A Phase I study of indoximod in patients with advanced malignancies

被引：114

作者：

Soliman, Hatem H. ^{[1
]}

Minton, Susan E. ^{[1
]}

Han, Hyo Sook ^{[1
]}

Ismail-Khan, Roohi ^{[1
]}

Neuger, Anthony ^{[1
]}

Khambati, Fatema ^{[1
]}

Noyes, David ^{[1
]}

Lush, Richard ^{[1
]}

Chiappori, Alberto A. ^{[1
]}

Roberts, John D. ^{[2
]}

Link, Charles ^{[3
]}

Vahanian, Nicholas N. ^{[3
]}

Mautino, Mario ^{[3
]}

Streicher, Howard ^{[4
]}

Sullivan, Daniel M. ^{[1
]}

Antonia, Scott J. ^{[1
]}

机构：

[1] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA

[2] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA

[3] NewLink Genetics Inc, Ames, IA USA

[4] NCI, Canc Therapeut Evaluat Program, Bethesda, MD 20892 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 16期

关键词：

indoleamine 2,3 dioxygenase; 1-methyl-D-tryptophan; indoximod; immunomodulator; INDOLEAMINE 2,3-DIOXYGENASE IDO; T-CELL; TUMOR-SUPPRESSOR; DENDRITIC CELLS; TRYPTOPHAN; BIN1; INHIBITION; EXPRESSION; MELANOMA; CANCER;

D O I：

10.18632/oncotarget.8216

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (similar to 12 mu 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.

引用

页码：22928 / 22938

页数：11

共 29 条

[1] A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type IIFN signaling following B7 ligation [J].