017 infusion to the first documentation of CR
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: PFS [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause
• Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: OS [ Time Frame: Up to 48 months post treatment ]
  Defined as the time from JCAR017 infusion to the date of death due to any cause

Original Secondary Outcome Measures (submitted: November 2, 2017)

• Phase 2: adverse events [ Time Frame: 30 days ]
  Proportion of subjects experiencing adverse events
• Phase 2: laboratory abnormalities [ Time Frame: 30 days ]
  Proportion of subjects experiencing laboratory abnormalities
• Phase 2: overall response rate [ Time Frame: Through post-randomization Month 24 ]
  Overall response rate based on Independent Review Committee assessment using iwCLL 2008 guidelines
• Phase 2: minimal residual disease (MRD)-negative response rate [ Time Frame: Through post-randomization Month 24 ]
  MRD will be measured via IgHV deep sequencing and flow cytometry of peripheral blood and bone marrow
• Phase 2: overall survival [ Time Frame: Through post-randomization Month 24 ]
  Overall survival
• Phase 2: Progression-free survival [ Time Frame: Through post-randomization Month 24 ]
  Progression-free survival
• Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
  AUC of JCAR017 in blood and bone marrow
• Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
  Cmax of JCAR017 in blood and bone marrow
• Phase 2: PK [ Time Frame: Through post-randomization Month 24 ]
  Tmax of JCAR017 in blood and bone marrow
• Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
  EuroQol instrument EQ-5D-5L Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
• Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
  EORTC QLQ-C30 Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days
• Phase 2: health-related quality of life and health economics and outcomes research [ Time Frame: Through post-randomization Month 24 ]
  CLL-specific module QLQ-CLL Numbers of intensive care unit (ICU) inpatient days and non-ICU inpatient days

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
• Official Title: An Open-Label, Phase 1/2 Study of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (017004)
• Brief Summary: This is a Phase 1/2, open-label, multicenter study to determine the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory CLL or SLL. The study will include a Phase 1 part to determine the recommended dose of JCAR017 monotherapy in subjects with relapsed or refractory CLL or SLL, followed by a Phase 2 part to further assess the efficacy and safety of JCAR017 monotherapy treatment at the recommended dose. A separate Phase 1 cohort will assess the combination of JCAR017 and concurrent ibrutinib. Another separate Phase 1 cohort will assess the combination of JCAR017 and concurrent venetoclax. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase 1: subjects will be assigned to receive JCAR017, or JCAR017 + ibrutinib Phase 2: subjects will be assigned to receive JCAR017 at the recommended dose

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma, Small Lymphocytic

Intervention

• Biological: JCAR017 (lisocabtagene maraleucel)
  Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.
• Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
  Participants eligible for this cohort should be receiving ibrutinib at the time of screening. For participants who previously discontinued ibrutinib, ibrutinib will be started as soon as possible after eligibility is confirmed. Ibrutinib treatment will continue for up to 90 days after JCAR017 infusion (or longer for participants who are receiving benefit from ibrutinib). Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging chemotherapy for disease control. Upon successful generation of JCAR017 product, participants will receive treatment with JCAR017 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.
• Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax
  Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.

Study Arms

• Experimental: Phase 1 JCAR017 monotherapy
  Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel)
  Intervention: Biological: JCAR017 (lisocabtagene maraleucel)
• Experimental: Phase 1 JCAR017 + ibrutinib
  Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose + ibrutinib
  Intervention: Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
• Experimental: Phase 2 JCAR017 monotherapy
  Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm
  Intervention: Biological: JCAR017 (lisocabtagene maraleucel)
• Experimental: Phase 1 JCAR017 + venetoclax
  Subjects will receive venetoclax as bridging anticancer therapy until lymphodepletion chemotherapy/ JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm. After JCAR017 infusion subjects will receive venetoclax until Day 90.
  Interventions:

  • Biological: JCAR017 (lisocabtagene maraleucel)
  • Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax

Publications *

• Teoh J, Brown LF. Developing lisocabtagene maraleucel chimeric antigen receptor T-cell manufacturing for improved process, product quality and consistency across CD19(+) hematologic indications. Cytotherapy. 2022 Sep;24(9):962-973. doi: 10.1016/j.jcyt.2022.03.013. Epub 2022 May 21.
• Siddiqi T, Soumerai JD, Dorritie KA, Stephens DM, Riedell PA, Arnason J, Kipps TJ, Gillenwater HH, Gong L, Yang L, Ogasawara K, Thorpe J, Wierda WG. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022 Mar 24;139(12):1794-1806. doi: 10.1182/blood.2021011895.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 22, 2022): 188
• Original Estimated Enrollment (submitted: November 2, 2017): 205
• Estimated Study Completion Date: September 15, 2026
• Estimated Primary Completion Date: September 15, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of:

  1. CLL with an indication for treatment based on the Investigator's opinion and measurable disease, or
  2. SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease that is biopsy-proven SLL)
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have been deemed ineligible for BTKi therapy.

• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received previous treatment as follows:

  1. Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy.
  2. Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy.

• Subjects in the ibrutinib + JCAR017 combination therapy cohort must either:

  1. be receiving ibrutinib and progressing at the time of study enrollment
  2. be receiving ibrutinib for at least 6 months with a response less than complete response/remission (CR) and have high-risk features as defined in inclusion criterion 5a
  3. have BTK or PLCgamma2 mutations per local laboratory assessment, with or without progression on ibrutinib
  4. have previously received ibrutinib and have no contraindications to restarting ibrutinib
• Eastern Cooperative Oncology Group performance status of ≤ 1
• Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy

• Adequate organ function, defined as:

  1. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance > 30 mL/min
  2. Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or leukemic infiltration of the liver)
  3. Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air
  4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% as assessed by echocardiogram or multiple uptake gated acquisition scan performed within 30 days prior to determination of eligibility
• Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
• If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy.
• Subjects in ibrutinib + JCAR017 combination cohort must have progressed on a BTKi and have received prior therapy with venetoclax

• Subjects in venetoclax + JCAR017 combination cohort must:

  1. have failed at least 1 prior line of therapy, including failed BTKi therapy or have been deemed ineligible to receive BTKi
  2. be venetoclax naive (required for dose expansion) or
  3. if prior venetoclax (only for dose escalation)
  4. have no contraindictions to re-initiation of venetoclax based on prior intolerance and have had at least 6 months elapsed since the last dose of venetoclax, if either, best response was stable disease, or subject experienced disease progression on venetoclax, or within 6 months of venetoclax discontinuation
• subjects in the venetoclax + JCAR017 combination must have hemoglobin >=9 g/dL, absolute neutrophil count >=500mm3 and platelets>= 75,000/mm3, unless cytopenias are judged by investigator to be due to CLL infiltration of the bone marrow
• must have diagnosis of CLL or SLL with an indication for treatment based on the investigator's opinion and measurable disease (any of the following measurable lymph nodes ≥1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly) and demonstration of CLL cells in the peripheral blood by flow cytometry

Exclusion Criteria:

• Subjects with known active central nervous system (CNS) involvement by malignancy. Those with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging.
• History of another primary malignancy that has not been in remission for at least 2 years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.)
• Subjects with Richter's transformation
• Prior treatment with any gene therapy product
• Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV) infection
• Systemic fungal, bacterial, viral, or other infection that is not controlled
• Presence of acute or extensive chronic graft versus host disease (GVHD)
• History of any one of the following cardiovascular conditions within the past 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
• History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,cerebral edema, or psychosis
• Pregnant or nursing (lactating) women

• Use of any of the following medications or treatments within the noted time prior to leukapheresis:

  1. Alemtuzumab within 6 months prior to leukapheresis
  2. Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis
  3. Cladribine within 3 months prior to leukapheresis
  4. Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis
  5. Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis
  6. Fludarabine within 4 weeks prior to leukapheresis
  7. GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL 6R]) within 4 weeks prior to leukapheresis
  8. Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis
  9. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis
  10. Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis
  11. Venetoclax within 4 days prior to leukapheresis
  12. Idelalisib or duvelisib within 2 days prior to leukapheresis
  13. Lenalidomide within 1 day prior to leukapheresis
  14. Experimental agents, including off-label use of approved drugs (with the exception of acalabrutinib which may be continued up to the day before leukapheresis), within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis
• Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol
• Progressive vascular tumor invasion, thrombosis, or embolism
• Deep vein thrombosis or embolism not managed on a stable regimen of anticoagulation
• Use of any of the following medications or treatments within the noted time prior to leukapheresis lenalidomide or acalabrutinib within 1 day prior to leukapheresis experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis.
• Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation
• For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03331198
• Other Study ID Numbers: 017004; TRANSCEND-CLL-004 ( Other Identifier: Juno Therapeutics, Inc. )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Juno Therapeutics, a Subsidiary of Celgene
• Original Responsible Party: Juno Therapeutics, Inc.
• Current Study Sponsor: Juno Therapeutics, a Subsidiary of Celgene
• Original Study Sponsor: Juno Therapeutics, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Juno Therapeutics, a Subsidiary of Celgene
• Verification Date: September 2022