Siltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease

NCT ID: NCT04838860

Last Updated: 2021-04-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-31
• Study Completion Date: 2021-04-01

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.

Conditions

Idiopathic Multicentric Castleman's Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Siltuximab

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Siltuximab

Intervention Type: DRUG

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.

Interventions

Siltuximab

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.

Intervention Type: DRUG

Other Intervention Names

Sylvant

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)

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

RECORDATI GROUP

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chris Keuker, MD

Role: STUDY_DIRECTOR

Syneos Health

Locations

Edward W. Sparrow Hospital

Lansing, Michigan, United States

Countries

United States

Other Identifiers

EUSA SYL 0002

Identifier Type: -

Identifier Source: org_study_id