Results of Phase I Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis

Abstract Background: The murine (Mu) monoclonal antibody (mAb) 11-1F4 prepared against human light-chain-related fibrils recognizes an amyloid-associated conformational epitope when administered to mice bearing human AL amyloidomas and elicits a neutrophil/macrophage response that led to rapid and complete elimination of the amyloid tumors with no evidence of toxicity in the animals. PET/CT using I-124 labeled Mu mAb 11-1F4 revealed uptake by the organs known to contain amyloid in the majority of patients studied.1,2 These results led to production of GMP-grade amyloid fibril-reactive chimeric (Ch) IgG1 mAb 11-1F4 by the NCI's Biological Resource Branch for a Phase I clinical trial in patients with AL amyloidosis. Methods: This is an open-label, dose-escalation Phase I clinical trial of Ch IgG1 mAb 11-1F4 in patients with relapsed or refractory AL amyloidosis. The trial was conducted under the auspices of an Experimental Therapeutic Investigational New Drug (IND) with a primary objective of defining the maximum tolerated dose, and tolerability and safety of Ch IgG1 mAb 11-1F4 when given as a single intravenous infusion. Secondary objectives included pharmacokinetics, safety, and organ response. Patients were eligible if they had received prior systemic therapy for relapsed or refractory AL-Amyloidosis or had declined or were ineligible for standard systemic therapy and a life expectancy of at least 3 months. Patients were excluded if they had ventricular ejection fraction less than 40 percent, an interventricular septal thickness greater than 25mm, a history of sustained ventricular tachycardiac or cardiac arrest, 24 hour creatinine clearance of less than 30cc/min, alkaline phosphatase greater than three times the upper limit of normal, or total bilirubin greater than 3.0mg/dL. A dose-escalation "up and down" design was used with 7 sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2. Results: As of July 14, 2015, dose level 6 was completed including six patients who completed the study. Two patients had primarily cardiac, 2 patients primarily skin, and 2 primarily gastrointestinal (GI) involvement. All patients tolerated the dose received and no grade 3, 4 adverse events (AE) or deaths occurred. The AE included: dose level 5, one patient with grade 1 nausea and diarrhea and at dose level 4 one patient grade 2 rash for 11 days. Skin biopsy revealed previously undiagnosed cutaneous amyloid deposits and a neutrophilic infiltrate that may represent proof of antibody binding amyloid fibrils. Though the primary objective of the trial was to evaluate safety, 3 of 6 patient had evidence of organ response (2 cardiac and 1 GI) after only one infusion of Ch IgG1 mAb 11-1F4. Conclusions: To date, Ch IgG1 mAb 11-1F4 was well tolerated by all study subjects without any adverse reactions and promising organ response after completion of 6 dose levels. Development of an AL-fibril-specific mAb treatment would be an invaluable adjunct in the treatment of patients with AL amyloidosis and lead to improved medical management of this incurable and ultimately fatal disease. Clinical Trial Information: NCT02245867 References 1. Wall, J., Kennel, S.J., Stuckey, A.C., Long, M.J, Townsend, D.W., Smith, G.T., Wells, K.J., Fu, Y., Stabin, M.G., Weiss, D.T., and Solomon, A. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis, Blood. 116: 2241-2244, 2010. 2. Solomon, Alan. Personal Communication. Apr 2014. Disclosures Lentzsch: Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Axiom: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Monoclonal antibody 11-1F4 is the drug under investigation in this trial as a therapy for amyloidosis. It currently has no FDA approved indication..