Back to resultsSiltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease (SISREMCAD)
Primary Purpose
Idiopathic Multicentric Castleman's Disease
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Siltuximab
Sponsored by
About this trial
This is an interventional treatment trial for Idiopathic Multicentric Castleman's Disease
Eligibility Criteria
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)
Sites / Locations
- Edward W. Sparrow Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Parallel Arm of iMCD Patients
Parallel Arm of TAFRO-iMCD Patients
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Assess the Clinical Benefit Response (CBR) of Siltuximab
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 Outcome Measures
To evaluate the safety and tolerability of increased Siltuximab doses
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)
Pharmacokinetics (Vd)
To test the patient's drug propensity
Pharmacokinetics (CL)
To test the volume of plasma cleared of drug per unit time
Pharmacokinetics (AUC)
To test the extent of exposure to a drug and its clearance rate from the body
Pharmacokinetics (Cmin / Cmax)
To test the minimum (Cmin) and the maximum (Cmax) blood plasma concentration
Pharmacokinetics (Ctrough)
To test the minimum drug concentration after a dose
Pharmacokinetics (Tmax)
To test the time taken to reach Cmax
Evaluate the efficacy of increased siltuximab doses after disease progression on prior siltuximab treatment.
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.
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
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
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.
Full Information
NCT ID
NCT04838860
First Posted
February 25, 2021
Last Updated
April 15, 2021
Sponsor
EusaPharma (UK) Limited
1. Study Identification
Unique Protocol Identification Number
NCT04838860
Brief Title
Siltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease
Acronym
SISREMCAD
Official Title
A Phase 2 Study of Intrapatient Siltuximab Dose Escalation in Patients With Idiopathic Multicentric Castleman Disease That Has Progressed After Prior Siltuximab Treatment
Study Type
Interventional
2. Study Status
Record Verification Date
March 2021
Overall Recruitment Status
Terminated
Why Stopped
Internal Company Decision
Study Start Date
March 31, 2021 (Actual)
Primary Completion Date
April 1, 2021 (Actual)
Study Completion Date
April 1, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EusaPharma (UK) Limited
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Multicentric Castleman's Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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.
Masking
None (Open Label)
Masking Description
No masking
Allocation
Non-Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Parallel Arm of iMCD Patients
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Parallel Arm of TAFRO-iMCD Patients
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Siltuximab
Other Intervention Name(s)
Sylvant
Intervention Description
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.
Primary Outcome Measure Information:
Title
Assess the Clinical Benefit Response (CBR) of Siltuximab
Description
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).
Time Frame
12 Weeks
Secondary Outcome Measure Information:
Title
To evaluate the safety and tolerability of increased Siltuximab doses
Description
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)
Time Frame
12 Weeks
Title
Pharmacokinetics (Vd)
Description
To test the patient's drug propensity
Time Frame
12 Weeks
Title
Pharmacokinetics (CL)
Description
To test the volume of plasma cleared of drug per unit time
Time Frame
12 Weeks
Title
Pharmacokinetics (AUC)
Description
To test the extent of exposure to a drug and its clearance rate from the body
Time Frame
12 Weeks
Title
Pharmacokinetics (Cmin / Cmax)
Description
To test the minimum (Cmin) and the maximum (Cmax) blood plasma concentration
Time Frame
12 Weeks
Title
Pharmacokinetics (Ctrough)
Description
To test the minimum drug concentration after a dose
Time Frame
12 Weeks
Title
Pharmacokinetics (Tmax)
Description
To test the time taken to reach Cmax
Time Frame
12 Weeks
Title
Evaluate the efficacy of increased siltuximab doses after disease progression on prior siltuximab treatment.
Description
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
Time Frame
12 Weeks
Title
Evaluate the immunogenicity of increased siltuximab doses after disease progression on prior siltuximab treatment.
Description
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.
Time Frame
12 Weeks
Title
To evaluate the patient-reported outcomes (PROs) using the EQ-5D Instrument
Description
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
Time Frame
12 Weeks
Title
To evaluate the patient-reported outcomes (PROs) using the MCD-SS Instrument
Description
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.
Time Frame
12 Weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chris Keuker, MD
Organizational Affiliation
Syneos Health
Official's Role
Study Director
Facility Information:
Facility Name
Edward W. Sparrow Hospital
City
Lansing
State/Province
Michigan
ZIP/Postal Code
48912
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Siltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease
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