A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors
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// Hatem H. Soliman 1 , Erica Jackson 2 , Tony Neuger 1 , E. Claire Dees 3 , R. Donald Harvey 4 , Hyo Han 1 , Roohi Ismail-Khan 1 , Susan Minton 1 , Nicholas N. Vahanian 5 , Charles Link 5 , Daniel M. Sullivan 1 , Scott Antonia 1 1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 2 University of South Florida, Tampa, FL 3 University of North Carolina/Lineberger Cancer Center, Chapel Hill, NC 4 Winship Cancer Institute of Emory University, Atlanta, GA 5 NewLink Genetics Inc, Ames, IA Correspondence to: Dr. Hatem Soliman MD, e-mail: Hatem.soliman@moffitt.org Keywords: Indoximod, 1-methyl-D-tryptophan, immunomodulator, docetaxel, indoleamine 2, 3 dioxygenase Received: June 12, 2014 Accepted: August 16, 2014 Published: August 21, 2014 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/m 2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m 2 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.
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Prior studies demonstrated that serum Kyn:Trp correlates with response to anti-PD-1.
“Prior studies have demonstrated serum Kyn:Trp correlate with response to anti-PD-1 (76,77)”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [77]
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- Authors
- Soliman, H. H., Jackson, E., Neuger, T., Dees, E. C., Harvey, R. D., Han, H., Ismail-Khan, R., Minton, S., Vahanian, N. N., Link, C., Sullivan, D. M., & Antonia, S.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- University of North Carolina at Chapel Hill (US)
- Winship Cancer Institute (US)
- NewLink Genetics (United States) (US)
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2014-09-30
- Volume
- 5
- Issue
- 18
- Pages
- 8136-8146
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4226672
- OpenAlex
- W1502816311
- Cited by
- 174
- References
- 26
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 8 · 2023: 7 · 2022: 3 · 2021: 19 · 2020: 13 · 2019: 17 · 2018: 32 · 2017: 28 · 2016: 15 · 2015: 18 · 2013: 1
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Emory University
- Moffitt Cancer Center
- Winship Cancer Institute
- National Cancer Institute (HHSN261201100100C, P30CA076292)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- indoximod, docetaxel, indoleamine 2,3-dioxygenase inhibition, oral immunomodulator, metastatic solid tumors, combination chemotherapy, dose-limiting toxicity, recommended phase 2 dose, immunosuppression, 1-methyl-D-tryptophan, serum drug concentration, enterocolitis
- MeSH terms
- Docetaxel, Administration, Oral, Adult, Antineoplastic Combined Chemotherapy Protocols, Drug Administration Schedule, Female, Florida, Humans, Immunologic Factors, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, Time Factors, Tryptophan, Treatment Outcome, Drug Monitoring, Maximum Tolerated Dose, Taxoids, Administration, Intravenous
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