Maurizio Zangari

A phase 1 dose-escalation study of antibody BI-505 in relapsed/refractory multiple myeloma

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505′s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206). Clin Cancer Res; 21(12); 2730–6. ©2015 AACR.

Cardiovascular Complications in Patients with AL Amyloidosis

Amyloidosis is a disease characterized by aberrant precursor molecules whose misfolded intermediate forms aggregate and are deposited as interstitial fibrils. The most common type of systemic amyloidosis is immunoglobulin light-chain amyloidosis (AL). Less common types of systemic amyloidosis are the transthyretin (ATTR) types caused by either mutant (hereditary) variants or wild-type (senile systemic) transthyretin. Although rare in developed countries secondary amyloidosis is associated with autoimmune or inflammatory diseases, chronic infections and malignancies. Different precursor proteins can coexist in the same patient as in the African-American population, which has a 4% incidence of an hereditary ATTR variant (Val122Ile) and a significant incidence of monoclonal gammopathy (1, 2). The amyloids are highly ordered cross-┚ sheet protein with extra cellular deposition in single or multiple organs. Cardiac deposition, leading to an infiltrative/restrictive cardiomyopathy, is a common feature and may be present at the diagnosis or discovered while investigating a patient presenting with non-cardiac amyloidosis. AL amyloidosis, is associated with clinical cardiac involvement in about half of all cases, although subclincal involvement may be detected in almost every case at autopsy on endomyocardial biopsy. Laser micro dissection with mass spectrometry assessing the constituents of the Congophilic deposits is now the gold standard for amyloid typing, obtaining protein type identification in over 98% of cases (3). Evaluation for cardiac involvement is a critical step of the initial staging of amyloidosis. Criteria for the assessment of organ involvement at baseline and after treatment have been standardized (4). In systemic AL amyloidosis the extent of cardiac involvement has prognostic indications, with a median survival of 6 months for untreated or non-responding patients (5, 6).