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A Study of KZR-616 in Patients With SLE With and Without Lupus Nephritis (MISSION)

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ClinicalTrials.gov Identifier: NCT03393013
Recruitment Status : Recruiting
First Posted : January 8, 2018
Last Update Posted : April 29, 2021
Sponsor:
Information provided by (Responsible Party):
Kezar Life Sciences, Inc.

Tracking Information
First Submitted Date  ICMJE December 21, 2017
First Posted Date  ICMJE January 8, 2018
Last Update Posted Date April 29, 2021
Actual Study Start Date  ICMJE March 7, 2018
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
  • Phase 1b: To evaluate the safety and tolerability of KZR-616 [ Time Frame: Baseline through 25 weeks ]
    To evaluate the safety and tolerability of KZR-616 when administered as a SC injection weekly for 13 weeks in adult patients with SLE with and without lupus nephritis
  • Phase 2: To assess the number of patients with lupus nephritis with a 50% reduction in UPCR [ Time Frame: 24 weeks ]
    To assess the number of patients with lupus nephritis with a 50% reduction in UPCR after 24 weeks of weekly SC injections with KZR-616 when compared to baseline
Original Primary Outcome Measures  ICMJE
 (submitted: January 4, 2018)
Phase 1 and Phase 2: Safety and Tolerability assessed by monitoring incidence and severity of adverse events [ Time Frame: Baseline through 25 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
  • Phase 1b: Identify Recommended Phase 2 dose levels (RP2Ds) of KZR-616 [ Time Frame: 4 weeks ]
    Determined through assessment of all AEs and any dose limiting toxicities (DLTs)
  • Phase 1b: To characterize the PK of KZR-616 [ Time Frame: Day 1 ]
    To characterize the pharmacokinetics of KZR-616
  • Phase 2: To evaluate the safety and tolerability of KZR-616 when administered as a SC injection weekly for 24 weeks [ Time Frame: 37 weeks ]
    Determined through assessment of all AEs
  • Phase 2: To characterize the efficacy of KZR-616 on parameters of renal function when administered as a SC injection weekly for 24 weeks [ Time Frame: 24 weeks ]
    Determined through assessment of UPCR after 24 weeks when compared to baseline
Original Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2018)
  • Phase 1: Identify Recommended Phase 2 dose levels (RP2Ds) of KZR-616 [ Time Frame: 4 weeks ]
    Determined through assessment of all AEs and any dose limiting toxicities (DLTs)
  • Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 1 ]
  • Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 29 ]
  • Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 1 ]
  • Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 29 ]
  • Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 1 ]
  • Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 29 ]
  • Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 1 ]
  • Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 29 ]
  • Phase 2: The number of patients with a 50% reduction in urine protein to creatinine ratio (UPCR) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: The number of patients with a complete renal response [ Time Frame: Every 4 weeks through 25 weeks ]
    UPCR of ≤ 0.5; estimated Glomerular Filtration Rate (eGFR) of ≥ 60 mL/min or no worsening of eGFR from baseline of > 20%; No discontinuation of investigational product or use of restricted medication beyond the protocol-allowed thresholds from Days 1 to 85
  • Phase 2: Change from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: Change from baseline in British Isles Lupus Assessment Group (BILAG) score [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: Change from baseline in Levels of Autoantibodies (ANA and anti-dsDNA) and Complement (C3 and C4) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: Change from baseline in UPCR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: Change from baseline in eGFR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  • Phase 2: Change from baseline in daily glucocorticoid use [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: January 4, 2018)
  • Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 1 ]
  • Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 29 ]
  • Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 1 ]
  • Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 29 ]
 
Descriptive Information
Brief Title  ICMJE A Study of KZR-616 in Patients With SLE With and Without Lupus Nephritis
Official Title  ICMJE A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis
Brief Summary This is a Phase 1b/2, multi-center study in which patients will receive KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks (Phase 1b) or 24 weeks (Phase 2).
Detailed Description

The study consists of 2 parts:

Part 1, Phase 1b, is an open-label multiple dose escalation study to evaluate the safety and tolerability of KZR-616 in patients with systemic lupus erythematosus (SLE) with and without lupus nephritis. The Phase 1b part of this study is fully enrolled and active as of September 2020.

Part 2, Phase 2, is an open-label study to evaluate the efficacy and safety of KZR-616 in patients with active proliferative lupus nephritis (LN) to assess the number of patients with a 50% reduction in UPCR after 24 weeks of weekly SC injections with KZR-616 when compared to baseline.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lupus Nephritis
  • Systemic Lupus Erythematosus
Intervention  ICMJE Drug: KZR-616
Subcutaneous Injection of KZR-616
Other Name: KZR-616 Lyophile
Study Arms  ICMJE
  • Experimental: KZR-616 60 mg + standard therapy (Phase 2)
    60 mg dose level of KZR-616 selected based on data from the Phase 1 dose escalation and administered to patients with active Lupus Nephritis in combination with standard therapy.
    Intervention: Drug: KZR-616
  • Experimental: KZR-616 45 mg + standard of care therapy (Phase 1b)
    Dose escalation cohort of patients with SLE with and without nephritis to receive 45 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and active.
    Intervention: Drug: KZR-616
  • Experimental: KZR-616 60 mg + standard of care therapy (Phase 1b)
    Dose escalation cohort of patients with SLE with and without nephritis to receive 60 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and active.
    Intervention: Drug: KZR-616
  • Experimental: KZR-616 75 mg + standard of care therapy (Phase 1b)
    Dose escalation cohort of patients with SLE with and without nephritis to receive 75 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and active.
    Intervention: Drug: KZR-616
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 12, 2020)
68
Original Estimated Enrollment  ICMJE
 (submitted: January 4, 2018)
72
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

PHASE 1b (fully enrolled):

  • Male or female patients aged 18 to 75 (inclusive)
  • Body Mass Index (BMI) of 18-40 kg/m2
  • Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
  • Have at least one of the following at screening per central lab:

    1. Positive antinuclear antibody (ANA) test (1:80 or higher); or
    2. Anti-double stranded deoxyribonucleic acid (dsDNA) antibodies elevated to above normal (i.e. positive results); or
    3. Anti-Smith antibody elevated to above normal (i.e., positive results)
  • Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score ≥4 at screening
  • Must have received 1 or more of the following therapies for SLE, each administered at or higher than the minimum dose indicated for at least 12 weeks (unless discontinued or dose adjusted for documented drug-related toxicity or size/weight):

    1. Hydroxychloroquine 200 mg orally daily in combination with prednisone 10 mg daily or equivalent
    2. MMF orally 1 g/day or MPA orally 720 mg/day
    3. Methotrexate orally or SC 15 mg/wk., or leflunomide orally 10 mg/day
    4. Azathioprine (AZA) 100 mg/day or 6-mercaptopurine 50 mg/day (50 or 25 mg/day, respectively, permitted in cases of documented thiopurine methyltransferase [TPMT] polymorphism) orally
    5. Cyclosporine or tacrolimus at doses documented to maintain at least 100 or 5 ng/mL during the required duration, respectively
    6. Cyclophosphamide 500 mg intravenously (IV) every 2 weeks or 500 mg/m2 IV once monthly
    7. Belimumab 10 mg/kg IV every 2 weeks for 3 doses, followed by 10 mg/kg every 4 weeks; or 200 mg SC weekly
    8. Rituximab 1 g IV (may be given as 500 mg twice)
  • Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria
    2. Adequate hepatic function
    3. eGFR ≥40 mL/min/1.73 m2
    4. IgG ≥500 mg/dL
  • Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test prior to the first dose
  • Male patients must use an effective contraception method (e.g. condom with spermicide) from signing the ICF until their completion of the study

PHASE 2 (enrolling):

  • Male or female patients aged 18 to 75 years (inclusive)
  • BMI of ≥18kg/m2
  • Fulfills the 2012 SLICC classification criteria for SLE
  • At least one of the following at Screening per central lab:

    1. Positive ANA test; or
    2. Anti-dsDNA antibodies elevated to above normal; or
    3. Anti-Smith antibody at Screening elevated to above normal
  • Active lupus nephritis with UPCR ≥1.0 measured in 24-hour urine collection
  • Currently receiving one or more immunosuppressive agents
  • Renal biopsy with a histologic diagnosis of LN (ISN/RPS) Classes III, IV-S or IV-G, (A) or (A/C) +/- Class V
  • Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria
    2. Adequate hepatic function
    3. eGFR ≥30mL/min/1.73 m2
    4. IgG ≥500 mg/dL
  • Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline
  • Male patients with a partner of childbearing potential must be either congenitally sterile or surgically sterile (by vasectomy) or willing to use a condom in addition to having their female partner use another form of contraception

Key Exclusion Criteria:

PHASE 1b (fully enrolled):

  • Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment.
  • Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study.
  • History of antiphospholipid syndrome with thromboembolic event within 12 months of screening or not on an adequate anticoagulation regimen. However, presence of antiphospholipid antibodies alone (without a history of thromboembolic event) is not exclusionary.
  • Receipt of any of the following treatments within the following timeframes before Screening

    1. Systemic corticosteroids ≥ 100 mg prednisone or equivalent: 4 weeks
    2. Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
    3. Intravenous Immunoglobulin (IVIg): 4 weeks
    4. Other non-biologic immunosuppressive agents, such as cyclosporine, tacrolimus: 4 weeks
    5. Cyclophosphamide: 12 weeks
    6. Cytokine antagonists, including but not limited to interleukin (IL)-1, IL-6, IL-17, IL-12/23, IL-23, interferon (IFN), integrin, and tumor necrosis factor (TNF)-α antagonists: 12 weeks
    7. B-cell-depleting therapies (e.g., rituximab): 24 weeks with levels of circulating cluster of differentiation 19+ (CD19+) B cells within normal limits or 48 weeks if CD19+ count is not available
    8. Belimumab, abatacept, or atacicept: 12 weeks
    9. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
    10. Transfusion with blood, packed red blood cells, platelets or treatment with plasmapheresis or plasma exchange: 6 weeks
  • Patient has had recent serious or ongoing infection, or risk for serious infection

    1. Acute or chronic infections:

      • Requiring systemic antibiotic, antifungal, or antiviral (antimicrobial) therapy within 14 days of Week 1, Day 1
      • Requiring hospitalization or a course of IV antimicrobial therapy within 24 weeks prior to screening
    2. History of severe and/or disseminated viral infections, and/or opportunistic infections
    3. Known seropositivity for or active infection by human immunodeficiency virus (HIV)
    4. Active, chronic, or resolved hepatitis B or hepatitis C infection
    5. History of progressive multifocal leukoencephalopathy
    6. Active or latent tuberculosis (TB), as suggested by chest x-ray within the 12 weeks prior to screening and/or QuantiFERON®-TB Gold at Screening
    7. Receipt of a live-attenuated vaccine within 12 weeks of first day of study treatment (Week 1, Day 1)
    8. Primary immunodeficiency (unless otherwise considered, in the opinion of the investigator and medical monitor, to confer a clinically insignificant infection risk, such as deficiency in immunoglobulin A (IgA), C1q, C2, or C4 without a history of recurrent infections [3 or more infections in 1 year requiring antimicrobial therapy])
  • History of any concurrent illness that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF
  • Clinical evidence of significant unstable or uncontrolled acute or chronic diseases
  • History of cancer, except for in situ cancer that has been completely excised or has been curatively treated cancer with no sign of disease for > 5 years
  • Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period

PHASE 2 (enrolling):

  • Any of the following: dialysis within 12 months prior to screening, rapidly progressive glomerulonephritis (RPGN), chronic kidney disease not due to lupus nephritis, >50% sclerosed glomeruli on most recent renal biopsy
  • Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study. Secondary sicca or Sjogren's syndrome and antiphospholipid antibody syndrome are allowed
  • History of antiphospholipid syndrome with history of thromboembolic event within 12 months of screening
  • Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment.
  • Active or chronic infection
  • Patient has or had any of the following:

    1. Progressive multifocal leukoencephalopathy
    2. Active or untreated latent TB, per QuantiFERON-TB Gold at Screening
    3. Receipt of a live-attenuated vaccine within 12 weeks of Baseline (Week 1, Day 1)
    4. Primary immunodeficiency (unless otherwise considered, in the opinion of the investigator and medical monitor, to confer a clinically insignificant infection risk, such as deficiency in IgA, C1q, C2, or C4 without a history of recurrent infections [3 or more infections in 1 year requiring antimicrobial therapy])
    5. Primary hematopoietic cell or solid organ transplant
  • Any active or suspected malignancy or history of documented malignancy within the last 5 years before Screening
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kezar Life Sciences, Inc. (650)822-5600 clinicaltrials@kezarbio.com
Listed Location Countries  ICMJE Australia,   Colombia,   Mexico,   Poland,   Russian Federation,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03393013
Other Study ID Numbers  ICMJE KZR-616-002
Has Data Monitoring Committee Not Provided
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  ICMJE
Plan to Share IPD: No
Responsible Party Kezar Life Sciences, Inc.
Study Sponsor  ICMJE Kezar Life Sciences, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Kezar Kezar Life Sciences, Inc.
PRS Account Kezar Life Sciences, Inc.
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP