A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis (MISSION)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 69
- 试验地点
- 36
- 主要终点
- Phase 1b: Number of Patients Who Experienced at Least One Treatment-Related Treatment-Emergent Adverse Event
研究概览
简要总结
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).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
- •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
研究组 & 干预措施
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.
Two Phase 1b cohorts received 45 mg at some point during the study.
Cohort 1 received 45 mg zetomipzomib frozen maleate weekly for 13 weeks.
Cohort 2a followed a step-up dosing procedure. Patients received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks.
KZR-616 was administered as a SC injection.
干预措施: KZR-616 (Drug)
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.
Four Phase 1b cohorts received 60 mg at some point during the study.
Cohort 2 received 60 mg zetomipzomib frozen maleate weekly for 13 weeks.
Cohorts 2a, 2b, and 2c all followed a step-up dosing procedure. Patients in Cohort 2a received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks. Patients in Cohort 2b received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks. Patients in Cohort 2c (tolerability strategies cohort) received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks.
KZR-616 was administered as a SC injection.
干预措施: KZR-616 (Drug)
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.
One Phase 1b cohort received 75 mg at some point during the study.
Cohort 3 followed a step-up dosing procedure. Patients in Cohort 3 received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 75 mg weekly for 12 weeks.
KZR-616 was administered as a SC injection.
干预措施: KZR-616 (Drug)
KZR-616 60 mg + standard therapy (Phase 2)
60 mg dose level of KZR-616 selected based on data from the phase 1b dose escalation and administered to patients with active lupus nephritis in combination with standard therapy including at least one immunosuppressive agent.
KZR-616 was administered as a SC injection weekly at a dose of 60 mg for 24 weeks (including a step-up from an initial Week 1 dose of 30 mg).
** See Limitations/Caveats for additional information
干预措施: KZR-616 (Drug)
结局指标
主要结局
Phase 1b: Number of Patients Who Experienced at Least One Treatment-Related Treatment-Emergent Adverse Event
时间窗: 25 weeks
The safety and tolerability of zetomipzomib (KZR-616) when administered as a subcutaneous injection weekly for 13 weeks in adult patients with systemic lupus erythematous (SLE) with and without nephritis, as assessed by number of patients who experienced at least one treatment-related treatment-emergent adverse event. For additional information about the safety and tolerability of KZR-616, please reference the adverse events section of this posting.
Phase 2: Number of Patients With Lupus Nephritis With a 50% Reduction in UPCR
时间窗: 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.
次要结局
- Phase 2: Number of Patients With a Partial Renal Response(24 weeks)
- Phase 1b: Recommended Phase 2 Doses of Zetomipzomib When Administered as a Subcutaneous Injection(25 weeks)
- Phase 1b: PK of KZR-616 (Cmax)(8 hours)
- Phase 1b: PK of KZR-616 (Tmax)(8 hours)
- Phase 1b: PK of KZR-616 (AUC)(8 hours)
- Phase 2: Safety and Tolerability of KZR-616 When Administered as a SC Injection Weekly for 24 Weeks(37 weeks)