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: 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
• Journal: International journal of oncology (Int J Oncol) Vol. 45 Issue 6 Pg. 2221-31 (Dec 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25270361 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Neoplasm Proteins
• Transforming Growth Factor beta1

Topics

• Adenocarcinoma (drug therapy, immunology, pathology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug-Related Side Effects and Adverse Reactions
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Proteins (biosynthesis)
• Neoplasms (drug therapy, immunology, pathology)
• Transforming Growth Factor beta1 (antagonists & inhibitors, immunology)