A phase I dose-escalation study to a predefined dose of a transforming growth factor-β1 monoclonal antibody (TβM1) in patients with metastatic cancer

Cohn,Allen; Lahn,Michael M.; Williams,Kristen E.; Cleverly,Ann L.; Pitou,Celine; Kadam,Sunil K.; Farmen,Mark W.; Desaiah,Durisala; Raju,Robert; Conkling,Paul; Richards,Donald

doi:10.3892/ijo.2014.2679

A phase I dose-escalation study to a predefined dose of a transforming growth factor-β1 monoclonal antibody (TβM1) in patients with metastatic cancer

Authors:
- Allen Cohn
- Michael M. Lahn
- Kristen E. Williams
- Ann L. Cleverly
- Celine Pitou
- Sunil K. Kadam
- Mark W. Farmen
- Durisala Desaiah
- Robert Raju
- Paul Conkling
- Donald Richards
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Affiliations: Rocky Mountain Cancer Center - Midtown, Denver, CO, USA, Eli Lilly and Company, Indianapolis, IN, USA, Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK, Innovation Center Kettering Medical Center, Kettering, OH, USA, Virginia Oncology Associates, Norfolk, VA, USA, Tyler Cancer Center, Tyler, TX, USA
Published online on: September 26, 2014 https://doi.org/10.3892/ijo.2014.2679
Pages: 2221-2231
Copyright: © Cohn et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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