Clinical trial NCT04838860: Siltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Idiopathic Multicentric Castleman's Disease
Lead sponsor: RECORDATI GROUP
Sponsor class: INDUSTRY
First posted: 2021-04-09
Enrollment: 22
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Assess the Clinical Benefit Response (CBR) of Siltuximab
timeFrame: 12 Weeks
Secondary outcomes:
measure: To evaluate the safety and tolerability of increased Siltuximab doses
timeFrame: 12 Weeks
measure: Pharmacokinetics (Vd)
timeFrame: 12 Weeks
measure: Pharmacokinetics (CL)
timeFrame: 12 Weeks
measure: Pharmacokinetics (AUC)
timeFrame: 12 Weeks
measure: Pharmacokinetics (Cmin / Cmax)
timeFrame: 12 Weeks
measure: Pharmacokinetics (Ctrough)
timeFrame: 12 Weeks
measure: Pharmacokinetics (Tmax)
timeFrame: 12 Weeks
measure: Evaluate the efficacy of increased siltuximab doses after disease progression on prior siltuximab treatment.
timeFrame: 12 Weeks
measure: Evaluate the immunogenicity of increased siltuximab doses after disease progression on prior siltuximab treatment.
timeFrame: 12 Weeks
measure: To evaluate the patient-reported outcomes (PROs) using the EQ-5D Instrument
timeFrame: 12 Weeks
measure: To evaluate the patient-reported outcomes (PROs) using the MCD-SS Instrument
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Lansing
country: United States
facility: Edward W. Sparrow Hospital
state: Michigan
Study officials:
affiliation: Syneos Health
name: Chris Keuker, MD
role: STUDY_DIRECTOR
References: