AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation
Authors: Fernandez Pau Montesinos , Recher Christian , Doronin Vadim , Calado Rodrigo T. , Jang Jun Ho , Miyazaki Yasushi , Wang Jianxiang , Gianolio Diego A , Daigle Scott R. , Winkler Thomas , Zhang Vickie , Paschka Peter 
Published: November 2019

Background: Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (AG-120) is a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, and is FDA-approved for the treatment of mIDH1 newly diagnosed AML in patients ≥75 years of age or who have comorbidities precluding the use of intensive induction chemotherapy, and for the treatment of mIDH1 relapsed/refractory AML. In vitro, combination treatment of leukemic cell lines with ivosidenib and the hypomethylating agent azacitidine enhanced cellular differentiation and apoptosis compared with either agent alone. In an ongoing phase 1b study (NCT02677922), 23 treatment-naïve patients with mIDH1 AML were treated with ivosidenib 500 mg once daily (QD) in combination with subcutaneous azacitidine 75 mg/m2 for 7 days (in a 28-day schedule). Patients had a median age of 76 years (range 61-88), 12 patients (52%) were ≥75 years of age, and 12 of 23 were female. De novo and secondary AML was present in 15 (65.2%) and 8 (34.8%) patients, respectively. As of February 19, 2019, 10 patients (43.5%) remained on study treatment. Patients have been treated for a median of 15 cycles (range 1-30), and the spectrum of adverse events has been consistent with monotherapy experiences with ivosidenib or azacitidine. Investigators reported 4 cases of IDH differentiation syndrome. Of those, 3 were deemed to be serious adverse events, but all 4 cases resolved. The overall response rate (ORR) was 78.3% (18 of 23 patients), including 60.9% (14 of 23 patients) who achieved a complete remission (CR). Median time to response was 1.8 months (range 0.7-3.8) and to CR was 3.7 months (range 0.8-15.7); median response duration has not been reached. Preliminary mIDH1 clearance in bone marrow mononuclear cells was observed in 69% of patients (11 of 16) with CR or CR with partial hematologic recovery (CRh), including 71% (10 of 14) with CR.
Methods: AGILE is a global, double-blind, randomized, placebo-controlled, phase 3 trial in patients with previously untreated mIDH1 AML who are not candidates for intensive therapy (NCT03173248). Currently, a total of 172 study centers in North America, South America, Asia, and Europe are participating in the study. Patients are being randomized 1:1 to receive either ivosidenib 500 mg QD + azacitidine 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or matched placebo + azacitidine. Randomization is stratified by region and by de novo versus secondary AML. Key eligibility criteria include patients with previously untreated mIDH1 AML (according to WHO criteria) who are not candidates for or not willing to receive intensive chemotherapy, who have an ECOG performance status 0-2, and who have received no prior treatment with a hypomethylating agent or mIDH1 inhibitor. Patients with an antecedent hematological disorder, such as myelodysplastic syndrome or myeloproliferative neoplasms, can be included if not pretreated with an mIDH1 inhibitor or hypomethylating agent. The primary outcome measure is overall survival, and key secondary outcome measures include event-free survival, CR rate, CR+CRh rate, and ORR. AGILE is currently open for enrollment globally.

Disclosures
Fernandez: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recher:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Celgene: Research Funding; chugai: Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Gianolio:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Daigle:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Paschka:Abbvie: Other: Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Other: Travel expenses, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Janssen: Other: Travel expenses; Amgen: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Takeda: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Ivosidenib (AG-120) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1)Adult patients with newly-diagnosed AML who are more than 75 years old, or who have comorbidities that preclude use of intensive induction chemotherapy 2)Adult patients with relapsed or refractory AML. It is being investigated in clinical trials in combination with azacitidine in patients with DH1-mutant newly diagnosed AML.