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A phase I study of indoximod in patients with advanced malignancies.

ABSTRACT: 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 ?M 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.

SUBMITTER: Soliman HH

PROVIDER: S-EPMC5008412 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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A phase I study of indoximod in patients with advanced malignancies.

Soliman Hatem H HH Minton Susan E SE Han Hyo Sook HS Ismail-Khan Roohi R Neuger Anthony A Khambati Fatema F Noyes David D Lush Richard R Chiappori Alberto A AA Roberts John D JD Link Charles C Vahanian Nicholas N NN Mautino Mario M Streicher Howard H Sullivan Daniel M DM Antonia Scott J SJ

Oncotarget 20160401 16

<h4>Purpose</h4>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.<h4>Experimental design</h4>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/d ...[more]

PMID: 27008709

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A phase I study of indoximod in patients with advanced malignancies.

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A phase I study of indoximod in patients with advanced malignancies.

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