Clinical and Biological Effects of an Agonist Anti- XXXX Antibody: A Cancer Research UK Phase I Study.

@entity1 @entity10911 @entity137 @entity1075 @entity5 @entity2936 @entity12868 @entity1892 @entity2071
PURPOSE: This phase I study aimed to establish the biologic effects and MTD of the agonistic IgG1 chimeric anti- @entity2936 antibody ChiLob7/4 in @entity1 (pts) with a range of @entity2936 -expressing solid @entity5 and diffuse large @entity1892 , resistant to conventional therapy. Potential mechanisms of action for agonistic anti- @entity2936 include direct cytotoxic effects on @entity5 cells and conditioning of antigen-presenting cells. EXPERIMENTAL DESIGN: ChiLob7/4 was given by IV infusion weekly for 4 doses at a range from 0.5 to 240 mg/dose. Validated ELISAs were used to quantify ChiLob7/4 in serum and test for anti-chimeric MAb (HACA) responses. Pharmacodynamic assessments included quantitation of T-cell, natural killer-cell, and B-cell numbers and activation in blood by flow cytometry and a panel of cytokines in plasma by Luminex technology. Planned dose escalation was in cohorts of 3 @entity1 until MTD or biologic effect, defined as reduction of peripheral blood @entity1075 (+) B cells to 10% or less of baseline. RESULTS: Twenty-nine courses of treatment were given to 28 subjects. The MTD was 200 mg * 4, with dose-limiting @entity137 of liver transaminase elevations at 240 mg. At 200 mg (range between 2.1 mg/kg and 3.3 mg/kg based on @entity1 body weight), the trough level pretreatment was above 25  g/mL. Grade 1-2 infusion reactions were seen above the dose of 16 mg, but could be prevented with single-dose corticosteroid premedication. HACA responses were seen after doses between 1.6 mg and 50 mg, but not above this. There were dose-dependent falls in blood B-cell numbers accompanied by reduced expression of @entity10911 , and transient reductions in NK cell numbers with increased @entity2071 expression from 50 mg upward. @entity12868 and IL12 plasma concentrations rose after doses above 16 mg. Fifteen of 29 treatments were accompanied by disease stabilization for a median 6 months, the longest for 37 months. CONCLUSIONS: ChiLob7/4 can activate B and NK cells at doses that can be administered safely, and should be tested in combination with other antibodies and chemotherapy agents. Clin Cancer Res; 21(6); 1321-8.   2015 AACR.
