Phase I Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer

• Published in: The oncologist (Dayton, Ohio) Vol. 27; no. 9; pp. 716 - e689
• Main Authors: Karasic, Thomas B, Brown, Timothy J, Schneider, Charles, Teitelbaum, Ursina R, Reiss, Kim A, Mitchell, Tara C, Massa, Ryan C, O'Hara, Mark H, DiCicco, Lisa, Garcia-Marcano, Luis, Amaravadi, Ravi K, O'Dwyer, Peter J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 02.09.2022
• Subjects: Angiogenesis Inhibitors - therapeutic use; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Benzamides; Care and treatment; Chemotherapy, Combination; Clinical Trial Results; Clinical trials; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Development and progression; Diagnosis; Dosage and administration; Drug therapy; Epigenetic inheritance; Humans; Hydroxychloroquine; Hydroxychloroquine - adverse effects; Medical research; Medicine, Experimental; Metastasis; Phenylurea Compounds - adverse effects; Product development; Pyridines; Testing; Tyrosine; Weight Loss; United States; phase I; autophagy; colorectal cancer; antiangiogenesis; epigenetics
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1093/oncolo/oyac078

The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response. This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy. Twenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed. The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC. NCT03215264.