Anti–Interleukin-1 Alpha Antibody MABp1 Is Well Tolerated, Safe, and Active in Phase I Trial in Refractory Cancers
Expression of the inflammatory cytokine interleukin (IL)-1 alpha is a very early step in the inflammatory response that characterizes the malignant phenotype and that is associated with angiogenesis, tumor invasiveness, metastasis, and cachexia. In a phase I dose-escalation study reported in The Lancet Oncology, Hong et al found that the true human anti–IL-1 alpha antibody MABp1 was well tolerated, safe, and associated with disease control in patients with refractory cancers. No dose-limiting toxicity or immunogenicity was observed.
MABp1 is a natural antibody cloned from an affinity-matured in vivo human immune response and has undergone no sequence modifications to alter binding affinity. As noted by the investigators, all marketed antibodies described as “fully human” have undergone in vitro affinity maturation in the attempt to improve activity.
Study Details
In the study, 52 patients with metastatic disease refractory to standard treatments or for which no standard treatment exists were treated at MD Anderson Clinical Center for Targeted Therapy with intravenous MABp1 once every 3 weeks at 0.25 mg/kg (n = 3), 0.75 mg/kg (n = 3), 1.25 mg/kg (n = 3), or 3.75 mg/kg (n = 27). After the dose-escalation phase, another group received MABp1 every 2 weeks at 3.75 mg/kg (n = 16). Patients had 18 different malignancies, including non–small cell lung, colorectal, pancreatic, renal, nasopharyngeal, and thyroid cancers.
Safety and Tolerability
Median follow-up was 228 days. More than 300 infusions were administered with no infusion reactions or immunogenicity. No dose reductions or delays or discontinuations of treatment for toxicity were required, and there were no treatment-related deaths. Since a maximum tolerated dose was not reached, the highest dose administered (3.75 mg/kg every 2 weeks) was selected for use in phase II testing.
Pharmacokinetic data were consistent at all dose levels, with no evidence of accumulation or increased clearance of MABp1 with increasing doses. Among 34 patients who could be restaged, 1 had a partial response and 10 had stable disease. Among 30 assessable patients, lean body mass increased by a mean of 1.02 kg (P = .02) by week 8. The most common adverse events considered possibly related to study drug were proteinuria (21%), nausea (13%), and fatigue (13%). The most common grade 3 or 4 adverse events irrespective of relation to treatment were fatigue (6%), dyspnea (4%), and headache (4%). Two patients (4%) died due to disease progression.
In a post hoc analysis of survival in 14 patients with colorectal cancer, median overall survival was 8.7 months. Median overall survival was 19.3 months in patients with increased lean body mass vs 6.6 months in those with decreased lean body mass (P = .098).
The investigators concluded, “MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted.”
David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.
The study was funded by XBiotech. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
