Clinical Research Papers:
A phase I study of indoximod in patients with advanced malignancies
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Hatem H. Soliman1, Susan E. Minton1, Hyo Sook Han1, Roohi Ismail-Khan1, Anthony Neuger1, Fatema Khambati1, David Noyes1, Richard Lush1, Alberto A. Chiappori1, John D. Roberts2, Charles Link3, Nicholas N. Vahanian3, Mario Mautino3, Howard Streicher4, Daniel M. Sullivan1 and Scott J. Antonia1
1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
2 Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
3 NewLink Genetics Inc., Ames, Iowa, USA
4 Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA
Hatem H. Soliman, email:
Keywords: indoleamine 2,3 dioxygenase, 1-methyl-D-tryptophan, indoximod, immunomodulator
Received: February 11, 2016 Accepted: March 10, 2016 Published: March 20, 2016
Purpose: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates.
Experimental Design: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption.
Results: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels.
Conclusions: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.
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