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
Mené sur 65 patients atteints d'une tumeur solide (dont 58 patients atteints d'un gliome), cet essai de phase I évalue la dose maximale tolérée et l'activité clinique d'un composé appelé LY2157299, un inhibiteur de la signalisation du facteur de croissance de transformation bêta
Purpose: Transforming growth factor-beta (TGF-β) signaling plays a key role in tumor progression, including malignant glioma. Small molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGF-β signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a First-in-Human Dose (FHD) study in cancer patients. 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. Anti-tumor 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 12/56 patients with glioma (21.4%). LY2157299 was safe with no cardiac adverse events. Conclusions: Based on the safety, PK and antitumor activity in glioma patients, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.