First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma

Jordi Rodon, Michael A. Carducci, Juan M. Sepulveda-Sánchez, Analia Azaro, Emiliano Calvo, Joan Seoane, Irene Braña, Elisabet Sicart, Ivelina Gueorguieva, Ann L. Cleverly, N. Sokalingum Pillay, Durisala Desaiah, Shawn T. Estrem, Luis Paz-Ares, Matthias Holdhoff, Jaishri Blakeley, Michael M. Lahn, Jose Baselga

    Research output: Contribution to journalArticleResearchpeer-review

    134 Citations (Scopus)

    Abstract

    ©2014 AACR. Purpose: TGFβ signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFβ signaling and reduce tumorprogressionin preclinicalmodels. Touse LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer. Experimental Design: Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria. Results: In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events. Conclusions: On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.
    Original languageEnglish
    Pages (from-to)553-560
    JournalClinical Cancer Research
    Volume21
    Issue number3
    DOIs
    Publication statusPublished - 1 Feb 2015

    Fingerprint Dive into the research topics of 'First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma'. Together they form a unique fingerprint.

    Cite this