Introduction
Biological functions of IDO1
The rate-limiting enzyme in the Kyn pathway of Trp metabolism
Expression, function of IDO1 and its relationship with tumor immune escape
Structural biology of IDO1
IDO1 inhibitors and peptide vaccines in clinical trials
Drug | Strategy | Tumor type | Phase | Clinical efficacy | Safety | Trial number | Status |
---|---|---|---|---|---|---|---|
Indoximod | Single agent | Healthy | Phase I | Unknown | Unknown | NCT03372239 | Completed |
Healthy | Early phase I | Unknown | Unknown | NCT03852446 | Completed | ||
Progressive brain tumors or newly diagnosed DIPG | Phase II | Unknown | Unknown | NCT04049669 | Recruiting | ||
Pembrolizumab/nivolumab | Advanced or metastatic melanoma | Phase I/II | Unknown | Unknown | NCT02073123 | Completed | |
Temozolomide | Refractory metastatic prostate cancer | Phase II | Stable disease (SD) 50% | Constipation, diarrhea, fatigue, pain, | NCT01560923 | Completed | |
Adenovirus-p53 transduced dendritic cell (DC) vaccine | Breast cancer | Not applicable | Unknown | Unknown | NCT01302821 | Withdrawn | |
Epacadostat | Single agent | Epithelial ovarian, fallopian tube or primary peritoneal carcinoma | Early phase I | Unknown | Unknown | NCT02042430 | Active, not recruiting |
Locally advanced rectal cancer | Phase I | Unknown | Unknown | NCT03516708 | Recruiting | ||
Pembrolizumab | Gastrointestinal stromal tumors | Phase II | Unknown | Unknown | NCT03291054 | Active, not recruiting | |
Head and neck cancer | Phase II | Unknown | Unknown | NCT03238638 | Withdrawn | ||
Squamous cell carcinoma of the head and neck | Phase II | Unknown | Unknown | NCT03325465 | Withdrawn | ||
Head and neck cancer patients, who failed prior PD-1/PD-L1 therapy | Phase II | Unknown | Unknown | NCT03463161 | Terminated | ||
Advanced pancreatic cancer | Phase II | Unknown | Unknown | NCT03432676 | Withdrawn | ||
Recurrent Clear cell carcinoma of the ovary | Phase II | Unknown | Unknown | NCT03602586 | Suspended | ||
Non-metastatic esophageal/gastroesophageal squamous cell and adenocarcinomas treated with neoadjuvant chemoradiation | Phase II | Unknown | Unknown | NCT03592407 | Withdrawn | ||
Recurrent/metastatic endometrial carcinoma | Phase II | Unknown | Unknown | NCT03310567 | Pembrolizumab | ||
Lung cancer | Phase II | Unknown | Unknown | NCT03322540 | Active, not recruiting | ||
Urothelial cancer (UC) | Phase III | Unknown | Unknown | NCT03374488 | Active, not recruiting | ||
Renal cell carcinoma (RCC) | Phase III | PR: 29.7%, CR + PR: 31.3%, [63] | Anaemia, diarrhoea, hypothyroidism, nausea, fatigue, pruritus | NCT03260894 | Recruiting | ||
Muscle-invasive bladder cancer | Phase II | Unknown | Unknown | NCT03832673 | Not yet recruiting | ||
Head and neck cancer | Phase III | Unknown | Hypothyroidism, vomiting, asthenia | NCT03358472 | Active, not recruiting | ||
Extensive stage small cell lung carcinoma | Phase II | Unknown | Unknown | NCT03402880 | Withdrawn | ||
Pembrolizumab/azacitidine | Metastatic colorectal cancer | Phase I/II | Unknown | Unknown | NCT03182894 | Withdrawn | |
Pembrolizumab/chemotherapy | Advanced solid tumors | Phase I | Unknown | Unknown | NCT02862457 | Active, not recruiting | |
Lung cancer | Phase II | Unknown | Nausea | NCT03322566 | Active, not recruiting | ||
INCB001158/pembrolizumab | Solid tumors | Phase I/II | Unknown | Unknown | NCT03361228 | Terminated | |
Electroporation/pembrolizumab | Squamous cell carcinoma of the head and neck | Phase II | Unknown | Unknown | NCT03823131 | Recruiting | |
Nivolumab/Ipilimumab | Advanced or metastatic malignancies | Phase I/II | Unknown | Unknown | NCT03347123 | Active, not recruiting | |
Nivolumab/chemotherapy | Lung cancer | Phase III | Unknown | Unknown | NCT03348904 | Terminated | |
Nivolumab/chemotherapy | Phase III | Unknown | Unknown | NCT03342352 | Withdrawn | ||
Durvalumab | Unresectable, recurrent, and metastatic EBV + NPC | Phase II | Unknown | Unknown | NCT04231864 | Not yet recruiting | |
Cladribine/cytarabine | Relapsed/refractory AML patients | Phase I | Unknown | Unknown | NCT03491579 | Withdrawn | |
Idarubicin/cytarabine/Daunorubicin | Phase 1 | Phase I | Unknown | Unknown | NCT03444649 | Withdrawn | |
Rapamycin | Advanced malignancy | Phase I | Unknown | Unknown | NCT03217669 | Recruiting | |
INCMGA00012 + RT + bevacizumab | Recurrent gliomas | Phase II | Unknown | Unknown | NCT03532295 | Recruiting | |
M7824 + BN-Brachyury + ALT-803 + Epacadostat (Immunotherapy) | Solid tumor | Phase I/II | Unknown | Unknown | NCT03493945 | Recruiting | |
INCMGA00012, Epacadostat 600 mg BID, SV-BR-1-GM combination | Metastatic or locally recurrent breast cancer patients | Phase I/II | Unknown | Unknown | NCT03328026 | Recruiting | |
Intralesional SD101, Radiotherapy | Advanced solid tumors lymphoma | Phase I/II | Unknown | Unknown | NCT03322384 | Recruiting | |
Itacitinib/INCB050465 | Solid tumors | Phase I | Unknown | Unknown | NCT02559492 | Terminated | |
BMS-986205 | Single agent | Healthy volunteers | Phase I | Unknown | Unknown | NCT03378310 | Completed |
NCT03374228 | |||||||
NCT03312426 | |||||||
NCT03362411 | |||||||
NCT03247283 | |||||||
Nivolumab | Advanced malignant solid tumors | Phase I/ II | Unknown | Unknown | NCT03792750 | Active, not recruiting | |
Recurrent or persistent endometrial carcinoma or endometrial carcinosarcoma | Phase II | Unknown | Unknown | NCT04106414 | Recruiting | ||
Squamous cell carcinoma of the head and neck | Phase II | Unknown | Unknown | NCT03854032 | Recruiting | ||
Resectable stage III or IV melanoma | Phase II | Unknown | Unknown | NCT04007588 | Withdrawn | ||
Relatlimab/nivolumab | Advanced malignant tumors | Phase I/ II | Unknown | Unknown | NCT03459222 | Recruiting | |
Nivolumab/BCG | BCG-unresponsive, high-risk, non-muscle invasive bladder cancer | Phase II | Unknown | Unknown | NCT03519256 | Recruiting | |
Itraconazole/rifampin | Malignancies multiple | Phase I | Unknown | Unknown | NCT03346837 | Completed | |
Nivolumab/chemotherapy | Muscle-invasive bladder cancer | Phase III | Unknown [64] | NCT03661320 | Recruiting | ||
Nivolumab/radiotherapy or chemoradiotherapy | Glioblastoma | Phase I | Unknown | Unknown | NCT04047706 | Recruiting | |
Omeprazole | Healthy | Phase I | Unknown | Unknown | NCT03936374 | Completed | |
Navoximod (GDC-0919, NLG-919) | Single agent | Recurrent advanced solid tumors | Phase I | Fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%) | NCT02048709 | Completed | |
PF-06840003 | Single agent | Malignant glioma | Phase I | Grade 4 alanine and aspartate aminotransferase elevations | NCT02764151 | Terminated | |
KHK2455 | Avelumab | Urothelial carcinoma | Phase I | Unknown | Unknown | NCT03915405 | Recruiting |
Mogamulizumab | Locally advanced or metastatic solid tumors | Phase I | Unknown | Unknown | NCT02867007 | Active, not recruiting | |
LY3381916 | Single agent or in combination with anti-programmed cell death ligand 1 (PD-L1) checkpoint antibody (LY3300054) | Solid tumor, non-small cell lung cancer, renal cell carcinoma, triple negative breast cancer | Phase I | Unknown | Unknown | NCT03343613 | Terminated |
Indoximod (1-methyl-D-tryptophan, 1MT, NLG-8189)
Epacadostat (INCB024360)
BMS-986205
Navoximod (GDC-0919, NLG-919)
PF-06840003
Other inhibitors
Peptide vaccines for IDO1
Medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials
Epacadostat (INCB024360)
Species | CL (L/h/kg) | Vss (L/kg) | iv t1/2 (h) | AUC (μM h) | F (%) | t1/2 (h) |
---|---|---|---|---|---|---|
Rat | 1.1 | 2.0 | 1.4 | 1.3 | 11 | 2.2 |
Dog | 0.5 | 0.7 | 3.1 | 29 | 59 | 4.9 |
Cyno | 0.8 | 1.8 | 3.3 | 9.3 | 33 | 2.7 |
BMS-986205
Species | CL (mL/min/kg) | Vss (L/kg) | t1/2 (h) | F (%) |
---|---|---|---|---|
Rat | 27 | 3.8 | 3.9 | 4 |
Dog | 25 | 5.7 | 4.7 | 39 |
Cyno | 19 | 4.1 | 6.6 | 10 |
PF-06840003
Species | CL (mL/min/kg) | Vss (L/kg) | t1/2 (h) | F (%) | AUC (ng h/mL) |
---|---|---|---|---|---|
Rat | 3.7 | 0.639 | 2.42 | 94.0 | 6940 |
Dog | 24.3 | 0.957 | 0.840 | 18.6 | 237 |
Human | 0.64 | 1.1 | 19 | 64 | ND |
Navoximod (GDC-0919, NLG-919)
Species | CL (mL/min/kg) | Cmax (ng/mL) | t1/2 (h) | F (%) | AUC (ng h/mL) |
---|---|---|---|---|---|
Rat | 44.6 | 1560 | 1.44 | 41.5 | 3930 |
Mice | 27.5 | 2257 | 3.9 | 69.0 | 6132 |
Dog | 53.7 | 1400 | 4.8 | 22.3 | 3127 |
The effector inhibitor indoximod (1-methyl-D-tryptophan, 1MT, NLG-8189) and its prodrug NLG802
Compound | Dose (μM/kg) | Cmax (μM) | AUC0–24 (μM h) | t1/2 (h) |
---|---|---|---|---|
Indoximod (5) | 143 | 9.3 ± 2.2 | 36.4 ± 9 | 3 |
287 | 17.2 ± 3.7 | 77.7 ± 21.6 | 2.8 | |
573 | 26 ± 11.1 | 153.6 ± 79.2 | 3.1 | |
1147 | 51.7 ± 25.4 | 348.2 ± 115.2 | 3.4 | |
NLG802 (6) | 143 | 35 ± 25.3 | 105.4 ± 68.5 | 2.9 |
287 | 68.9 ± 3.9 | 142.3 ± 64.6 | 2.2 | |
573 | 65.7 ± 34.1 | 150.8 ± 76.1 | 3.1 | |
1147 | 101.4 ± 38.9 | 374.3 ± 180.7 | 3.2 |