AGILE: A phase 3, multicenter, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adult patients with previously untreated acute myeloid leukemia with an IDH1 mutation.

Stein, Eytan M.; DiNardo, Courtney D.; Jang, Jun Ho; Miyazaki, Yasushi; Martínez, Roberto Ovilla; Auer, Julia; Zhang, Vickie; Koralek, Daniel O.; Wu, Bin

doi:10.1200/jco.2018.36.15_suppl.tps7074

Cited by 8 publications

(7 citation statements)

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“…In another currently-recruiting phase 3 study azacitidine is combined with either Ivosidenib or placebo as therapy for previously untreated AML with IDH1 mutations (NCT03173248). This study is planning on enrolling 392 patients, but data as of September 2017 indicated that out of 11 patients who received both Ivosidenib and azacitidine, 8 of them achieved a response, including 4 who had complete remission (92). As mentioned above, another active phase 1 study is examining treatment with either Ivosidenib or Enasidenib, depending on IDH1 vs. IDH2 mutational status, alongside standard induction or consolidation therapy for AML (ClinicalTrials.gov NCT02632708).…”

Section: Clinical Trialsmentioning

confidence: 99%

“…Incidence of serious adverse events were similar to those reported with azacitidine monotherapy (94). A phase 3 multicenter randomized controlled trial entitled “AGILE” will evaluate the efficacy of the Ivosidenib + azacitidine regimen compared to a placebo + azacitidine control in a similar patient population (92).…”

Section: Limitations and Potential For Combination Therapymentioning

confidence: 99%

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Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

et al. 2019

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The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.

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Section: Clinical Trialsmentioning

confidence: 99%

Section: Limitations and Potential For Combination Therapymentioning

confidence: 99%

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

et al. 2019

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“…Preclinical data have suggested a synergistic effect of enasidenib and 5-AZA leading to the initiation of a clinical phase I/II trial of enasidenib and 5-AZA (ClinicalTrials.gov identifier: NCT02677922) and a phase III trial of ivosidenib and 5-AZA for newly diagnosed AML patients ineligible for standard intensive chemotherapy (ClinicalTrials.gov identifier: NCT03173248). 45,52,53 While neither of these trials has been published in a peer-reviewed journal yet, data available in abstract form seem promising with an ORR of 73% [ n = 11; complete remission (CR): 50%] in treatment-naïve, IDH1-mutated AML patients treated with ivosidenib and 5-AZA. 52 Preliminary data for the enasidenib + 5-AZA trial showed a 66% response rate ( n = 6 patients; CR: 33%) in patients with newly diagnosed AML with nausea and hyperbilirubinemia being the most common adverse events.…”

Section: Combination Of Hmas With Other Epigenetic Therapymentioning

confidence: 99%

“…45,52,53 While neither of these trials has been published in a peer-reviewed journal yet, data available in abstract form seem promising with an ORR of 73% [ n = 11; complete remission (CR): 50%] in treatment-naïve, IDH1-mutated AML patients treated with ivosidenib and 5-AZA. 52 Preliminary data for the enasidenib + 5-AZA trial showed a 66% response rate ( n = 6 patients; CR: 33%) in patients with newly diagnosed AML with nausea and hyperbilirubinemia being the most common adverse events. 54…”

Section: Combination Of Hmas With Other Epigenetic Therapymentioning

confidence: 99%

Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Bewersdorf

Shallis

Stahl

2019

Therapeutic Advances in Hematology

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Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.

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“…The use of ivosidenib as a front-line therapy as a single agent38,48 has been analyzed in a Phase Ib clinical trial [NCT02074839] (Table 2), and it has shown a promising 42.4% CR/CRh rate among the 33 subjects. Ongoing clinical trials are testing in IDH1 mut -untreated AML patients, the safety and efficacy of different combinations of ivosidenib with azacitidine [NCT03173248; NCT02677922]49–51 or intensive chemotherapy [NCT02632708]52 (Table 2). It is worth noting that a new international Phase III randomized clinical trial aiming to enroll a large number of patients will compare AZA+IVO vs AZA in newly diagnosed IDH1 mut patients unfit for intensive chemotherapy [NCT03173248].…”

Section: Novel Approaches In Idh1-mutated Relapsed or Refractory Amlmentioning

confidence: 99%

<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p>

Megías‐Vericat¹,

Ballesta-López²,

Barragán³

et al. 2019

BLCTT

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The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 mut ), present in 7–14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 mut inhibitors and other agents in adult patients with IDH1 mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1 mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 mut inhibitors in therapeutic strategies of AML.

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AGILE: A phase 3, multicenter, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adult patients with previously untreated acute myeloid leukemia with an IDH1 mutation.

Cited by 8 publications

References 0 publications

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p>

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