siltuximab in siltuximab-relapsed/refractory multicentric castleman disease

Conditions: Idiopathic Multicentric Castleman's Disease

Summary: phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with imcd

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 \ 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)