A phase I study of indoximod in patients with advanced malignancies

Authors: Hatem Soliman, Susan Minton, Hyo S. Han, Roohi Ismail‐Khan, Anthony Neuger, Fatema Khambati, David Noyes, Richard M. Lush, Alberto Chiappori, John D. Roberts, Charles Link, Nicholas N. Vahanian, Mario R. Mautino, Howard Streicher, Daniel M. Sullivan, Scott Antonia - Oncotarget 2016 cited by 144

// Hatem H. Soliman 1 , Susan E. Minton 1 , Hyo Sook Han 1 , Roohi Ismail-Khan 1 , Anthony Neuger 1 , Fatema Khambati 1 , David Noyes 1 , Richard Lush 1 , Alberto A. Chiappori 1 , John D. Roberts 2 , Charles Link 3 , Nicholas N. Vahanian 3 , Mario Mautino 3 , Howard Streicher 4 , Daniel M. Sullivan 1 and Scott J. Antonia 1 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 Correspondence to: 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 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 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.