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

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ClinicalTrials.gov Identifier: NCT03393013
Recruitment Status : Recruiting
First Posted : January 8, 2018
Last Update Posted : August 7, 2018
Sponsor:
Information provided by (Responsible Party):
Kezar Life Sciences, Inc.

Brief Summary:

This is a Phase 1b/2, multi-center study in which patients will receive KZR-616, administered as a subcutaneous injection weekly for 13 weeks.

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).


Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematosus Lupus Nephritis Drug: KZR-616 Drug: Placebo Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis
Actual Study Start Date : March 7, 2018
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lupus

Arm Intervention/treatment
Experimental: KZR-616 Dose Level 1 + standard therapy
1 of 2 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with Mycophenolate Mofetil and prednisone
Drug: KZR-616
Subcutaneous Injection of KZR-616

Experimental: KZR-616 Dose Level 2 + standard therapy
1 of 2 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with Mycophenolate Mofetil and prednisone
Drug: KZR-616
Subcutaneous Injection of KZR-616

Placebo Comparator: Placebo + standard therapy
Placebo administered with Mycophenolate Mofetil and prednisone
Drug: Placebo
Subcutaneous injection of matching placebo




Primary Outcome Measures :
  1. Phase 1 and Phase 2: Safety and Tolerability assessed by monitoring incidence and severity of adverse events [ Time Frame: Baseline through 25 weeks ]

Secondary Outcome Measures :
  1. 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)

  2. Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 1 ]
  3. Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 29 ]
  4. Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 1 ]
  5. Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 29 ]
  6. Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 1 ]
  7. Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 29 ]
  8. Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 1 ]
  9. Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 29 ]
  10. 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 ]
  11. 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

  12. 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 ]
  13. Phase 2: Change from baseline in British Isles Lupus Assessment Group (BILAG) score [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  14. 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 ]
  15. Phase 2: Change from baseline in UPCR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  16. Phase 2: Change from baseline in eGFR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  17. Phase 2: Change from baseline in daily glucocorticoid use [ Time Frame: Baseline and every 4 weeks through 25 weeks ]

Other Outcome Measures:
  1. Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 1 ]
  2. Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 29 ]
  3. Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 1 ]
  4. Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 29 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

PHASE 1:

  1. Body Mass Index (BMI) of 18-40 kg/m2
  2. Fulfils the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
  3. 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)
  4. Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score ≥ 4 at screening
  5. Must have received 1 or more therapies for SLE
  6. Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria:
    2. Adequate hepatic function:
    3. Pancreatic enzymes
    4. eGFR ≥ 40 mL/min/1.73 m2 (estimated based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula)
    5. IgG ≥ 500 mg/dL
  7. 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
    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 onconcmitant folic or folinic acid supplementation if using methotrexate)
      • Leflunomide (≤ 20 mg/day) orally

PHASE 2:

  1. BMI of 18-40 kg/m2
  2. Fulfils the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE.
  3. Undergoing an ACR-recommended MMF- or MPA-based induction therapy regimen for lupus nephritis for 4 to 12 weeks, and willing to continue at least the MMF/MPA portion of the regimen unaltered throughout the duration of the study. Must be receiving a stable regimen of oral corticosteroids for at least 2 weeks prior to screening
  4. The patient has at least one of the following at screening per central lab:

    1. Positive ANA test (1:40 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)
  5. Kidney biopsy within 26 weeks prior to randomization 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 (NOTE: Patients meeting all inclusion criteria with a kidney biopsy of greater than 26 weeks will be allowed following a repeat biopsy which shows the necessary histologic diagnosis prior to study entry.)
  6. UPCR of ≥ 1.0 in 24-hour urine collection
  7. Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria:
    2. Adequate hepatic function:
    3. Pancreatic enzymes
    4. eGFR ≥ 40 mL/min/1.73 m2 estimated based on CKD-EPI formula
    5. IgG ≥ 500 mg/dL

Exclusion Criteria:

PHASE 1:

  1. Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment
  2. Fulfills diagnostic criteria for another rheumatic (overlap) disease that may confound clincal assessments in the study
  3. History of severe antiphospholipid syndrome within 12 months of screening or not on an adequate anticoagulation regimen.
  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
  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
  2. Isolated Class V membranous LN on a renal biopsy obtained within 26 weeks prior to signing ICF or during the screening period
  3. Known intolerance to MMF or MPA
  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 ≥140 mmHg and diastolic blood pressure ≥90 mmHg at rest)

    o If currently on RAS blockade (ACE-I, ARB, direct renin inhibitors), 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 day 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) for ≥ 4 weeks, cyclophosphamide: 24 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. Antimalarials, if used, must have been started or stopped at least 12 weeks prior to first dose, with stable dosage regimen for at least 4 weeks prior to first dose of study treatment
    10. Abatacept: 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 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
  13. History of cancer, except for in situ cancer that has been completely excised or has been curatively treated with no sign of disease for > 5 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03393013


Contacts
Contact: Director of Clinical Operations 650 822-5617 dbomba@kezarbio.com

Locations
United States, California
KZR Research Site Recruiting
Thousand Oaks, California, United States, 91360
KZR Research Site Not yet recruiting
Upland, California, United States, 91786
United States, Florida
KZR Research Site Not yet recruiting
DeBary, Florida, United States, 32713
KZR Research Site Recruiting
Miami, Florida, United States, 33136
KZR Research Site Recruiting
Miami, Florida, United States, 33165
KZR Research Site Recruiting
Orlando, Florida, United States, 32810
KZR Research Site Recruiting
Palm Harbor, Florida, United States, 34684
KZR Research Site Recruiting
Tampa, Florida, United States, 33613
KZR Research Site Recruiting
Winter Park, Florida, United States, 32789
United States, New York
KZR Research Site Not yet recruiting
Great Neck, New York, United States, 11021
KZR Research Site Not yet recruiting
Manhasset, New York, United States, 11030
KZR Research Site Not yet recruiting
Rochester, New York, United States, 14642
United States, Ohio
KZR Research Site Not yet recruiting
Columbus, Ohio, United States, 43210
United States, Tennessee
KZR Research Site Recruiting
Memphis, Tennessee, United States, 38119
United States, Texas
KZR Research Site Recruiting
Houston, Texas, United States, 77034
KZR Research Site Recruiting
Houston, Texas, United States, 77084
Australia, Victoria
KZR Research Site Not yet recruiting
Parkville, Victoria, Australia, 3052
Colombia
KZR Research Site Not yet recruiting
Bucaramanga, Santander, Colombia
Sponsors and Collaborators
Kezar Life Sciences, Inc.
Investigators
Study Director: Kezar Kezar

Responsible Party: Kezar Life Sciences, Inc.
ClinicalTrials.gov Identifier: NCT03393013     History of Changes
Other Study ID Numbers: KZR-616-002
First Posted: January 8, 2018    Key Record Dates
Last Update Posted: August 7, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Kezar Life Sciences, Inc.:
immunoproteasome inhibition
selective proteasome inhibition
proteasome

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Nephritis
Lupus Nephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Mycophenolic Acid
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action