Idiopathic Multicentric Castleman's Disease
Conditions
Brief summary
Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD
Detailed description
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.
Interventions
DRUGSiltuximab
Participants will receive intravenous (IV) infusion of siltuximab 22 mg/kg over 2 hours every 3 weeks, then possibly dose escalating to 33 mg/kg IV over 3 hours +/- 44 mg/kg IV over 4 hours every 3 weeks if clinically indicated in the absence of dose-limiting toxicity.
Sponsors
RECORDATI GROUP
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
No masking
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess the Clinical Benefit Response (CBR) of Siltuximab | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (Vd) | 12 Weeks | To test the patient's drug propensity |
| Pharmacokinetics (CL) | 12 Weeks | To test the volume of plasma cleared of drug per unit time |
| Pharmacokinetics (AUC) | 12 Weeks | To test the extent of exposure to a drug and its clearance rate from the body |
| Pharmacokinetics (Cmin / Cmax) | 12 Weeks | To test the minimum (Cmin) and the maximum (Cmax) blood plasma concentration |
| Pharmacokinetics (Ctrough) | 12 Weeks | To test the minimum drug concentration after a dose |
| To evaluate the safety and tolerability of increased Siltuximab doses | 12 Weeks | Incidence of Adverse Events (AEs), serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs), incidence of abnormal laboratory test results incidence of dose-limiting toxicities (DLTs) |
| Evaluate the efficacy of increased siltuximab doses after disease progression on prior siltuximab treatment. | 12 Weeks | The primary efficacy endpoint is CBR defined as CR, PR, or SD lasting ≥12 weeks per CDCNRC based on evaluation of biochemical, lymph node, and symptom response |
| Evaluate the immunogenicity of increased siltuximab doses after disease progression on prior siltuximab treatment. | 12 Weeks | Immunogenicity will be assessed through the detection of antibodies against siltuximab, and will be conducted via immunoassay ± serum IL-6 levels on Day 1 of Cycle 1, 3, 6 and every 4 cycles thereafter, before administration of siltuximab. |
| To evaluate the patient-reported outcomes (PROs) using the EQ-5D Instrument | 12 Weeks | The secondary outcome measures will include the health status measures of the EuroQuality of Life Five Dimensions (EQ-5D) has the following dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions |
| To evaluate the patient-reported outcomes (PROs) using the MCD-SS Instrument | 12 Weeks | The Multicentric Castleman disease symptom score (MCD-SS) lists 10 symptoms which are graded on a scale: Did not experience (0); Very mild (2); Mild (4); Moderate (6); Severe (8); Very Severe (10). The mean score of the ten items is calculated and a higher score indicates more severe symptoms. |
| Pharmacokinetics (Tmax) | 12 Weeks | To test the time taken to reach Cmax |
Countries
United States
Outcome results
None listed