P1, N=72, Recruiting, Institut de Recherches Internationales Servier | Trial primary completion date: Mar 2024 --> Feb 2025

P3, N=319, Completed, Celgene | Active, not recruiting --> Completed

P3, N=316, Not yet recruiting, Hutchmed

P2, N=68, Active, not recruiting, Groupe Francophone des Myelodysplasies | Recruiting --> Active, not recruiting | Trial completion date: Feb 2023 --> Mar 2026

Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.

This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas.

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

This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

P1/2, N=48, Recruiting, Stanford University | Trial completion date: Jan 2024 --> Aug 2024 | Trial primary completion date: Jan 2024 --> Aug 2024

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.

P1/2, N=84, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P1/2

P1, N=49, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: May 2024 --> May 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=40, Completed, Celgene | Active, not recruiting --> Completed

P2, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=75, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

P1, N=15, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3; Trial completion date: Dec 2023 --> Mar 2024

P2, N=15, Not yet recruiting, Washington University School of Medicine

P1/2, N=345, Completed, Celgene | Active, not recruiting --> Completed

P1, N=16, Completed, Institut de Recherches Internationales Servier | Recruiting --> Completed

P1, N=90, Active, not recruiting, Hutchmed | Recruiting --> Active, not recruiting

No abstract available

P1/2, N=130, Active, not recruiting, Celgene | Phase classification: P1b/2 --> P1/2

P1/2, N=27, Terminated, University Health Network, Toronto | Trial completion date: Jul 2023 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2023 --> Oct 2023; Insufficient Funding

P1, N=60, Completed, Eli Lilly and Company

P1, N=42, Completed, Eli Lilly and Company

P2, N=30, Not yet recruiting, National Cancer Institute (NCI)

P2, N=6, Completed, John Mascarenhas | Trial completion date: Dec 2022 --> May 2023 | Trial primary completion date: Dec 2022 --> May 2023

P1, N=15, Recruiting, City of Hope Medical Center | Phase classification: P1b --> P1 | Trial completion date: Mar 2024 --> May 2025 | Trial primary completion date: Mar 2024 --> May 2025

Patient 1 maintains a complete remission (CR) with enasidenib after intolerance to chemotherapy. Patient 3 was treated with venetoclax and gilteritinib at the time of relapse and maintained a CR with gilteritinib for 8 months. These cases suggest that FLT3 and IDH inhibitors could represent a viable therapeutic option for ALL patients with these mutations.

In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML. Treatment delays and dose reductions were commonly seen; however, most patients completed their 2-years maintenance.

P3, N=331, Active, not recruiting, Institut de Recherches Internationales Servier

This study is partially supported by Astellas Pharma Global Development, Inc. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e. g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study.

P2, N=6, Completed, John Mascarenhas | Recruiting --> Completed | N=32 --> 6 | Trial completion date: Apr 2025 --> Dec 2022 | Trial primary completion date: Apr 2024 --> Dec 2022

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

INDIGO is the first randomized Phase 3 study of targeted therapy in grade 2 mIDH1/2 diffuse glioma. HRQoL, as measured by FACT-Br, was maintained during treatment with vorasidenib. These data support the clinical benefit of vorasidenib in this patient population for whom chemotherapy and radiotherapy are being delayed.

No abstract available

Introduction: Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ)...Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown...Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment.

Introduction: Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain...The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ...Clinically, the patient has no symptoms from tumor. Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.