Clinical trial NCT03393013: A Study of KZR-616 in Patients With SLE With and Without Lupus Nephritis
Official title: A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis (MISSION)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lupus Nephritis
Systemic Lupus Erythematosus
Keywords: immunoproteasome inhibition
selective proteasome inhibition
proteasome
lupus nephritis
lupus
nephritis
active proliferative lupus nephritis
open-label
systemic lupus erythematosus
lupus erythematosus
Lead sponsor: Kezar Life Sciences, Inc.
Sponsor class: INDUSTRY
First posted: 2018-01-08
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This was a Phase 1b/2, multi-center study in which patients received KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks (Phase 1b) or 24 weeks (Phase 2).

Detailed description: This was a Phase 1b/2, open-label, multi-center study in which patients received zetomipzomib administered as a SC injection weekly for either 13 weeks (Phase 1b) or for 24 weeks (Phase 2). In both phases, safety assessments continued for up to 12 weeks following the last dose of zetomipzomib.

Phase 1b was an open-label, multiple dose escalation study designed to evaluate the safety and tolerability of escalating doses of zetomipzomib when administered in addition to standard-of-care therapy in patients with SLE with or without nephritis. For each cohort, at least 6 patients were to be enrolled to assure the availability of at least 4 evaluable patients. Decisions to escalate, expand, or decrease the dose level or dosing frequency following the first 4 weeks of dosing for at least 4 evaluable patients in a cohort were made following review by a data monitoring committee (DMC).

The zetomipzomib formulations and doses administered by cohort in Phase 1b were:

* Cohort 1: zetomipzomib frozen maleate, 45 mg weekly × 13 weeks
* Cohort 2: zetomipzomib frozen maleate, 60 mg weekly × 13 weeks
* Cohort 2a: zetomipzomib frozen maleate, 30 mg weekly × 2 weeks, followed by 45 mg weekly × 2 weeks, followed by 60 mg weekly × 9 weeks
* Cohort 2b: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks
* Cohort 2c: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks (tolerability strategies cohort)
* Cohort 3: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 75 mg weekly × 12 weeks

The Phase 2 portion of the open-label study was designed to evaluate the renal response, safety, and tolerability of a single dose level (60 mg) of zetomipzomib administered weekly in addition to standard therapy in patients with active proliferative lupus nephritis (LN) (Class III or IV, with or without Class V disease) with a UPCR ≥1.0. Patients must have been on standard therapy for LN including at least 1 immunosuppressive agent. Zetomipzomib was administered as a SC injection weekly for 24 weeks (including a step up from an initial Week 1 dose of 30 mg).

Eligibility criteria: Key Inclusion Criteria:

Phase 1b:

* Fulfilled the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification for SLE
* Had a positive antinuclear antibody (ANA) titer, anti-double stranded DNA (dsDNA) antibody titer, or a positive anti-Smith antibody titer
* Had active SLE (as indicated by Systemic Lupus Erythematosus Disease Activity Index 2000 \[SLEDAI-2K\] score ≥4), and
* Had received at least 1 prior therapy for SLE

Phase 2:

* Had active proliferative LN (Class III or IV, with or without Class V disease)
* Had a UPCR ≥1.0 measured in 24-hour urine collection
* Had a histologic diagnosis of LN on renal biopsy within the prior 2 years; for biopsies \> 1 year before the Screening visit, one of the following must also be present at screening: low C3, low C4, or anti-ds-DNA elevated to above normal range
* Fulfilled the 2012 SLICC classification for SLE
* Had a positive ANA titer, anti-dsDNA antibody titer, or anti-Smith antibody titer, and
* Were currently receiving ≥1 immunosuppressive agent at a stable dose and route of administration for ≥8 weeks. If the patient is also on corticosteroids then must be on a stable dose for ≥ 2 weeks prior to Baseline

Key Exclusion Criteria:

Phase 1b:

* Current or medical history of:

  * Central nervous system manifestations by autoimmune disease
  * Overlapping autoimmune condition that may affect study assessments/outcomes
  * Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening
  * Malignancy of any type, with exceptions for in situ cancer that has been completely excised and certain cancers \>5 years ago
* Positive test at Screening for HIV, hepatitis B/C
* Major surgery within 4 weeks before signing informed consent form or planned major surgery during the study period

Phase 2:

* Current or medical history of:

  * Central nervous system manifestations of SLE
  * Overlapping autoimmune condition that may affect study assessments/outcomes
  * Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening
  * Malignancy of any type within the last 5 years, with exceptions for appropriately excised and cured cervical carcinoma in situ or excised basal or squamous cell carcinomas of the skin
* Has received dialysis within the 52 weeks prior to Screening
* Positive test at Screening for HIV, hepatitis B/C
* Major surgery within 12 weeks before signing informed consent form or planned major surgery during the study period
* Use of investigational therapy or device, and/or participation in an investigational trial \<8 weeks or 5 half-lives, whichever is longer, prior to Baseline; Patients who participated in Phase 1b of KZR-616-002 are excluded from Phase 2

Primary outcomes:
measure: Phase 1b: Number of Patients Who Experienced at Least One Treatment-Related Treatment-Emergent Adverse Event
timeFrame: 25 weeks
measure: Phase 2: Number of Patients With Lupus Nephritis With a 50% Reduction in UPCR
timeFrame: 24 weeks
Secondary outcomes:
measure: Phase 1b: PK of KZR-616 (Cmax)
timeFrame: 8 hours
measure: Phase 1b: PK of KZR-616 (Tmax)
timeFrame: 8 hours
measure: Phase 1b: PK of KZR-616 (AUC)
timeFrame: 8 hours
measure: Phase 2: Number of Patients With a Partial Renal Response
timeFrame: 24 weeks
measure: Phase 2: Safety and Tolerability of KZR-616 When Administered as a SC Injection Weekly for 24 Weeks
timeFrame: 37 weeks
measure: Phase 1b: Recommended Phase 2 Doses of Zetomipzomib When Administered as a Subcutaneous Injection
timeFrame: 25 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Academic Medical Research Institute
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials, Inc.
state: California
city: Miami
country: United States
facility: SouthCoast Research Center, Inc.
state: Florida
city: Miami
country: United States
facility: Hope Clinical Trials, Inc.
state: Florida
city: Orlando
country: United States
facility: Omega Research Maitland
state: Florida
city: Palm Harbor
country: United States
facility: Arthritis Center, Inc
state: Florida
city: Tampa
country: United States
facility: Advent Health Medical Group
state: Florida
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Great Neck
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: NYU Langone Orthopedic Center - Seligman Center for Advanced Therapeutics
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Orangeburg
country: United States
facility: SC Nephrology & Hypertension Center, Inc.
state: South Carolina
city: Memphis
country: United States
facility: Ramesh C. Gupta, MD
state: Tennessee
city: El Paso
country: United States
facility: MedResearch, Inc.
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research, Inc.
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Management, LLC
state: Texas
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Barranquilla
country: Colombia
facility: Centro Integral de Reumatologia de Caribe CIRCARIBE S.A.S
state: Atlantico
city: Barranquilla
country: Colombia
facility: Clinica de la Costa
state: Atlantico
city: Santander
country: Colombia
facility: Medicity SAS
state: Bucaramanga
city: Bucaramanga
country: Colombia
facility: Servimed S.A.S.
state: Santander
city: Cali
country: Colombia
facility: Clinica de Artritis Temprana
state: Valle Del Cauca
city: Guadalajara
country: Mexico
facility: Centro Integral de Reumatologia SA de CV
state: Jalisco
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr José Eleuterio Gonzalez
state: Nuevo Leon
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cardiología Ignacio Chavez
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutricion "Salvador Zubiran"
city: Trujillo
country: Peru
facility: Centro de Investigación Clínica Trujillo E.I.R.L/ Clínica Peruano Americana S.A.
state: La Libertad
city: Lima
country: Peru
facility: Investigaciones Clinicas SAC
city: Lima
country: Peru
facility: Unidad de Investigacion en Reumatologia e Inmunologia Clinica San Juan Bautista
city: Łódź
country: Poland
facility: Bioclinica
city: Kemerovo
country: Russian Federation
facility: Kuzbass Clinical Hospital
city: Kemerovo
country: Russian Federation
facility: Medical Center Revma-Med
city: Togliatti
country: Russian Federation
facility: Tolyatti City Clinical Hospital #1
city: Kyiv
country: Ukraine
facility: Harmoniya Krasy
state: Kyiv Governorate
Study officials:
affiliation: Kezar Life Sciences, Inc.
name: Kezar
role: STUDY_DIRECTOR
References: