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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03393013
Recruitment Status : Recruiting
First Posted : January 8, 2018
Last Update Posted : January 21, 2020
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 January 21, 2020
Actual Study Start Date  ICMJE March 7, 2018
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 16, 2020)
Phase 1 and Phase 2: Safety and Tolerability assessed by monitoring incidence and severity of adverse events (AEs) [ Time Frame: Baseline through 37 weeks ]
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: January 16, 2020)
  • 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 partial renal response [ Time Frame: Every 4 weeks through 25 weeks ]
    UPCR reduction; estimated Glomerular Filtration Rate (eGFR) of ≥ 60 mL/min or no worsening of eGFR from baseline of > 20%; No use of prohibited medication
  • Phase 2: The number of patients with a complete renal response [ Time Frame: Every 4 weeks through 25 weeks ]
    UPCR reduction; estimated Glomerular Filtration Rate (eGFR) of ≥ 60 mL/min or no worsening of eGFR from baseline of > 20%; No use of prohibited medication
  • 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 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 corticosteroid use [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
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
 (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 ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without 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).

The study consists of 2 parts. Part 1, the 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 nephritis. Part 2, the Phase 2, is a randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of KZR-616 in patients with active proliferative lupus nephritis (LN).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Systemic Lupus Erythematosus
  • Lupus Nephritis
Intervention  ICMJE
  • Drug: KZR-616
    Subcutaneous Injection of KZR-616
  • Drug: Placebo
    Subcutaneous injection of matching placebo
Study Arms  ICMJE
  • Experimental: KZR-616 30 mg + standard therapy
    1 of 3 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with standard therapy
    Intervention: Drug: KZR-616
  • Experimental: KZR-616 45 mg + standard therapy
    1 of 3 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with standard therapy
    Intervention: Drug: KZR-616
  • Experimental: KZR-616 60 mg + standard therapy
    1 of 3 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with standard therapy
    Intervention: Drug: KZR-616
  • Placebo Comparator: Placebo + standard therapy
    Placebo administered in combination with standard therapy
    Intervention: Drug: Placebo
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: January 16, 2020)
124
Original Estimated Enrollment  ICMJE
 (submitted: January 4, 2018)
72
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

PHASE 1b:

  1. Male or female patients aged 18 to 75 (inclusive)
  2. Body Mass Index (BMI) of 18-40 kg/m2
  3. Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
  4. 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)
  5. Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score ≥ 4 at screening
  6. Must have received 1 or more therapies for SLE
  7. 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
  8. If taking the following SLE therapies:

    1. Oral glucocorticoids (up to 20 mg/day prednisone or equivalent): must be on a stable dosage regimen of oral corticosteroid at least 4 weeks prior to screening and maintain stable dose until randomization
    2. Hydroxychloroquine (≤ 400 mg/day) or chloroquine (≤ 500 mg/day) orally or other anti-malarials: must be started or stopped at least 12 weeks prior to screening, with stable dosage regimen for at least 4 weeks prior to screening
    3. Immunosuppressive agents: must be started or stopped at least 12 weeks prior to screening, with stable dosage regimen, including route of administration, for at least 4 weeks prior to screening:

      • Mycophenolate mofetil (≤ 3 g/day) or mycophenolic acid (≤ 2.16 g/day) orally
      • Azathioprine (≤ 200 mg/day) orally
      • Methotrexate (≤ 25 mg/week) orally, SC, or intramuscularly (patients must be on concomitant folic or folinic acid supplementation if using methotrexate)
      • Leflunomide (≤ 20 mg/day) orally
  9. 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 and must agree to use a highly effective method of birth control from signing the informed consent form (ICF) until their completion of the study (or 30 days following the last dose of study drug in case of early withdrawal).
  10. Male patients must use an effective contraception method (e.g., condom with spermicide) from signing the ICF until their completion of the study (or 12 weeks following the last dose of study drug in case of withdrawal) or be congenitally or surgically sterile (e.g., vasectomy with documented confirmation of post-surgical aspermia)
  11. Willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements

PHASE 2:

  1. Male or female patients aged 18 to 75 years (inclusive)
  2. BMI of 18-40 kg/m2
  3. Fulfills the 2012 SLICC classification criteria for SLE.
  4. Undergoing an ACR-recommended MMF- or MPA-based or Eurolupus CYC-based induction therapy regimen for LN up to 12 weeks prior to randomization, and willing to continue at least the MMF/MPA/CYC portion of the regimen unaltered throughout the duration of the study.
  5. The patient has at least one of the following at screening per central lab:

    1. Positive ANA test (1:80 or higher) or
    2. Anti-dsDNA antibodies elevated to above normal (i.e., positive results); or
    3. Anti-Smith antibody at screening elevated to above normal (i.e., positive results)
  6. Kidney biopsy within 52 weeks prior to screening with a histologic diagnosis of LN (International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis [ISN/RPS]) Classes III, IV-S or IV-G, (A) or (A/C); Patients with Class III or IV and concomitant Class V will be permitted
  7. UPCR of ≥ 1.0 in 24-hour urine collection
  8. Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria:
    2. Adequate hepatic function:
    3. eGFR ≥ 40 mL/min/1.73 m2 estimated based on CKD-EPI formula
    4. IgG ≥ 500 mg/dL
  9. Women of childbearing potential must have a negative serum beta-hCG pregnancy test at screening and negative urine pregnancy test prior to the first dose and must agree to use a highly effective method of birth control from signing the ICF until their completion of the study (or 30 days following the last dose of study drug in case of early withdrawal).
  10. Male patients must use an effective contraception method (e.g., condom with spermicide) from signing the ICF until completion of the study (or 12 weeks following the last dose of study drug in case of early withdrawal) or be congenitally or surgically sterile (e.g., vasectomy with documented confirmation of post-surgical aspermia)
  11. Willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements

Exclusion Criteria:

PHASE 1b:

  1. Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Headache treated only with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or approved doses of triptans is permitted with medical monitor approval.
  2. Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study. Secondary sicca or Sjogren's syndrome, antiphospholipid antibody syndrome, and overlap with rheumatoid arthritis without erosive joint disease ("rhupus") are allowed
  3. 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.
  4. 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: 12 weeks
    7. B-cell-depleting therapies (e.g., rituximab): 24 weeks
    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
  5. Patient has had recent serious or ongoing infection, or risk for serious infection
  6. 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
  7. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases that, in the opinion of the investigator or sponsor, could confound the results of the study, put the patient at undue risk, or interfere with protocol adherence
  8. 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
  9. Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period

PHASE 2:

  1. Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Headache treated only with acetaminophen, NSAIDs, or approved doses of triptans is permitted with medical monitor approval.
  2. Isolated Class V membranous LN on a renal biopsy obtained within 52 weeks prior to signing ICF or during the screening period
  3. Known intolerance to MMF (or MPA) and CYC
  4. History of dialysis within 12 months prior to signing the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 6-month period after enrollment
  5. History of Rapidly Progressive Glomerulonephritis (RPGN) and/or other renal disease
  6. History of chronic kidney disease not directly due to LN
  7. Uncontrolled blood pressure (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg at rest)

    o If currently on RAS blockade, dose must be stable for at least 4 weeks prior to screening

  8. Receipt of any of the following treatments within the following timeframes before first dose of study treatment:

    1. IVIg: 4 weeks
    2. Corticosteroids ≥ 1 g/day prednisone or equivalent: 4 weeks
    3. Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
    4. Conventional disease-modifying antirheumatic drugs, including methotrexate, leflunomide, sulfasalazine, cyclosporine, tacrolimus: 12 weeks
    5. MMF of ≥ 3 g (or 2.16 g of MPA): 4 weeks
    6. Cytokine antagonists: 12 weeks
    7. B-cell-depleting therapies (e.g., rituximab): 24 weeks
    8. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
    9. Hydroxychloroquine (>400 mg/day) or chloroquine (>500 mg/day) or other antimalarials above the recommended dose.
    10. Abatacept: 12 weeks
    11. NIH (high-dose) CYC or oral CYC: 12 weeks
  9. Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period
  10. History of any other concurrent illness, including drug induced SLE, 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
  11. Patient has had recent serious or ongoing infection, or risk for serious infection
  12. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases in the opinion of the investigator
  13. Any active or suspected malignancy or history of documented malignancy within the last 5 years before Screening, except appropriately excised and cured cervical carcinoma in situ or basal or squamous cell carcinoma of the skin; patients with a history of basal or squamous cell carcinomas of the skin must have had 3 or fewer in their lifetime to be eligible
  14. Presence of another rheumatic (overlap) disease that nay confound clinical assessment in the study.
  15. History of antiphospholipid syndrome with history of thromboembolic event within 12 months of screening or not an adequate anticoagulation regimen. However history of antiphospholipid antibodies alone (without history of thromboembolic event) is not exclusionary.
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: Clinical Operations 650 822-5600 clinicaltrials@kezarbio.com
Listed Location Countries  ICMJE Australia,   Colombia,   Mexico,   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: Undecided
Responsible Party Kezar Life Sciences, Inc.
Study Sponsor  ICMJE Kezar Life Sciences, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Kezar Kezar
PRS Account Kezar Life Sciences, Inc.
Verification Date January 2020

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