346 Phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of GDC-0919 in patients with recurrent/advanced solid tumors

Nayak, Asha; Hao, Zhonglin; Sadek, Ramses; Dobbins, Robin; Marshall, L.; Vahanian, Nicholas N.; Ramsey, Jay; Kennedy, Eugene P.; Mautino, Mario R.; Link, Charles J.; Lin, Ray; Royer-Joo, Stephanie; Morrissey, Kari M.; Mahrus, Sami; McCall, Bruce; Pirzkall, Andrea; Munn, David H.; Janik, John E.; Khleif, Samir N.

doi:10.1016/s0959-8049(16)30209-x

Cited by 19 publications

(14 citation statements)

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“…Later development of an imidazoisoindole series incorporated some of these insights but also yielded novel information incorporated into the clinical lead navoximod (92, 93) (Figure 6E). X-ray structural information shows that the ring planes of the PI and imidazoisoindole series assume similar but not identical positions in the active site (94).…”

Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

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Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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Small molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds – indoximod, epacadostat and navoximod – that were first to be evaluated as IDO inhibitors in clinical trials. As ‘immunometabolic adjuvants’ to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic.

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Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

“…In patients with recurrent/advanced solid tumors and the safety, pharmacokinetic and pharmacodynamic results from a Phase 1A study have been reported (93). As monotherapy, it was well tolerated at up to 600 mg twice daily on a 21/28 day cycle, with stable disease observed in 7/17 patients.…”

Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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“…In the clinical setting, GDC-0919 has been studied as monotherapy so far in patients with recurrent/advanced solid tumors and the safety, pharmacokinetic and pharmacodynamic results from the Phase 1a study were reported (Nayak et al , 2015). Overall, GDC-0919 was well tolerated up to 800 mg BID on a 21/28 day cycle.…”

Section: Lead Clinical Agents: Indoximod Epacadastat and Gdc-0919/namentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Prendergast

Malachowski

Mondal

et al. 2018

International Review of Cell and Molecular Biology

233

214

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The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance ‘immunogenic’ chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation and metastasis beyond effects on adaptive immune tolerance. Discovery and development of small molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in Phase II/III human trials (epacadastat and GDC-0919/navoximod, respectively). Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer.

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“…Subsequently Kumar moved to NewLink Genetics Corporation where the medicinal chemistry effort yielded an imidazoisoindole series of Trp non-competitive inhibitors that was developed independently. From this root navoximod was ultimately generated as a clinical lead compound [125, 126]. Structural information demonstrated that the ring planes of the phenylimidazole and imidazoisoindole classes were oriented slightly differently in the active site [127], consistent with distinct SAR.…”

Section: Therapeutic Approaches To Block Ido Functionmentioning

confidence: 99%

“…In mice, its administration reduced plasma Kyn levels by ~50% and enhanced vaccine responses against B16 melanoma or the efficacy of anti-PD-L1 against EMT6 mammary carcinoma in a manner associated with elevated CD8+ T/Treg ratios, plasma interferon-γ levels, and activated intratumoral macrophages and DC [128]. Early clinical studies showed it to be well tolerated up to 600 mg twice daily with some evidence of cancer control [126, 129]. …”

Section: Therapeutic Approaches To Block Ido Functionmentioning

confidence: 99%

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

Prendergast¹,

Mondal²,

Dey³

et al. 2018

Trends in Cancer

146

116

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We discuss how small molecule inhibitors of the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDOi) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO activation in cancer supports inflammatory processes that IDOi can re-program to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes TDO and IDO2 may also safely broaden efficacy. Understanding IDOi as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting its collateral damage.

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346 Phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of GDC-0919 in patients with recurrent/advanced solid tumors

Cited by 19 publications

References 0 publications

Discovery of IDO1 Inhibitors: From Bench to Bedside

Discovery of IDO1 Inhibitors: From Bench to Bedside

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

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