title: A phase I study of indoximod in patients with advanced malignancies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Soliman
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Minton
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Hyo Sook
authors.initials: HS
authors.lastname: Han
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Roohi
authors.initials: R
authors.lastname: Ismail-Khan
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Neuger
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Fatema
authors.initials: F
authors.lastname: Khambati
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: David
authors.initials: D
authors.lastname: Noyes
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: NewLink Genetics Inc., Ames, Iowa, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Link
authors.affiliation: NewLink Genetics Inc., Ames, Iowa, USA.
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Vahanian
authors.affiliation: NewLink Genetics Inc., Ames, Iowa, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Mautino
authors.affiliation: Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Streicher
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Antonia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014364:Tryptophan / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; C525396:1-methyltryptophan
keywords: 1-methyl-D-tryptophan; 3 dioxygenase; immunomodulator; indoleamine 2; indoximod