Venetoclax + Azacytidine for Newly Diagnosed ETP-like ALL and T-ALL With Myeloid Mutations

Phase 2

Recruiting

• Conditions: Early T Acute Lymphoblastic Leukemia; T-Acute Lymphoblastic Leukemia; Mixed Phenotype Acute Leukemia, T/Myeloid, Nos
• Interventions: Drug: Venetoclax; Drug: Azacitidine; Drug: Cytarabine

• Registration Number: NCT07012447
• Lead Sponsor: yuejun Liu

Brief Summary

The goal of this clinical trial is to evaluate the efficacy and safety of venetoclax combined with azacitidine in treating newly diagnosed early T-cell precursor (ETP)-like acute lymphoblastic leukemia (ALL), T-ALL with myeloid mutations, or T/myeloid mixed-phenotype acute leukemia (T/My-MPAL).

Participant population: Patients aged ≥14 years diagnosed with ETP-like leukemia, T-ALL with myeloid mutations, or T/My-MPAL, regardless of sex/gender.

The main question it aims to answer: Does venetoclax plus azacitidine achieve a significantly higher overall response rate (ORR: CR + CRi) compared to historical controls (54% vs. 90%) after two induction cycles?

Comparison group: Researchers will compare ORR outcomes to historical data from conventional chemotherapy regimens to assess treatment superiority.

Participants will:

* Receive two 28-day cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m²/day SC, D1-7).

* Undergo serial bone marrow biopsies, blood tests, and imaging (e.g., PET-CT) for response assessment.

* Follow dose adjustment protocols for toxicity management (e.g., neutropenia, thrombocytopenia).

Detailed Description

This study addresses the unmet need for effective therapies in high-risk T-ALL subtypes, including ETP-like leukemia and T/My-MPAL, which exhibit myeloid-like genetic profiles (e.g., FLT3, DNMT3A, RUNX1 mutations) and poor outcomes under conventional chemotherapy (5-year OS \<40%). Preclinical and pilot clinical data demonstrate that venetoclax, a BCL-2 inhibitor, synergizes with azacitidine, a hypomethylating agent, to induce apoptosis in leukemia stem cells by targeting oxidative phosphorylation and epigenetic dysregulation. Building on a pilot study, this Phase II trial employs a single-arm design to validate efficacy in a larger cohort.

Patients receive two induction cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7), with response assessed via bone marrow morphology, flow cytometry, and molecular testing (Days 22-35).

Early Efficacy Evaluation: After the first induction cycle (Days 22-35), response is assessed via bone marrow morphology, flow cytometry, and molecular profiling.

Stopping Criteria:

Patients failing to achieve at least partial remission (PR) after Cycle 1 will be withdrawn from the study.

Patients failing to achieve CR or CRi at the end of Cycle 2 will also discontinue study treatment.

Consolidation strategies include allo-HSCT or high dose cytarabine (HiDAC) for fit patients or maintenance therapy for unfit individuals.

Rigorous safety monitoring follows NCI-CTCAE v5.0 criteria, with dose adjustments for hematologic/non-hematologic toxicities.

Statistical analysis includes intent-to-treat and per-protocol populations, with ORR analyzed via exact binomial tests and survival endpoints via Kaplan-Meier/Cox regression. The study integrates translational biomarkers (e.g., BCL-2 expression, mutational profiling) to identify predictors of response, aiming to establish a novel, mechanism-driven regimen for these aggressive leukemias.

Study Timeline

• Study Start: 2025-04-01
• Study First Submitted: 2025-04-21
• Status Verified: 2025-06
• Study First Submitted QC: 2025-06-02
• Last Update Submitted: 2025-06-02
• Study First Posted: 2025-06-10
• Last Update Posted: 2025-06-10
• Primary Completion: 2027-04-01
• Study Completion: 2028-05-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. No gender restrictions

2. Age ≥ 14 years

3. Confirmed diagnosis of one of the following:

   ETP-like leukemia (CD7⁺, CD1a-, CD8-, with CD5 expression stratified as ETP-ALL ≤75% or Near-ETP-ALL >75%) T-cell acute lymphoblastic leukemia (T-ALL) with myeloid mutations (including FLT3, DNMT3A, STAG2, IDH1/2, RUNX1, EZH2, WT1, ASXL1/2, SF3B1, TET2, BCOR, BCORL1, and MLL-PTD) T/myeloid mixed phenotype acute leukemia (T/My-MPAL) (with concurrent T-lineage and myeloid markers, e.g., cCD3⁺/mCD3⁺, CD7⁺, MPO⁺)

4. Newly diagnosed patients without prior induction therapy Limited prior therapy allowed: hydroxyurea, dexamethasone, or low-dose cytarabine/venetoclax (cumulative dose <0.5g), and leukocytapheresis

5. Expected survival time ≥ 3 months

6. Liver function: total bilirubin ≤ 2× ULN; ALT/AST ≤ 3× ULN (or ≤ 5× ULN if liver infiltration by leukemia is present) ; Renal function: endogenous creatinine clearance ≥ 30 ml/min; Cardiac function: left ventricular ejection fraction > 45%

7. Demonstrated capacity to understand the study and willingness to provide informed consent

Exclusion Criteria

1. Presence of recurrent genetic abnormalities such as t(8;21), t(15;17), inv(16)/t(16;16) leukemia
2. Prior hypersensitivity to study drugs or compounds of similar chemical structure
3. Active uncontrolled infections as determined by the investigator
4. Active bleeding
5. Recent history (within 1 year) of thrombosis, embolism, or cerebral hemorrhage
6. Pregnancy, breastfeeding, or unwillingness to use contraception in women of childbearing potential
7. Drug addiction or chronic alcoholism that could interfere with trial evaluation
8. Psychiatric disorders or other conditions that would prevent obtaining informed consent or compliance with trial requirements
9. Any condition deemed unsuitable for trial participation by the investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Investigational ( venetoclax, azacytidine)	Venetoclax	Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT. For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.
Investigational ( venetoclax, azacytidine)	Azacitidine	Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT. For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.
Investigational ( venetoclax, azacytidine)	Cytarabine	Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT. For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.

Primary Outcome Measures

Name	Time	Method
Overall response rate (ORR) after two treatment cycles of induction therapy	time from the date of enrollment to 2 cycles of induction before consolidation therapy（100 days）	Rates of complete remission (CR), and complete remission with incomplete hematologic recovery (CRi)

Secondary Outcome Measures

Name	Time	Method
OS: overall survival	2 years	time from the date of enrollment to death from any cause or the last follow-up
LFS：leukemia-free survival	2 years	the duration from the date of enrollment to the occurrence of treatment failure, relapse, death from any cause, or the last follow-up.
DOR: duration of remission	2 years	Time between the first remission and relapse
AE	Within 60 days after treatment	Adverse events during the induction treatment.
Volume of infused blood products	Within 60 days	The volume of infused blood products during the induction treatment.

Trial Locations

Locations (1)

Ethical Committee of the First Affliated Hospital of Soochow University; 🇨🇳 Suzhou, Jiangsu, China