Abstract A211: A phase I study of MABp1, a first-in-human, first-true human monoclonal antibody against the IL-1 in patients with advanced cancers.
Authors: Hong David S. , Naing Aung , Falchook Gerald S. , Piha-PAul Sarina , Wheler Jennifer J. , Fu Siqing , Tsimberidou Apostolia M. , Hui David , Scott Rebecca , Khan Rabia , Mistry Reena , Talley Julia , Chauhan Seema , Bermudez Derrick , Stecher Michael , Simard John , Kurzrock Razelle 
Published: June 2012

Background: IL-1 is associated with pathological inflammatory responses, including inflammation that supports a malignant phenotype in the tumor microenvironment. Targeting IL-1α may reduce tumor potential by undermining one or more aspects of tumor-driven angiogenesis, tissue matrix remodeling and metastasis. MABp1 is a true human therapeutic antibody generated by a natural human immune response and was cloned directly from a human peripheral B lymphocyte. MABp1 binds IL-1α with high-affinity and is a potent blocker of IL-1α biological activity. Blocking IL-1α activity using MABp1 may be a safe and effective means of interrupting the chronic inflammatory response that supports tumor growth and invasiveness.

Methods: This is an open label, first-in-man, phase I trial of MABp1 in patients with advanced cancers both metastatic and refractory to standard of care treatment. The trial included two dosing arms: arm A (4 levels of MABp1, administered once every 3 weeks); arm B consisted of the highest dose concentration in arm A administered once every 2 weeks. The trial followed a 3+3 design. Pharmacokinetics was measured at pre-screening and on days 1 (post-infusion), 8 and 15 during each cycle for the first 3 cycles and on day 1 of each subsequent cycle post-infusion. Pharmacodynamic sampling of CRP, IL-6 and IL-1 receptor antagonist (IL-1RA) occurred at screening and on days 1, 8 and 15 of each cycle.

Results: Thirty-six patients were enrolled in arm A. Enrollment in arm B, the biweekly dosing cohort, is still ongoing. Pharmacokinetic investigation of patients in the highest dosing cohort of arm A showed an average peak serum concentration of 80 micrograms per milliliter, with a half-life of approximately 3 days. The most common possibly drug related adverse events (AEs) included 7 patients with grade I-II proteinuria (19%), 5 patients with grade I nausea (14%), and 4 patients with grade I-II fatigue (11%). A maximum dose of 3.75 mg/kg was reached on arm A, the highest dose concentration, with one dose-limiting toxicity (DLT) of a possibly drug-related infection. Of the 36 patients enrolled in arm A, 6 patients had (17%) had stable disease for &gt;6 months (colorectal (CRC), Castleman's lymphoma, rectal, non-small cell lung (NSCLC), neuroendocrine, pseudomyxoma peritonei. One patient with KRAS+ CRC had a PR (−33% by RECIST) and continued on study for 18 months. Low IL-1RA at baseline (&lt;400 pg/ml) was associated with patients with PR or on study &gt;6 months.

Conclusions: MABp1 was well tolerated with minimal AEs at the 3.75 mg/kg dose given every 3 weeks. MABp1 showed evidence of anti-tumor activity and altered disease progression in CRC, NSCLC, and other tumor subtypes. Reducing tumor-driven inflammation through IL-1α antagonism may be an effective disease modifying anti-cancer agent in advanced stage disease. Patient responses and an association of positive outcomes with low baseline IL1-RA levels support this finding. Further study is warranted in advanced cancers with MABp1.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A211.