An Open-label Phase 3b Study of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy.

Study Overview
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Brief Summary
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The purpose of this study is to learn more about the safety and efficacy of ivosidenib taken with azacitidine to treat adult patients with acute myeloid leukemia (AML) who are presenting a gene mutation called IDH1 (isocitrate dehydrogenase1 mutation-positive [IDH1m]) and cannot receive treatment with intensive chemotherapy (IC).

Detailed Description
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Participants who are eligible and enroll in the study will attend a study visit on the first day of each 28-day cycle. Study visits will consist of a physical exam, blood work, electrocardiogram (ECG) and other assessments. After treatment discontinuation participants will be contacted every 12 weeks through the end of the study (currently planned for 2026) to assess survival. The study drug, Ivosidenib, will be taken once daily throughout the duration of participation in the study, and Azacitidine will only be administered for 7 days at the beginning of each 28 day cycle. If at any point ivosidenib is made available as a medical prescription at the patient's site, the patient will switch to commercial product and will continue to be followed according to the protocol.

Official Title
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A Single Arm, Open-label Phase 3b Study to Describe the Safety and Tolerability of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Ivosidenib 500mg Oral Tablet
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has untreated Acute Myeloid Leukemia (AML) Have a documented IDH1 R132 gene-mutated disease Have at least one of the following making yourself ineligible for intensive chemotherapy (IC): 75 years or older, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2, or any comorbidity that the investigator judges to be incompatible with IC including but not limited to severe cardiac or pulmonary disorder, creatinine clearance less than 45 mL/minute, or bilirubin greater than 1.5 times the upper limit of normal Has adequate hepatic (liver) and renal (kidney) function Female participants of reproductive potential must have a negative blood pregnancy test and must use effective contraception during treatment and for at least 6 months following treatment Fertile male participants with female partners of reproductive potential must use effective contraception during treatment and for at least 3 months following treatment Exclusion Criteria: Has received any prior treatment for AML, with the exception of hydroxyurea or leukapheresis for white blood cell count control Has received prior treatment with an IDH1 inhibitor Is a woman who is pregnant or breastfeeding Has an active, uncontrolled, systemic fungal, bacterial, or viral infection (including human immunodeficiency virus [HIV], active hepatitis B (HBV), or hepatitis C virus [HCV]) without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment Has had significant active cardiac disease within 6 months prior to the start of study treatment, including Class III or IV congestive heart failure, myocardial infarction (heart attack), unstable angina (chest pain), and/or stroke Has dysphagia (difficulty swallowing), short-gut syndrome, gastroparesis (stomach paralysis), or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs Has uncontrolled hypertension (high blood pressure)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Ivosidenib in combination with Azacitidine<br>All participants will receive both Ivosidenib and Azacitidine for a maximum of 28 cycles. Each cycle will be 4 weeks or 28 days long. Ivosidenib will be taken continuously throughout each cycle and Azacitidine will be taken only for 7 days at the beginning of each cycle. | Drug: Ivosidenib 500mg Oral Tablet<br>* Provided as tablets, taken orally as two 250mg tablets once daily.<br>Drug: Azacitidine<br>* Administered subcutaneously (SC) or intravenously (IV) at a dose of 75mg/m2/day for 7 days, either consecutively on Days 1-7 or discontinuously for Days 1-5 and 8-9 of each cycle. The 7 days of administration will occur at the beginning of every 4 week-long cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) | Adverse events (AEs) will be graded according to the CTCAE v5.0 | up to week 116 | 
| Number of Serious Adverse Events (SAEs) | Adverse events (AEs) will be graded according to the CTCAE v5.0 | up to week 116 | 
| Differentiation Syndrome of Grade 2 or higher |  | up to week 116 | 
| Number of Adverse Events (AEs) leading to ivosidenib + azacitidine discontinuation |  | up to week 112 | 
| Number of Adverse Events (AEs) leading to ivosidenib + azacitidine interruption |  | up to week 112 | 
| Number of Adverse Events (AEs) leading to ivosidenib + azacitidine dose reduction |  | up to week 112 | 
| Number of Adverse Events (AEs) leading to death |  | up to week 116 | 
| Number of clinical laboratory anomalies assessed as Adverse Events (AEs) |  | up to week 116 | 
| Number of patients requiring transfusion (platelet and RBC) and the average number of units transfused |  | up to week 116 | 
| Rate of infections | Infection rates will be summarized by classification and will include a count and proportion. | up to week 116 | 
| QT Prolongation event assessed as Grade 3 or higher |  | up to week 116 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) |  | up to week 116 | 
| Proportion of patients who achieve a complete remission (CR) |  | up to week 116 | 
| Proportion of patients who achieve complete remission plus complete remission with partial hematologic recovery rate (CR + CRh) |  | up to week 116 | 
| Proportion of patients who achieve complete remission plus complete remission with incomplete hematologic recovery rate (CR + CRi) |  | up to week 116 | 
| Duration of response (DOR) |  | up to week 116 | 
| Time to response (TTR) |  | up to week 116 | 
| Overall survival (OS) |  | until study closure | 
| Quality of life (QoL), as measured by Hematologic Malignancy-Patient-Reported Outcome (HM-PRO) | For patients with a baseline assessment and at least 1 post-baseline assessment that generates a score | up to week 116 | 
| Quality of life (QoL), as measured by Family Reported Outcome Measure (FROM-16), for caregivers and/or family | For patients with a baseline assessment and at least 1 post-baseline assessment that generates a score | up to week 116 | 
| Health economic measures, as assessed by the 5-level EuroQol 5-Dimensions (EQ-5D-5L) | For patients with a baseline assessment and at least 1 post-baseline assessment that generate a score | up to week 116 | 
| Average proportion of days at home | Defined by subtracting the number of care days (days hospitalized or seen in an ED / oncology clinic / infusion center) from the total days of follow-up, divided by total days of follow-up | up to week 116 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDH1 Mutation AML