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

Sponsor

Kezar Life Sciences, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03393013

Collaborator

(none)

Enrollment

Locations

Arms

53.8

Anticipated Duration (Months)

1.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Lupus Nephritis Systemic Lupus Erythematosus	Drug: KZR-616	Phase 1/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 fully enrolled October 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 Design

Study Type:

Interventional

Anticipated Enrollment :

68 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

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 :

Mar 7, 2018

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: KZR-616 Subcutaneous Injection of KZR-616 Other Names: KZR-616 Lyophile
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 complete.	Drug: KZR-616 Subcutaneous Injection of KZR-616 Other Names: KZR-616 Lyophile
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 complete.	Drug: KZR-616 Subcutaneous Injection of KZR-616 Other Names: KZR-616 Lyophile
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 complete.	Drug: KZR-616 Subcutaneous Injection of KZR-616 Other Names: KZR-616 Lyophile

Outcome Measures

Primary Outcome Measures

Phase 1b: To evaluate the safety and tolerability of KZR-616 [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 [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

Secondary Outcome Measures

Phase 1b: Identify Recommended Phase 2 dose levels (RP2Ds) of KZR-616 [4 weeks]
Determined through assessment of all AEs and any dose limiting toxicities (DLTs)
Phase 1b: To characterize the PK of KZR-616 [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 [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 [24 weeks]
Determined through assessment of UPCR after 24 weeks when compared to baseline

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

Positive antinuclear antibody (ANA) test (1:80 or higher); or
Anti-double stranded deoxyribonucleic acid (dsDNA) antibodies elevated to above normal (i.e. positive results); or
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):

Hydroxychloroquine 200 mg orally daily in combination with prednisone 10 mg daily or equivalent
MMF orally 1 g/day or MPA orally 720 mg/day
Methotrexate orally or SC 15 mg/wk., or leflunomide orally 10 mg/day
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
Cyclosporine or tacrolimus at doses documented to maintain at least 100 or 5 ng/mL during the required duration, respectively
Cyclophosphamide 500 mg intravenously (IV) every 2 weeks or 500 mg/m2 IV once monthly
Belimumab 10 mg/kg IV every 2 weeks for 3 doses, followed by 10 mg/kg every 4 weeks; or 200 mg SC weekly
Rituximab 1 g IV (may be given as 500 mg twice)

Acceptable screening laboratory values of concern, including:

Adequate hematologic criteria
Adequate hepatic function
eGFR ≥40 mL/min/1.73 m2
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:

Positive ANA test; or
Anti-dsDNA antibodies elevated to above normal; or
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:

Adequate hematologic criteria
Adequate hepatic function
eGFR ≥30mL/min/1.73 m2
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

Systemic corticosteroids ≥ 100 mg prednisone or equivalent: 4 weeks
Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
Intravenous Immunoglobulin (IVIg): 4 weeks
Other non-biologic immunosuppressive agents, such as cyclosporine, tacrolimus: 4 weeks
Cyclophosphamide: 12 weeks
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
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
Belimumab, abatacept, or atacicept: 12 weeks
Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
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

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

History of severe and/or disseminated viral infections, and/or opportunistic infections
Known seropositivity for or active infection by human immunodeficiency virus (HIV)
Active, chronic, or resolved hepatitis B or hepatitis C infection
History of progressive multifocal leukoencephalopathy
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
Receipt of a live-attenuated vaccine within 12 weeks of first day of study treatment (Week 1, Day 1)
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:

Progressive multifocal leukoencephalopathy
Active or untreated latent TB, per QuantiFERON-TB Gold at Screening
Receipt of a live-attenuated vaccine within 12 weeks of Baseline (Week 1, Day 1)
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])
Primary hematopoietic cell or solid organ transplant

Any active or suspected malignancy or history of documented malignancy within the last 5 years before Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Academic Medical Research Institute	Los Angeles	California	United States	990022
2	Los Angeles Biomedical Research Institute at Harbor	Torrance	California	United States	90502
3	Inland Rheumatology Clinical Trials, Inc.	Upland	California	United States	91786
4	South Florida Nephrology Research, LLC	Coral Springs	Florida	United States	33071
5	SouthCoast Research Center, Inc.	Miami	Florida	United States	33136
6	Hope Clinical Trials, Inc.	Miami	Florida	United States	33165
7	Omega Research Maitland	Orlando	Florida	United States	32808
8	University of Iowa	Iowa City	Iowa	United States	52242
9	SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
10	Northwell Health	Great Neck	New York	United States	11021
11	Feinstein Institute for Medical Research	Manhasset	New York	United States	11030
12	NYU Lagone Orthopedic Center - Seligman Center for Advanced Therapeutics	New York	New York	United States	10016
13	Akron Nephrology Associates, Inc.	Akron	Ohio	United States	44302
14	UC Health Medical Arts Building	Cincinnati	Ohio	United States	45267
15	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
16	SC Nephrology & Hypertension Center, Inc.	Orangeburg	South Carolina	United States	29118
17	Ramesh C. Gupta, MD	Memphis	Tennessee	United States	38119
18	Texas Tech University Health Sciences Center	Amarillo	Texas	United States	79106
19	MedResearch, Inc.	El Paso	Texas	United States	79902
20	Accurate Clinical Research, Inc.	Houston	Texas	United States	77034
21	Accurate Clinical Management, LLC	Houston	Texas	United States	77084
22	Monash Health	Clayton	Victoria	Australia	3168
23	The Royal Melbourne Hospital	Parkville	Victoria	Australia	3052
24	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009
25	Hospital Pablo Tobon Uribe	Medellín	Antioquia	Colombia	50001
26	Centro Integral de Reumatologia de Caribe CIRCARIBE S.A.S	Barranquilla	Atlantico	Colombia	080020
27	Clinica de la Costa	Barranquilla	Atlantico	Colombia	080020
28	Medicity SAS	Santander	Bucaramanga	Colombia	680003
29	Preventive Care Sas	Chía	Cundinamarca	Colombia	250001
30	Servimed S.A.S.	Bucaramanga	Santander	Colombia	680003
31	Clinica de Artritis Temprana	Cali	Valle Del Cauca	Colombia	076001
32	Centro Integral de Reumatologia SA de CV	Guadalajara	Jalisco	Mexico	44160
33	Hospital Universitario Dr José Eleuterio Gonzalez	Monterrey	Nuevo Leon	Mexico	64020
34	Instituto Nacional de Cardiología Ignacio Chavez	Mexico City		Mexico	14080
35	Instituto Nacional de Ciencias Médicas y Nutricion "Salvador Zubiran"	Mexico City		Mexico	14080
36	Unidad de Investigacion en Medicina Interna y Enfermedades Criticas	Cayma	Arequipa	Peru	4000
37	Centro de Investigación Clínica Trujillo E.I.R.L	Trujillo	La Libertad	Peru	13011
38	Investigaciones Clinicas SAC	Lima		Peru	15023
39	Centro de Investigacion Delgado	Lima		Peru	15074
40	Unidad de Investigacion en Reumatologia e Inmunologia Clinica San Juan Bautista	Lima		Peru	15431
41	Medyczne Centrum	Poznań	Wielkopolska	Poland	60-218
42	Appletreeclinic Network	Łódź		Poland	90-349
43	Bioclinica	Łódź		Poland	90-368
44	Kuzbass Clinical Hospital	Kemerovo		Russian Federation	650066
45	Medical Center Revma-Med	Kemerovo		Russian Federation	650070
46	Regional Clinical Hospital	Omsk		Russian Federation	644111
47	Rostov State Medical University	Rostov-on-Don		Russian Federation	344022
48	Regional Clinical Hospital	Saratov		Russian Federation	410053
49	Tolyatti City Clinical Hospital #1	Togliatti		Russian Federation	445009
50	Harmoniya Krasy	Kyiv	Kyiv Governorate	Ukraine	01135