An All-Oral Combination of Ivosidenib, Sonrotoclax, and Chidamide for Newly Diagnosed Acute Myeloid Leukemia With an IDH1 Mutation (ISC) (ISC)
A Multicenter, Prospective, Exploratory Study Evaluating an All-oral Combination of Ivosidenib, Sonrotoclax, and Chidamide for the Treatment of Newly Diagnosed IDH1-mutated Acute Myeloid Leukemia
This prospective, multicenter, exploratory clinical study is designed to evaluate the efficacy and safety of an all-oral combination of ivosidenib, sonrotoclax, and chidamide in adults with newly diagnosed acute myeloid leukemia (AML) harboring an IDH1 R132 mutation.
Approximately 30 participants aged 18 years or older will be enrolled. Eligible participants must have previously untreated AML with a confirmed IDH1 R132 mutation and adequate heart, liver, and kidney function. Ivosidenib targets the abnormal IDH1 protein, sonrotoclax blocks BCL-2, a protein that helps leukemia cells survive, and chidamide affects gene regulation and may increase the sensitivity of leukemia cells to treatment. The study hypothesis is that combining these three medicines may produce deep and durable remissions with an acceptable safety profile while providing a treatment that can be taken entirely by mouth.
Treatment will be given in 28-day cycles. During induction treatment, all participants will receive oral ivosidenib, sonrotoclax, and chidamide. In the initial exploratory stage, participants will be assigned in a 1:1:1 ratio to one of three induction schedules. The schedules differ in the planned duration of sonrotoclax and chidamide treatment. A bone marrow examination will be performed on Day 10 or Day 14, depending on the assigned schedule, to determine whether sonrotoclax and/or chidamide should be continued through Day 28. Early remission results, adverse events, and overall tolerability will be reviewed to select a recommended induction schedule for the expansion stage.
Participants who achieve a response will receive at least three 28-day cycles of consolidation treatment with the three-drug combination. Treatment duration may be shortened or the next cycle may be delayed if blood cell counts recover slowly or other clinically important side effects occur. After consolidation, measurable residual disease (MRD) will be assessed. MRD refers to the small number of leukemia cells that may remain after treatment even when remission has been achieved. Participants who become negative for IDH1 MRD will proceed to maintenance treatment with oral ivosidenib for up to 2 years. Participants with persistent IDH1 MRD may receive additional consolidation treatment, and allogeneic hematopoietic stem cell transplantation may be considered according to the protocol and clinical assessment.
The primary outcome is the 1-year event-free survival rate, defined by whether participants remain alive without relapse or disease progression. Secondary outcomes include the composite complete remission rate after induction treatment, MRD clearance and the time to MRD clearance, relapse-free survival, overall survival, and exploratory biological markers. Safety will be evaluated by recording adverse events and monitoring blood counts, bone marrow findings, liver and kidney function, electrocardiograms, and other clinically indicated tests. Participants will be followed regularly during treatment and follow-up.
A tanulmány áttekintése
Állapot
Körülmények
Beavatkozás / kezelés
Tanulmány típusa
Beiratkozás (Becsült)
Fázis
- 2. fázis
Kapcsolatok és helyek
Tanulmányi kapcsolat
- Név: Huafeng Wang, PhD
- Telefonszám: +86057187236898
- E-mail: 1509036@zju.edu.cn
Részvételi kritériumok
Jogosultsági kritériumok
Tanulmányozható életkorok
Egészséges önkénteseket fogad
Tanulmányozható nemek
Leírás
Inclusion Criteria:
- Patients with newly diagnosed AML. Diagnosis based on the 2022 WHO classification.
- Age >=18 years.
- Presence of an IDH1 R132 mutation (R132H, R132C, R132G, R132S, or R132L) confirmed by real-time quantitative PCR or NGS.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 (see Appendix 1).
- Echocardiographic LVEF >=45%; QTc interval <450 ms (males) or <470 ms (females).
- Renal function: creatinine clearance >=50 mL/min (calculated using the Cockcroft-Gault formula or measured via 24-hour urine collection).
- Liver function: aspartate aminotransferase (AST) <=3× ULN*; alanine aminotransferase (ALT) <=3× ULN*; total bilirubin <=1.5× ULN* (*unless attributed to leukemic infiltration).
- Male patients, women of childbearing potential (women are considered non-childbearing only if postmenopausal for at least 12 months), and their partners voluntarily agree to use contraceptive measures deemed effective by the investigator during treatment and for at least 12 months after the last dose of the study drug.
- Patient or guardian agrees to participate in the clinical trial and signs the informed consent form.
Exclusion Criteria:
- Acute promyelocytic leukemia (APL/M3); core-binding factor AML (CBF-AML) with t(8;21), inv(16), or t(16;16).
- Patients previously treated with anthracyclines, or those with prior treatment involving IDH1 inhibitors, BCL-2 inhibitors (e.g., venetoclax), or HDAC inhibitors (e.g., chidamide).
- Patients with AML known to involve the central nervous system (CNS).
- Subjects known to be infected with HIV (HIV testing will be performed at screening in accordance with local guidelines or institutional standards).
- Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as testing positive for the virus and having abnormal liver function).
- Subjects who have received treatment with strong or moderate CYP3A inducers/inhibitors within 5 half-lives (or within 7 days) prior to the start of study treatment.
- Subjects with a New York Heart Association (NYHA) functional classification > Class II. Class II is defined as heart disease where the patient has no symptoms at rest but experiences fatigue, palpitations, dyspnea, or angina during ordinary physical activity.
- Subjects with chronic respiratory disease requiring continuous supplemental oxygen.
- Patients unable to take oral medication or those with malabsorption syndrome.
- Presence of uncontrolled systemic infection (viral, bacterial, or fungal).
- Inability to sign the informed consent form.
Tanulási terv
Hogyan készül a tanulmány?
Tervezési részletek
- Elsődleges cél: Kezelés
- Kiosztás: N/A
- Beavatkozó modell: Egyetlen csoportos hozzárendelés
- Maszkolás: Nincs (Open Label)
Fegyverek és beavatkozások
Résztvevő csoport / kar |
Beavatkozás / kezelés |
|---|---|
|
Kísérleti: Arm
Ivosidenib, Chidamide, Sonrotoclax |
Cohort 1: Ivosidenib 500 mg qd po d1-28; Chidamide 10 mg qd po d1-28; Sonrotoclax 40 mg d1, 80 mg d2, 160 mg d3, 320 mg d4-10 po. On d10, Sonrotoclax is adjusted according to bone marrow findings: if blasts <5%, stop from d11; otherwise, continue 320 mg qd po to d28. Cohort 2: Ivosidenib 500 mg qd po d1-28; Chidamide 10 mg qd po d1-28; Sonrotoclax 40 mg d1, 80 mg d2, 160 mg d3, 320 mg d4-14 po. On d14, Sonrotoclax is adjusted: if blasts <5%, stop from d15; otherwise, continue 320 mg qd po to d28. Cohort 3: Ivosidenib 500 mg qd po d1-28; Chidamide 10 mg qd po d1-14; Sonrotoclax 40 mg d1, 80 mg d2, 160 mg d3, 320 mg d4-14 po. On d14, Chidamide and Sonrotoclax are adjusted: if blasts <5%, stop both from d15; otherwise, continue both to d28. The recommended induction schedule will be selected based on CRc, adverse events, and overall tolerability for the expansion stage. |
Mit mér a tanulmány?
Elsődleges eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
|---|---|---|
|
1-Year Event-Free Survival Rate (EFS)
Időkeret: From treatment initiation through 1 year.
|
Event-free survival is defined as the time from the date of initiation of study treatment to the earliest occurrence of documented relapse after remission, disease progression, or death from any cause. The 1-year EFS rate will be estimated using the Kaplan-Meier method. Participants without an event will be censored at the date of their last disease assessment. |
From treatment initiation through 1 year.
|
Másodlagos eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
|---|---|---|
|
Composite Complete Remission Rate After Two Cycles (CRc=CR+CRi)
Időkeret: At the end of Cycle 2（each cycle is 28 days）
|
After completion of two induction treatment cycles, CR and CRi will be assessed according to bone marrow morphology, peripheral blood cell counts, and the response criteria specified in the protocol. CRc is defined as CR plus CRi. |
At the end of Cycle 2（each cycle is 28 days）
|
|
Minimal Residual Disease (MRD) Negativity Rate
Időkeret: At the end of each Cycle（each cycle is 28 days），up to 2 years
|
MRD will be dynamically assessed using multiparameter flow cytometry, quantitative PCR, and/or NGS. Flow cytometric MRD negativity is defined as <0.01%, while molecular MRD negativity is determined according to the corresponding assay result. |
At the end of each Cycle（each cycle is 28 days），up to 2 years
|
|
Relapse-Free Survival (RFS)
Időkeret: up to 2 years
|
RFS is defined as the time from the first achievement of CR or CRi to disease relapse or death from any cause. Patients without an event are censored at the date of the last disease assessment. RFS will be analyzed using the Kaplan-Meier method. |
up to 2 years
|
|
Overall Survival (OS)
Időkeret: up to 5 years
|
OS is defined as the time from treatment initiation to death from any cause. Patients who remain alive at the end of the study are censored at the last date known to be alive. OS will be analyzed using the Kaplan-Meier method. |
up to 5 years
|
|
Incidence of Adverse Events and Serious Adverse Events
Időkeret: From day 1 of treatment to 28 days after the last dose
|
Adverse events and serious adverse events will be recorded according to their incidence, severity, relationship to the study drugs, and outcomes, and will be graded according to CTCAE Version 5.0. |
From day 1 of treatment to 28 days after the last dose
|
Együttműködők és nyomozók
Tanulmányi rekorddátumok
Tanulmány főbb dátumok
Tanulmány kezdete (Becsült)
Elsődleges befejezés (Becsült)
A tanulmány befejezése (Becsült)
Tanulmányi regisztráció dátumai
Először benyújtva
Először nyújtották be, amely megfelel a minőségbiztosítási kritériumoknak
Első közzététel (Tényleges)
Tanulmányi rekordok frissítései
Utolsó frissítés közzétéve (Tényleges)
Az utolsó frissítés elküldve, amely megfelel a minőségbiztosítási kritériumoknak
Utolsó ellenőrzés
Több információ
A tanulmányhoz kapcsolódó kifejezések
Kulcsszavak
További vonatkozó MeSH feltételek
Egyéb vizsgálati azonosító számok
- 2026CIIT NO158
Terv az egyéni résztvevői adatokhoz (IPD)
Tervezi megosztani az egyéni résztvevői adatokat (IPD)?
IPD terv leírása
Individual participant data will not be shared because this is an investigator-initiated exploratory study with a small sample size, and the data include sensitive clinical and genomic information. De-identified aggregate study results may be reported in publications or scientific presentations.
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