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This is a multicenter, randomized, controlled, open-label phase III trial evaluating the efficacy and safety of the VAG regimen (azacitidine, venetoclax, and gilteritinib) compared with standard 3+7 chemotherapy (cytarabine plus daunorubicin or idarubicin) combined with gilteritinib in newly diagnosed, fit patients with FLT3-mutated acute myeloid leukemia (AML). A total of 300 patients aged ≥14 to <75 years with FLT3-ITD or FLT3-TKD mutations will be enrolled and randomized 1:1 to the experimental or control arm, stratified by age (≤60 vs. >60 years). The primary endpoint is event-free survival (EFS). Secondary endpoints include composite complete remission (CRc) rate, minimal residual disease (MRD) negativity rate by flow cytometry and NGS, overall survival (OS), relapse-free survival (RFS), and 30-day and 60-day mortality.
This study is designed to investigate whether the triplet combination of azacitidine (a hypomethylating agent), venetoclax (a BCL-2 inhibitor), and gilteritinib (a FLT3 inhibitor) as induction therapy improves outcomes compared to standard intensive chemotherapy plus gilteritinib in patients with newly diagnosed FLT3-mutated AML who are fit for intensive chemotherapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| VAG Regimen ± VA Maintenance | Experimental | Induction (Age <60): Azacitidine 75 mg/m²/d d1-7; Venetoclax 100mg d1, 200mg d2, 400mg d3-14; Gilteritinib 120mg d1-14. Bone marrow assessment on d14: if blasts >5% with active marrow, Gilteritinib and Venetoclax may extend to d21. Induction (Age ≥60): Azacitidine 75 mg/m²/d d1-7; Venetoclax 100mg d1, 200mg d2, 400mg d3-7; Gilteritinib 120mg d1-7. Bone marrow assessment on d7: if blasts >5% with active marrow, Gilteritinib and Venetoclax may extend to d14. Re-induction (if not CR/CRh/CRi): Gilteritinib 80mg d1-28; Azacitidine 75 mg/m²/d d1-7; Venetoclax 100mg d1, 200mg d2, 400mg d3-14 (extend to d21 if d14 blasts >5%). Consolidation (after CR): Azacitidine 75 mg/m²/d d1-5; Venetoclax 400mg d1-14; Gilteritinib 120mg d1-14. For 2 cycles. Maintenance: Azacitidine 75 mg/m²/d d1-5; Venetoclax 400mg d1-7. For 6 cycles. |
|
| 3+7 Chemotherapy + Gilteritinib | Active Comparator | Induction: Cytarabine 100 mg/m²/d continuous IV d1-7; Daunorubicin 60 mg/m²/d (or Idarubicin 12 mg/m²/d) IV d1-3; Gilteritinib 120mg d8-21. Re-induction (if not CR/CRh/CRi): Cytarabine 100 mg/m²/d continuous IV d1-7 or d1-5; Daunorubicin 60 mg/m²/d (or Idarubicin 12 mg/m²/d) IV d1-3 or d1-2; Gilteritinib 120mg d8-21 or d6-19. Consolidation (after CR): Intermediate-dose Cytarabine 2 g/m² (age <60) or 1 g/m² (age ≥60) q12h d1-3; Gilteritinib 120mg d4-17. For 3 cycles. Maintenance: Gilteritinib 120mg daily. For up to 365 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gilteritinib + Azacitidine + Venetoclax | Drug | Patients randomized to this arm receive the novel triplet combination as first-line induction therapy. Patients who achieve complete remission (CR) will receive one repeat cycle of the induction therapy. |
| Measure | Description | Time Frame |
|---|---|---|
| Event-Free Survival (EFS) | From randomization until treatment failure, relapse after CRc, death from any cause, or last follow-up, assessed up to 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Composite Complete Remission Rate | After induction therapy (approximately 4-8 weeks) | |
| Measurable residual disease-negative CRc rate by flow cytometry | Measurable residual disease-negative CRc rate by flow cytometry after every courses therapy |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Hui Wei, MD | Contact | 13132507161 | weihui@ihcams.ac.cn |
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| Cytarabine + Daunorubicin (or Idarubicin) + Gilteritinib | Drug | Patients randomized to this arm receive the standard "3+7" intensive chemotherapy plus gilteritinib as the control regimen. |
|
| Re-induction Therapy | Drug | Cytarabine 100 mg/m²/d continuous IV d1-7 or d1-5; Daunorubicin 60 mg/m²/d (or Idarubicin 12 mg/m²/d) IV d1-3 or d1-2; Gilteritinib 120mg d8-21 or d6-19. |
|
| Consolidation Therapy | Drug | Applicable to: All patients achieving CRc (CR/CRh/CRi) following two cycles of induction in the experimental arm or one to two cycles in the control arm. Regimen: Intermediate-dose Cytarabine followed by Gilteritinib per group-specific criteria. Cytarabine (Both Arms): Age <60 years: 2 g/m² IV q12h, Days 1-3. Age ≥60 years: 1 g/m² IV q12h, Days 1-3. Gilteritinib Addition (120 mg oral, Days 4-17): Control Arm: Administered routinely in all patients. Experimental Arm: Added only if an FLT3 mutation is detectable by NGS-based MRD testing prior to the start of each consolidation cycle. |
|
| Maintenance Therapy | Drug | Applicable to: All patients who have completed consolidation therapy. Experimental Arm: Adjusted-dose VA regimen for 6 cycles. Azacitidine: 75 mg/m²/day, Days 1-7. Venetoclax: 400 mg daily, Days 1-7. Control Arm: Gilteritinib monotherapy for up to 1 year. Gilteritinib: 120 mg daily, Days 1-365. |
|
| At the time of achieving CRc |
| Measurable residual disease-negative CRc rate by NGS for FLT3-ITD | Measurable residual disease-negative CRc rate by NGS for FLT3-ITD after every courses therapy | At the time of achieving CRc |
| Relapse-Free Survival (RFS) | From achievement of CRc until relapse, death, or last follow-up, assessed up to 3 years |
| 30-day and 60-day mortality | 30 and 60 days after start of induction therapy |
| Overall Survival (OS) | From randomization until death from any cause, assessed up to 3 years |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C000609080 | gilteritinib |
| D001374 | Azacitidine |
| C579720 | venetoclax |
| D003561 | Cytarabine |
| D003630 | Daunorubicin |
| D015255 | Idarubicin |
| D008283 | Maintenance |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D001087 | Arabinonucleosides |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D005159 | Health Care Facilities Workforce and Services |
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