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NCT07748455

PHASE2

HMA-Venetoclax Induction in Newly Diagnosed AML

Sponsor: Pakistan Blood and Marrow Transplant (PBMT) Group

View on ClinicalTrials.gov

Summary

Acute myeloid leukaemia (AML) is a clonal haematological malignancy characterised by arrested myeloid differentiation and uncontrolled proliferation of blast cells in the bone marrow and peripheral blood. It is the most common acute leukaemia in adults and carries a high disease-related mortality. Globally, the median age of diagnosis is approximately 68 years; however, a significant proportion of patients are diagnosed below the age of 50 years, constituting the 'young fit' population for whom aggressive curative-intent therapy is most appropriate. The epidemiology of AML in South Asia and Pakistan remains incompletely characterised. Published single-centre and multi-centre data from Pakistan suggest that AML represents a major proportion of haematological malignancies presenting to tertiary centres. AFBMTC, as the largest haematology and transplant centre in Pakistan, has accumulated over 2,000 HSCT procedures since 2001 and has established the necessary infrastructure for prospective clinical research in this disease. Cytogenetic and molecular classification of AML profoundly influences prognosis and treatment decisions. The European LeukemiaNet (ELN) 2022 risk stratification framework categorises AML into Favourable, Intermediate, and Adverse risk groups based on chromosomal abnormalities and somatic mutations including NPM1, FLT3-ITD, IDH1/2, RUNX1, ASXL1, TP53, and others. This framework underpins post-remission pathway assignment in the current protocol.

Official title: HMA-Venetoclax Induction in Young, Fit Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Prospective, Single-Arm, Phase II Study

Key Details

Gender

All

Age Range

18 Years - 50 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2026-08-01

Completion Date

2027-12-31

Last Updated

2026-08-05

Healthy Volunteers

Conditions

AML AML (Acute Myeloid Leukemia)

Interventions

DRUG

Azacitidine 75 mg/m² SC/IV Days 1-7 + Venetoclax 400 mg orally Days 1-28 (Cycle 1 ramp-up per institutional TLS protocol); 28-day cycles; maximum 2 induction cycles

Induction Regimen: AZA-VEN The AZA-VEN induction regimen will be administered for a maximum of 2 cycles (each 28 days). Patients achieving CR/CRi/CRh after Cycle 1 will proceed directly to post-remission therapy. Drug Dose Route Days Cycle Duration Azacitidine 75 mg/m² SC or IV infusion (30 min) Days 1-7 28 days (repeat Cycle 2 if needed) Venetoclax 400 mg/day (target; after ramp-up) Oral (once daily with food or within 30 min of eating) Days 1-28 28 days Venetoclax Ramp-Up Schedule (Cycle 1 Only) To mitigate the risk of tumour lysis syndrome (TLS), venetoclax must be dose-ramped during Cycle 1. The ramp-up is not required in subsequent cycles. Days Daily Dose TLS Risk Mitigation Day 1 100 mg Hospitalise; IV hydration; allopurinol 300 mg/day initiated ≥48h before Day 2 200 mg Continue hydration; monitor electrolytes at 4, 8, 24h post first dose Day 3 400 mg (target) Continue hydration; check electrolytes at 4h post dose Day 3 Days 4-28 400 mg Outpatient permissible if TLS risk re

Inclusion Criteria Patients must satisfy ALL of the following criteria to be eligible for enrolment: 1. Age 18-50 years (inclusive) at the time of enrolment 2. Confirmed diagnosis of AML (non-APL) per WHO 2022 Classification: ≥20% blasts in bone marrow or peripheral blood, or documented leukaemia-defining cytogenetic abnormality regardless of blast count (e.g. t(8;21), inv(16), t(15;17) is excluded as APL). Diagnosis must be confirmed by bone marrow aspirate and/or biopsy with morphology, flow cytometry, and cytogenetics. 3. Newly diagnosed AML: no prior cytotoxic therapy for AML (excluding hydroxyurea for blast cytoreduction, which is permitted for ≤7 days prior to enrolment) 4. ECOG Performance Status 0-2 5. Adequate end-organ function at screening (within 7 days of first study drug administration): 1. Serum creatinine ≤2 × ULN or CrCl ≥40 mL/min (CKD-EPI formula) 2. ALT and AST ≤3 × ULN (≤5 × ULN if attributed to hepatic leukaemic infiltration) 3. Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert syndrome or hepatic leukaemic infiltration) 4. LVEF ≥45% by echocardiography or MUGA (assessed within 28 days of enrolment) 6. Willing and able to provide written informed consent (patient or legally authorised representative for patients with AMS at presentation) 7. Willingness to comply with all study procedures, including bone marrow assessments, follow-up visits, and MRD monitoring 8. For women of childbearing potential (WOCBP): negative serum or urine pregnancy test within 72 hours of Cycle 1 Day 1, and agreement to use effective contraception throughout study treatment and for 12 months after last dose 9. For male patients with female partners of childbearing potential: agreement to use effective contraception and refrain from sperm donation throughout treatment and for 6 months after last dose 5.2 Exclusion Criteria Patients will be excluded from participation if ANY of the following apply: 10. Acute promyelocytic leukaemia (APL) \[t(15;17); PML-RARA\]: patients with APL must be referred for ATRA-based therapy as per institutional standard 11. AML secondary to myeloproliferative neoplasm (MPN) in blast phase, where prior MPN was treated with ruxolitinib within 8 weeks of enrolment (due to drug interaction potential with venetoclax) 12. Prior exposure to a BCL-2 inhibitor (venetoclax, navitoclax, or other) at any time 13. Prior exposure to HMA therapy (azacitidine or decitabine) for a pre-existing MDS or MPN within 6 months of AML diagnosis 14. Active, uncontrolled systemic infection at the time of enrolment that in the investigator's judgement would preclude initiation of cytotoxic therapy (note: controlled infection with appropriate antimicrobial therapy is not an exclusion) 15. Known active hepatitis B virus (HBV) infection (HBsAg positive) without established antiviral prophylaxis; or active hepatitis C virus (HCV) infection with detectable viral load 16. Known HIV infection with CD4 count \<350 cells/μL or detectable viral load (HIV-positive patients with well-controlled disease on antiretroviral therapy may be enrolled after discussion with the Principal Investigator and Infectious Disease consultant) 17. Cardiac exclusions: 1. QTcF \>480 ms on screening ECG 2. Clinically significant and uncontrolled arrhythmia 3. NYHA Class III-IV heart failure 4. Acute coronary syndrome or stroke within 6 months of enrolment 18. Malabsorption syndrome or other gastrointestinal condition that would significantly impair oral absorption of venetoclax 19. Concomitant strong CYP3A4 inhibitors (e.g. ketoconazole, posaconazole, voriconazole, clarithromycin) or inducers (e.g. rifampicin, phenytoin, carbamazepine) that cannot be safely discontinued or dose-adjusted. (Note: azole antifungals require venetoclax dose reduction per label - see Section 7.4) 20. Concurrent active malignancy requiring systemic therapy (patients with adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix are eligible) 21. Pregnancy or breastfeeding 22. Participation in any other interventional clinical trial within 4 weeks of enrolment 23. Any condition that, in the investigator's judgement, would compromise patient safety, protocol compliance, or the integrity of study data

Locations (1)

National University of Medical Sciences, Clinical Trial Unit

Rawalpindi, Pakistan