title: A phase I dose-escalation study to a predefined dose of a transforming growth factor-β1 monoclonal antibody (TβM1) in patients with metastatic cancer.
abstract: Transforming growth factor β (TGF-β) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-β ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TβM1 is a humanized mAb optimized for neutralizing activity against TGF-β1. The objective of this clinical trial was to assess the safety and tolerability of TβM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤ 2 on the ECOG scale were administered TβM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TβM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TβM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-β1 expression signature in patients' whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study.
authors.affiliation: Rocky Mountain Cancer Center - Midtown, Denver, CO, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Cohn
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Williams
authors.affiliation: Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Cleverly
authors.affiliation: Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Pitou
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Kadam
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Farmen
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Durisala
authors.initials: D
authors.lastname: Desaiah
authors.affiliation: Innovation Center Kettering Medical Center, Kettering, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Raju
authors.affiliation: Virginia Oncology Associates, Norfolk, VA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Conkling
authors.affiliation: Tyler Cancer Center, Tyler, TX, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Richards
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009363:Neoplasm Proteins; D053773:Transforming Growth Factor beta1