P2, N=51, Active, not recruiting, Washington University School of Medicine | Trial primary completion date: Apr 2024 --> Jul 2024

P1/2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=113 --> 53

The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.

P1, N=17, Active, not recruiting, National Cancer Institute (NCI)

The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Consequently, this activation enables tumor cells to survive even in the face of heightened immune activity. These findings underscore the unforeseen adverse effects of apo-IDO1 inhibitors on tumor cells and highlight the potential of combining IL-6/JAK2/STAT3 inhibitors with apo-IDO1 inhibitors to improve their clinical efficacy.

Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

P3, N=861, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Nov 2023 --> Apr 2025

P3, N=89, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> Dec 2024

P1/2, N=113, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Efforts are underway to identify the proteome-wide direct target of BMS in CLL cells. In conclusion, our limited and preliminary data suggest that BMS could be considered as a potential therapeutic strategy to target CLL cells with a double hit: by blocking the pro-survival effect of BCR signaling, one of the driving forces for CLL cell survival and proliferation, and by inhibiting IDO1/kynurenine action to restore sensitivity to key leukemia treatments.

By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.

The quantitative method was validated according to FDA, ICH and EMA guidelines, later applied: i) to assess the impact of selective inhibition of hIDO1 or hTDO (human tryptophan 2,3-dioxygenase) on the kynurenine pathway in A375 (melanoma), MDA-MB-231 (breast cancer), and U87 (glioblastoma) cell lines using multivariate analysis (MVA); ii) to determine the IC values of both well-known (i.e., epacadostat, linrodostat) and the novel hIDO1 inhibitor (i.e., BL5) in the aforementioned cell lines. The proposed LC-MS/MS method is reliable and robust. Furthermore, it is highly versatile and suitable for applications in the preclinical drug research and in vitro assays.

This study aims to investigate the regulatory effects of Astragalus polysaccharide(APS) and APS combined with 5-fluorouracil(5-FU) on indoleamine-2,3-dioxygenase(IDO1) in the colon tumor microenvironment...The APS + 5-FU group showed significantly reduced infiltration of CD4~+ T lymphocytes and increased infiltration of CD8~+ T lymphocytes. APS inhibited the expression of IDO1 in the colon tumor microenvironment to increase CD8~+ T lymphocyte infiltration, and the combination of APS with 5-FU demonstrated better effect.

P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Sep 2024

Our pre-clinical study suggests that epacadostat is a candidate HCC immuno-preventive agent to be considered for early clinical testing in NAFLD patients at risk of developing HCC.

P1, N=33, Not yet recruiting, Antido Therapeutics (Australia) Pty Ltd

She was treated with standard concurrent chemotherapy and radiation, as well as a 2-year period of adjuvant temozolomide. She relapsed 2 ½ years after starting her initial therapy and was treated with bevacizumab and lomustine, but she relapsed. She was then placed on a phase 1/2 clinical trial that included KHK2455 and mogamulizumab-kpkc individually and in combination for almost 4 years. She had a rapid demise due to the development of a neutropenic pneumonia and treatment-induced acute myeloid leukemia (AML) and elected for hospice care.

P1, N=18, Active, not recruiting, Northwestern University | N=30 --> 18 | Trial primary completion date: Feb 2022 --> Feb 2024

Methods This is a cohort study performed at Karolinska University Hospital in Sweden including 98 subjects with advanced CMM (M1a-d), who received anti-PD1 alone (n=88), anti-PD1+ epacadostat (clinical trial, n=3) or ipilimumab + nivolumab (n=8) as 1st line therapy in most cases (85%). Conclusions Patients developing a GC-irAE had significantly increased PFS and OS compared to the other patients. Further studies on potential biomarkers for risk of developing hypophysitis are warranted to timely avoid serious complications.

The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities with few grade 3 toxicities; produced stable disease in 33% of patients. The PK of SE results were consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion with E levels observed across the three dose cohorts consistent with previously reports. Due to the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality.

Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.

P2, N=49, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | Trial completion date: Apr 2028 --> Apr 2026 | Trial primary completion date: Jan 2025 --> Apr 2024

P2, N=24, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

The combination treatment of Abrine and anti-PD-1 antibody has a synergistic effect on suppressing the tumor growth through up-regulating CD4 or CD8 T cells, down-regulating the Foxp3 Treg cells, and inhibiting the expression of IDO1, CD47, and PD-L1. Overall, this study reveals that Abrine as an IDO1 inhibitor has an inhibition effect on immune escape and has a synergistic effect with the anti-PD-1 antibody on the treatment of HCC.

We previously reported that cisplatin-resistant (CR) tumors survive via oxidative metabolism and amino acid uptake, reducing immunosurveillance and viable cytotoxic T-cell populations...Inhibiting IDO1 (epacadostat; 200mg/kg/day; PO) reduced tumor growth (30%, n=7; p<0.05) in CR-bearing mice but induced the expression of tryptophan 2,3-dioxygenase-2 (TDO2) (alternate tryptophan degrading enzyme)...Dual IDO1/TDO2 inhibition potently reduced tumor growth and enhanced tumor immunosurveillance in CR NSCLC in vivo models. These results may inform: (i) how the KYN pathway can be exploited in treating CR NSCLC, (ii) the future application of immunotherapy, based on an improved understanding of how CRcells evade immune surveillance.; Public health; Endoscopy and interventional pulmonology; Cell and molecular biology; General respiratory patient care; Respiratory intensive care; Epidemiology; Surgery

Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.

P1/2, N=39, Recruiting, Washington University School of Medicine | Phase classification: P1 --> P1/2 | Trial completion date: Jun 2027 --> Aug 2030 | Trial primary completion date: Dec 2026 --> Jul 2027

Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

P2, N=142, Terminated, Bristol-Myers Squibb | N=69 --> 142 | Completed --> Terminated; Insufficient Enrollment

Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.

P3, N=129, Active, not recruiting, Incyte Corporation | Trial completion date: Feb 2023 --> Dec 2024

In our study, the therapeutic potentials of two different IDO inhibitors (Epacadostat [EPA] and 1-methyl-L-tryptophan [L-1MT]) in triple-negative breast cancer (TNBC) cells were assessed with and without tumor necrosis factor-α (TNF-α) stimulation...Our findings showed that the efficacy of IDO inhibitors was mediated by pro-inflammatory cytokine. However, different molecular signaling pathways are associated with pro-inflammatory cytokines production, and the expression of IDO1 and PD-L1 calls for further investigations.

Although epacadostat was effective in preclinical models and in early phase trials, it gave negative results in a metastatic melanoma randomized phase III study to test the benefit of adding epacadostat to the reference pembrolizumab therapy. Our data suggest that a possible explanation of epacadostat ineffectiveness may rely on the ability of this drug to enhance the other IDO1 immunoregulatory mechanism, involving intracellular signaling function. These findings open up a new perspective for IDO1 inhibitors developed as new anticancer drugs, which should be carefully evaluated for their ability to block not only the catalytic but also the signaling activity of IDO1.

P1, N=15, Active, not recruiting, Chao Huang | Trial completion date: Aug 2023 --> Aug 2025 | Trial primary completion date: Apr 2023 --> Apr 2024

In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.

Additionally, Lip-EPA + Lip-gp100 significantly modulated intratumoral regulatory T cells which altogether resulted in the highest delay in tumor growth (TGD = 56.54%) and increased life span (ILS > 47.36%) in treated mice. Our study demonstrated that novel combination of Lip-EPA and Lip-gp100 was effective treatment with capability of being used in further clinical studies.

P1, N=30, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting | Trial completion date: Jun 2023 --> Jun 2025

Selective and potent inhibition of TDO2 does effectively block L-Kynurenine synthesis in the uterus but does not improve the menstrual bleeding pattern in a murine HMB disease model. As the transgenic TDO2 model does not completely mimic L-Kynurenine levels released by uterine fibroids, the predictive validity of this model might be limited. Further models are needed to understand the functional role of TDO2 in uterine fibroids and the pathophysiology of heavy menstrual bleeding.

We have identified and characterized crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells in which CR cells possessed higher indoleamine 2,3-dioxygenase-1 (IDO1) activity as determined by an increase in extracellular kynurenine concentration in vitro and in vivo...Inhibition of IDO1 by the selective IDO1 inhibitor epacadostat (200 mg/kg P.O. once a day for 15 days) attenuated tumor growth in these CR tumor-bearing mice...Support by Dept. of Veterans.

Similarly, when WT 4T1 tumor-bearing mice were administered GSK2656157 together with the IDO1 inhibitors Epacadostat, Indoximod or Navoximod, the attenuated neovascularization and elevated regional hypoxia in lung metastases elicited by IDO1 inhibition was accompanied by an increased level of tumor cell death. Co-administration of the hypoxia-activated prodrug Evofosfamide with Epacadostat likewise resulted in elevated metastatic tumor cell death. This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy.