A Phase 2 Study of Intrapatient Siltuximab Dose Escalation in Patients With Idiopathic Multicentric Castleman Disease That Has Progressed After Prior Siltuximab Treatment
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Assess the Clinical Benefit Response (CBR) of Siltuximab
研究概览
简要总结
Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD
详细描述
This is an open-label, two-stage, Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD who progressed with elevated and rising serum C reactive protein (CRP) levels after prior treatment with siltuximab 11 mg/kg every 3 weeks (q3w) without unacceptable toxicity, and is primarily designed to leverage opportunities for intrapatient dose escalation with available clinical, nonclinical, and PK justification as a means to restore or enable disease control.
Enrolling in Stage 1a and Stage 1b of this study in parallel will be up to 6 patients each with siltuximab-relapsed or refractory IL-6-driven iMCD and TAFRO-iMCD patients, respectively, who will undergo intrapatient dose escalation of siltuximab beginning with 22 mg/kg q3w, then possibly dose escalating to 33 mg/kg q3w then 44 mg/kg q3w if clinically indicated in the absence of DLT. The justifications for escalating siltuximab doses up to 44 mg/kg q3w will be based on intrapatient dose escalation and DLT assessments as described below.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No masking
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented history of consensus histologic, laboratory, and clinical diagnostic criteria of iMCD.
- •Archival and/or baseline incisional/excisional biopsy for retrospective central histologic confirmation of iMCD.
- •CDCNRC-defined disease progression on or after prior treatment with siltuximab at 11 mg/kg q3w without unacceptable toxicity within 12 weeks between the last dose of siltuximab and the date of signed patient informed consent form (ICF).
- •At least 1 measurable abnormal lymph node mass that is ≥1 cm in its longest transverse diameter as assessed by computerized tomography (CT) scan that has not been previously irradiated.
- •Elevated (>10 mg/L) and rising serum CRP in the absence of additional iMCD treatment.
- •Evidence of at least an additional one of the following laboratory or clinical signs of iMCD per international, evidence-based consensus diagnostic criteria for HIV or HHV 8-negative iMCD:
- •Anemia, thrombocytopenia, hypoalbuminemia, renal dysfunction, or polyclonal hypergammaglobulinemia.
- •Constitutional symptoms (night sweats, fever (>38°C), weight loss, or fatigue (CTCAE lymphoma B-symptoms score ≥2), large spleen and/or liver, fluid accumulation, eruptive cherry hemangiomatosis/violaceous papules, or lymphocytic interstitial pneumonitis.
- •Adequate clinical laboratory measurements within 3 weeks prior to study entry in all parameters below:
- •Absolute neutrophil count ≥1.0 × 109/L, hemoglobin <17 g/dL, and platelets ≥50 × 109/L without transfusion, hematopoietic growth factors, or both for >7 days prior to measurement.
- •AST, ALT, total bilirubin, and alkaline phosphatase ≤5 × ULN.
- •Fasting cholesterol <300 mg/dL and fasting triglyceride <400 mg/dL.
- •Age ≥12 years.
排除标准
- •Documentation of HIV or HHV-8 infection or presence of other infection-related disorders that resemble clinical or histological features of iMCD
- •Diagnosis of any malignant/benign lymphoproliferative disorders
- •Diagnosis of autoimmune/autoinflammatory disease
- •Treatment with corticosteroids (prednisone dose-equivalent >1 mg/kg/day) within 7 days prior to study entry.
- •History of solid organ transplant, allogeneic bone marrow transplant, or allogeneic peripheral blood stem cell transplant.
- •Previous malignancy with the following exceptions:
- •Past malignancy with treatment that was completed at least 2 years before signing informed consent and the patient has no evidence of disease, or
- •Concurrent malignancy that is clinically stable and does not require tumor-directed treatment (eg, nonmelanoma skin cancer and carcinoma in situ)
研究组 & 干预措施
Parallel Arm of iMCD Patients
Enrolling in Stage 1a of this study in parallel will be up to 6 patients each with siltuximab-relapsed or refractory IL-6-driven iMCD patients, respectively, who will undergo intrapatient dose escalation of siltuximab beginning with 22 mg/kg q3w, then possibly dose escalating to 33 mg/kg q3w then 44 mg/kg q3w if clinically indicated in the absence of DLT. The justifications for escalating siltuximab doses up to 44 mg/kg q3w will be based on intrapatient dose escalation and DLT assessments as described below.
干预措施: Siltuximab (Drug)
Parallel Arm of TAFRO-iMCD Patients
Enrolling in Stage 1b of this study in parallel will be up to 6 patients each with siltuximab-relapsed or refractory IL-6-driven TAFRO-iMCD patients, respectively, who will undergo intrapatient dose escalation of siltuximab beginning with 22 mg/kg q3w, then possibly dose escalating to 33 mg/kg q3w then 44 mg/kg q3w if clinically indicated in the absence of DLT. The justifications for escalating siltuximab doses up to 44 mg/kg q3w will be based on intrapatient dose escalation and DLT assessments as described below.
干预措施: Siltuximab (Drug)
结局指标
主要结局
Assess the Clinical Benefit Response (CBR) of Siltuximab
时间窗: 12 Weeks
Assess the clinical benefit response (CBR) of increased siltuximab doses in patients with IL-6-driven (C-reactive protein \[CRP\]-elevated and rising) idiopathic multicentric Castleman disease (iMCD) after disease progression on the standard siltuximab dose schedule. CBR defined as complete response (CR), partial response (PR), or stable disease (SD) lasting ≥12 weeks per Castleman Disease Collaborative Network Response Criteria (CDCNRC).
次要结局
- To evaluate the safety and tolerability of increased Siltuximab doses(12 Weeks)
- Pharmacokinetics (Vd)(12 Weeks)
- Pharmacokinetics (CL)(12 Weeks)
- Pharmacokinetics (AUC)(12 Weeks)
- Pharmacokinetics (Cmin / Cmax)(12 Weeks)
- Pharmacokinetics (Ctrough)(12 Weeks)
- Pharmacokinetics (Tmax)(12 Weeks)
- Evaluate the efficacy of increased siltuximab doses after disease progression on prior siltuximab treatment.(12 Weeks)
- Evaluate the immunogenicity of increased siltuximab doses after disease progression on prior siltuximab treatment.(12 Weeks)
- To evaluate the patient-reported outcomes (PROs) using the EQ-5D Instrument(12 Weeks)
- To evaluate the patient-reported outcomes (PROs) using the MCD-SS Instrument(12 Weeks)