IDH1 mutation

Finally, we demonstrate that our results extend to other demographic factors beyond patient race. Given these findings, we encourage regulatory and policy agencies to integrate demographic-stratified evaluation into their assessment guidelines.

P1, N=78, Active, not recruiting, Symphogen A/S | N=148 --> 78 | Trial completion date: Jan 2025 --> Jun 2024

Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

Significantly, compound 23h has the ability to cross the blood-brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

One (5.3%) patient proceeded to a hematopoietic stem cell transplant by data cut-off. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in patients with mIDH1 R/R MDS.

The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively...However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

P2, N=68, Active, not recruiting, Groupe Francophone des Myelodysplasies | Recruiting --> Active, not recruiting

The clinical value of IDH and ATRX mutations in prognostic assessment was confirmed (p ≤0.05). The overexpression of p53 had no significant impact on OS (p = 0.726). Therefore, p53 alone cannot predict survival in glioblastoma patients. Based on the results, these biomarkers may be a potential therapeutic target to prolong patient survival, hence the need for further investigations.

Furthermore, within the group of 15 patients with wild-type IDH1, 3 patients who received prophylactic antiepileptic drugs developed epilepsy, while 2 cases of epilepsy occurred among the 17 patients who did not receive prophylactic antiepileptic drugs, with no statistically significant difference (P > 0.05). In individuals with IDH1 mutant glioblastoma who have undergone surgical resection, the implementation of preventive antiepileptic therapy demonstrates a potential to diminish the occurrence of postoperative epilepsy.

The constructed core regulatory network and outcomes of in-silico network perturbations are supported by survival data from AML patients. We expect that the combined bioinformatics and systems-biology modeling approach will be generally applicable to elucidate the gene regulation of disease progression.

Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.

Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found.

P3, N=146, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Jun 2024 --> Jun 2026

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2025 --> Apr 2026 | Trial primary completion date: Feb 2025 --> Apr 2026

An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Total cfDNA may also assist with prognostic information. Further studies are needed to validate these findings and the clinical role of ctDNA in glioma.

Our results showed that higher CALR and lower GLP-1 expressions are found in HGGs compared to normal cerebral tissues.

Significant differences in GA and immune biomarkers are noted between IDH1/2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.

The U.S. Food and Drug Administration (FDA) approved Ivosidenib, a molecular entity that targets IDH1 with R132 mutations, as a promising therapeutic option for AML with mIDH1 in 2018...RMSD showed that the four dynamics simulation systems remained stable, and RMSF and Rg showed that the screened molecules have similar local flexibility and tightness to the positive drug. Finally, the lowest energy conformation, hydrogen bond analysis, and free energy decomposition results indicate that in the entire system the key residues LEU120, TRP124, TRP267, and VAL281 mainly contribute van der Waals forces to the interaction, while the key residues VAL276 and CYS379 mainly contribute electrostatic forces.

Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

P=N/A, N=63, Active, not recruiting, Massachusetts General Hospital | Unknown status --> Active, not recruiting | Phase classification: P2 --> PN/A | Trial completion date: Aug 2022 --> Nov 2025 | Trial primary completion date: Aug 2021 --> May 2025

Our method can be deployed in medical aid systems at very low cost, serving as a diagnostic or prognostic tool for glioma patients in medically underserved areas.

P1, N=95, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Dec 2023 --> Mar 2024

P3, N=300, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

CSF liquid biopsy has potential as a minimally invasive method of disease detection for measuring treatment response and longitudinal disease surveillance. lpWGS on CSF-derived cfDNA can identify tumor-derived sCNVs even when CSF cytology is negative for malignant cells. lpWGS can reveal sCNVs that are clinically actionable without need for a tissue biopsy.

P1/2, N=210, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

No abstract available

Approximately half of the gliomas were positive for the IDH1 mutation, with a slight male predominance. Our study provides crucial insights into the frequency of IDH1 mutations in gliomas in Kenya.

With advancements in molecular diagnostics and precision therapy, IDH inhibitors such as ivosidenib, vorasidenib and enasidenib are now mainstay in management of patients with a susceptible mutation. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit (RUO) is a fully automated qPCR assay for the qualitative detection of 15 common mutations in IDH1 (R132C/H/G/S/L) and IDH2 (R140Q/L/G/W, R172K/M/G/W/S) at codon level. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit demonstrates a high concordance with established reference methods across a range of different specimen types.

P2, N=97, Recruiting, Virogin Biotech Canada Ltd | Phase classification: P2a/2b --> P2 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Oct 2025

orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

P1, N=148, Active, not recruiting, Symphogen A/S | Phase classification: P1b --> P1

P2, N=247, Active, not recruiting, MimiVax, LLC | Recruiting --> Active, not recruiting

Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed...Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Our results showed significant differences in gene expression between IDH-mutant and IDH-wildtype diffuse gliomas, including higher levels of MAPT (Tau) in IDH-mutant tumors. We are in the process of incorporating the results of mass spectrometry and genome-wide methylation analysis in the context of gene expression data. We anticipate that this analysis will yield new insights into how the metabolic alterations in diffuse gliomas are influenced by epigenetic and gene expression changes.

P1/2, N=69, Not yet recruiting, Australasian Leukaemia & Lymphoma Group

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Feb 2025 | Trial primary completion date: Dec 2026 --> Feb 2025

We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

P1/2, N=190, Completed, Jounce Therapeutics, Inc. | Active, not recruiting --> Completed | N=281 --> 190