Tibsovo (ivosidenib)

P1/2, N=7, Completed, Servier Bio-Innovation LLC | Active, not recruiting --> Completed | N=92 --> 7 | Trial completion date: Mar 2026 --> Nov 2024 | Trial primary completion date: Mar 2026 --> Nov 2024

P=N/A, N=100, Recruiting, iOMEDICO AG | Not yet recruiting --> Recruiting

Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

P3, N=48, Recruiting, Institut de Recherches Internationales Servier | Not yet recruiting --> Recruiting

P2, N=76, Not yet recruiting, Technische Universität Dresden

P2, N=75, Not yet recruiting, Massachusetts General Hospital

The FGFR and IDH-1 pathways are the primary targets for therapy, with FGFR-2 and IDH-1 inhibitors, such as Pemigatinib and Ivosidenib respectively, already available on the market. This prospective study validates the prevalence of mutations documented in the literature and underscores the significance of NGS in presenting supplementary therapeutic avenues. Moreover, we demonstrated the role of other potential targets co-expressed with FGFR2 or IDH1 which could represent a crucial opportunity for novel combinations or sequences therapies.

These mutations are targetable using agents such as ivosidenib and vorasedinib in AML... The Biocartis Idylla IDH1-2 mutation assay shows good concordance with ddPCR and an LOD of 2.5% VAF. Though the analytical sensitivity of this assay is lower than ddPCR, this may not be a limitation in acute, newly diagnosed patients presenting with increased blast counts. This assay offers the advantage of direct specimen testing for PB and BM without DNA extraction with faster turnaround time than other methods.

Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML...Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax...Single arm studies show post-transplant maintenance is safe, however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.

P2, N=20, Recruiting, Washington University School of Medicine | N=15 --> 20 | Trial completion date: Jun 2026 --> Jan 2030 | Trial primary completion date: Jun 2026 --> Jan 2030

P=N/A, N=250, Recruiting, French Innovative Leukemia Organisation | Not yet recruiting --> Recruiting

P=N/A, N=40, Not yet recruiting, Duke University

P1, N=18, Recruiting, University of Chicago | Not yet recruiting --> Recruiting

In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

P2, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=17 --> 6

P1/2, N=29, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation has both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

P=N/A, N=100, Not yet recruiting, iOMEDICO AG

Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor)...To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.

P3, N=968, Active, not recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Recruiting --> Active, not recruiting | Trial completion date: May 2034 --> Sep 2034 | Trial primary completion date: Oct 2024 --> Apr 2027

P1/2, N=84, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=36, Not yet recruiting, Fudan University

Hypomethylating agents like azacitidine and decitabine have shown promise in improving relapse-free and overall survival, particularly in older patients with AML ineligible for transplantation. Combination regimens involving azacitidine and venetoclax have demonstrated encouraging outcomes post-hematopoietic stem cell transplantation. Targeted therapies, particularly FLT3 inhibitors like midostaurin and quizartinib, have shown significant benefits in improving survival outcomes, especially in FLT3-mutated AML cases. Gilteritinib and sorafenib also exhibit the potential to reduce relapse rates post-transplant. Isocitrate dehydrogenase inhibitors, including ivosidenib and enasidenib, present novel options for postchemotherapy and posttransplantation maintenance...The approval of oral azacitidine represents a significant advancement, emphasizing the need for further investigation into personalized maintenance approaches. In conclusion, the evolving landscape of maintenance therapy and integrating targeted therapies in AML offers promising avenues for improving patient outcomes.

P1/2, N=92, Active, not recruiting, Servier Bio-Innovation LLC | Recruiting --> Active, not recruiting

P3, N=968, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial completion date: Mar 2033 --> May 2034 | Trial primary completion date: Mar 2023 --> Oct 2024

P1, N=18, Not yet recruiting, University of Chicago | Initiation date: May 2024 --> Nov 2024

P2, N=12, Active, not recruiting, Servier | N=21 --> 12

P=N/A, N=120, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's comorbidities and AML genomic profile.

This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

P1, N=0, Withdrawn, University of Chicago | N=50 --> 0 | Recruiting --> Withdrawn

P3, N=136, Recruiting, Servier Bio-Innovation LLC | Not yet recruiting --> Recruiting | Trial completion date: Apr 2031 --> Nov 2030 | Trial primary completion date: Dec 2026 --> Feb 2028

P1, N=16, Recruiting, Case Comprehensive Cancer Center | Trial completion date: Oct 2024 --> Dec 2026 | Trial primary completion date: Oct 2024 --> Jul 2026

Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib.

P1/2, N=52, Not yet recruiting, Institut de Recherches Internationales Servier

mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported...Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

P2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Mar 2025 | Trial primary completion date: Dec 2025 --> Mar 2025

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Phase classification: P1b --> P1

Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.