A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors

• Type of Material: Article
• Authors: Hatem H. Soliman, University of South Florida; Erica Jackson, University of South Florida; Tony Neuger, University of South Florida; E. Claire Dees, University of North Carolina; R. Harvey, Emory University; Hyo Han, University of South Florida; Roohi Ismail-Khan, University of South Florida; Susan Minton, University of South Florida; Nicholas N. Vahanian, NewLink Genetics Inc.; Charles Link, NewLink Genetics Inc.; Daniel M. Sullivan, University of South Florida; Scott Antonia, University of South Florida
• Language: English
• Date: 2014-09-30
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Soliman et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.2357
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 5
• Issue: 18
• Start Page: 8136
• End Page: 8146
• Grant/Funding Information: This trial was conducted by the Southeast Phase 2 N01 Consortium under NCI contract #HHSN261201100100C.
• Keywords: Cell Biology; INHIBITION; Oncology; indoleamine 2; TRYPTOPHAN CATABOLISM; Life Sciences & Biomedicine; INDOLEAMINE 2,3-DIOXYGENASE; docetaxel; RESISTANCE MECHANISM; Science & Technology; CHEMOTHERAPY; SUPPRESSION; BREAST-CANCER; 3 dioxygenase; Indoximod; immunomodulator; IMMUNE-SYSTEM; 1-methyl-D-tryptophan; TRASTUZUMAB; IPILIMUMAB
• Research Categories: Health Sciences, Oncology

Abstract

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod. METHODS: Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.