Not Yet RecruitingPhase 3ACTRN12625001003460

ALLG AMLM29 CAVIAT-R (Chemotherapy and Venetoclax in Acute Myeloid Leukaemia (AML) Trial- Randomised): a multicentre phase III trial investigating venetoclax plus intensive chemotherapy for newly diagnosed AML

Sponsor

Australasian Leukaemia and Lymphoma Group

Enrollment

390 participants

Start Date

Jun 15, 2026

Study Type

Interventional

Conditions

Acute Myeloid Leukaemia

Summary

Unmet Need: Acute Myeloid Leukaemia (AML) remains a challenging disease with poor long-term outcomes despite intensive chemotherapy. While venetoclax has shown benefit in older or unfit patients, its role in fit adults receiving intensive chemotherapy is not yet defined. Who is it for: This study is for fit adults aged 18 and over with newly diagnosed AML who are suitable for intensive chemotherapy. Study Design: This is a phase III, multicentre, randomised (1:1) controlled trial comparing standard intensive chemotherapy (IC) with a modified regimen combining IC and venetoclax (IC-VEN). A total of 390 patients will be recruited across participating sites. It is hoped this study will: Determine whether adding venetoclax to a shortened course of intensive chemotherapy improves event-free survival (EFS), measurable residual disease (MRD) clearance, and other clinical outcomes. The trial also aims to establish a new standard of care for fit adults with AML.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria40

Age 18 years and over.
Newly diagnosed AML (patients with core binding factor rearrangement and Acute Promyelocytic Leukaemia are excluded), with equal or greater than10% blasts, considered suitable for intensive chemotherapy.
Consented to the ALLG National Blood Cancer Registry (NBCR).
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 inclusive .
Adequate hepatic function as demonstrated by:
a. Bilirubin equal or less than 1.5x Upper limit of normal (ULN) (unless due to Gilbert’s syndrome or of non-hepatic origin), AND
b. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) equal or less than 3x ULN
unless considered to be due to leukaemic organ involvement.
Adequate renal function with calculated creatinine clearance greater than 30ml/min calculated by the Cockcroft Gault formula or measured by 24-hours urine at screening
Cardiac ejection fraction greater than 45% by echocardiogram (ECHO) or gated blood pool scan (GHPS).
No prior treatment for AML (Note: hydroxyurea, cytarabine (1-2 doses only), and/or thioguanine for cytoreduction is allowed).
White Cell Count (WCC) less than 25 x109/L (cytoreductive agents as specified above permitted for management of high WCC).
No contraindication to the use of the investigational product venetoclax.
Female patients must either be
a. Post-menopausal as defined by:
i. Age greater than 55 years with no menses for 12 or more months without an alternative medical cause OR
ii. Age equal or younger than 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level greater than 40 IU/L OR
Age 18 years and over.
Newly diagnosed AML (patients with core binding factor rearrangement and Acute Promyelocytic Leukaemia are excluded), with equal or greater than10% blasts, considered suitable for intensive chemotherapy.
Consented to the ALLG National Blood Cancer Registry (NBCR).
ECOG performance status 0-2 inclusive.
Adequate hepatic function as demonstrated by:
a. Bilirubin equal or less than1.5x ULN (unless due to Gilbert’s syndrome or of non-hepatic origin), AND
b. AST and ALT equal or less than 3x ULN
unless considered to be due to leukaemic organ involvement.
Adequate renal function with calculated creatinine clearance greater than 30ml/min calculated by the Cockcroft Gault formula or measured by 24-hours urine at screening
Cardiac ejection fraction greater than45% by echocardiogram (ECHO) or gated blood pool scan (GHPS).
No prior treatment for AML (Note: hydroxyurea, cytarabine (1-2 doses only), and/or thioguanine for cytoreduction is allowed).
White Cell Count (WCC) less than25 x109/L (cytoreductive agents as specified above permitted for management of high WCC).
No contraindication to the use of the investigational product venetoclax.
Female patients must either be
a. Post-menopausal as defined by:
i. Age greater than 55 years with no menses for 12 or more months without an alternative medical cause OR
ii. Age equal or younger than 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level greater than 40 IU/L OR
b. Women of childbearing potential (WOCBP) must use a highly effective method of contraception, and must not donate or cryopreserve eggs, from randomisation until 30 days after completion of trial protocol treatment. Highly effective methods include:
i. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
ii. Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before randomisation . In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
iii. Male sterilisation (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that patient.
iv. Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate less than1%), for example hormone vaginal ring or transdermal hormone contraception.
Male patients who are sexually active with a WOCBP, even if the male patient has undergone a successful vasectomy, must agree from randomisation through at least 30 days after the last dose of trial protocol treatment to use condoms. Male patients must agree to refrain from sperm donation from randomisation through at least 30 days after the last dose of study drug.

Exclusion Criteria21

Secondary Acute Myeloid Leukemia (AML) with prior history of myeloproliferative neoplasm or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap. Patients with a history of myelodysplastic syndrome (MDS) are not excluded if untreated, but will be excluded if they have had prior exposure to a hypomethylating agent or B-cell lymphoma 2 (BCL2) inhibitor for treatment of MDS.
Acute Myeloid Leukemia (AML) following cytotoxic therapy as defined by World Health Organization 2022 (WHO 2022), which includes cytotoxic therapy and/or large-field radiation therapy.
Known active central nervous system (CNS) involvement with leukemia.
Unrelated malignancy with an expected survival of less than three years.
Evidence of cardiac, pulmonary, hepatic, or renal disease, or clinically significant uncontrolled condition(s), including but not limited to uncontrolled and/or active systemic infection (viral, bacterial, or fungal) likely to affect tolerance to investigational therapy.
Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
Evidence of other clinically significant uncontrolled condition(s), including but not limited to:
a. Clinically significant active systemic infection (viral, bacterial, or fungal) requiring therapy.
b. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment.
Note: Subjects with serologic evidence of prior vaccination to HBV (that is, hepatitis B surface antigen negative, anti-hepatitis B surface antibody positive, and anti-hepatitis B core antibody negative) or positive anti-hepatitis B core antibody from intravenous immunoglobulins (IVIG) may participate.
Patient unable to have a five-day washout prior to commencing first dose of venetoclax:
a. Strong or moderate cytochrome P450 3A (CYP3A) inducers such as rifampin, carbamazepine, phenytoin, and St John’s wort.
b. Strong or moderate CYP3A inhibitors such as voriconazole, fluconazole, ketoconazole, clarithromycin, fosaprepitant, and aprepitant.
Note: This does not apply to posaconazole, which is required as concomitant therapy with venetoclax.
Patient unable to have a three-day interval prior to the first dose of study drug from:
a. Grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), and star fruit.
Inability to swallow tablets, or conditions likely to significantly impair gastrointestinal absorption, such as short-gut syndrome or malabsorption syndromes.
Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.
Women who are pregnant or lactating. Women of childbearing potential must have negative results for a pregnancy test performed:
a. At screening with a serum sample obtained within seven days prior to the first study drug administration, and
b. Subjects with borderline pregnancy tests at screening must have a serum pregnancy test at least three days later to document continued lack of a positive result.

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Interventions

The intervention is Venetoclax in combination with a reduced intensive chemotherapy regimen in induction and consolidation therapy. Venetoclax is supplied as an oral tablet, 10 mg. Venetoclax will be

The intervention is Venetoclax in combination with a reduced intensive chemotherapy regimen in induction and consolidation therapy. Venetoclax is supplied as an oral tablet, 10 mg. Venetoclax will be administered over a period of 12 days, with a single dose each day as specified. Induction Treatment For participants under 65 years: Induction Cycle 1. Five days before the start of the main treatment: 10 mg of Venetoclax administered orally. Four days before the start of the of main treatment to Day 7: 50 mg of Venetoclax administered orally once daily. Day 1 to Day 7 of treatment period: Ara-C (Cytarabine) 100 mg/m²/day will be administered with continuous intravenous infusion (CIV). Day 1 to Day 3 of treatment period: Idarubicin 12 mg/m²/day will be administered as an intravenous (IV) bolus (administered 1 hour after Venetoclax dose). For participants 65 years and older: Five days before the start of the main treatment: 10 mg of Venetoclax administered orally. Four days before the start of the main treatment to Day 7: 50 mg of Venetoclax administered orally once daily. Day 1 to Day 5 of treatment period: Ara-C (Cytarabine) 100 mg/m²/day will be administered CIV. Day 2 to Day 3 of treatment period: Idarubicin 12 mg/m²/day administered as an IV bolus (administered 1 hour after Venetoclax dose). Induction cycle 2 chemotherapy will be administered to patients with persistent disease (equal or greater than 5% Bone Marrow blasts) after 28 days of commencing induction cycle 1 treatment. There are three options available: 1. Days 1 to Day 7 of treatment period: Filgrastim 5mcg/kg daily administered subcutaneously (SC) Day 2 to Day 6 of treatment period: Fludarabine 30mg/m^2 administered IV daily. Day 2 to Day 6 of treatment period: Cytarabine administered IV 4 hours after Fludarabine administration. (Patients aged 60 years or younger will receive 2g/m^2 daily. Patients older than 60 years will receive 2g/m^2 daily) Day 4 to Day 6 of treatment period: Idarubicin 8 mg/m^2 administered as an IV bolus daily. 2. Day 1 to Day 6: Ara-C 1g/m^2 administered IV twice a day. Day 4 to Day 6: Amsacrine 120mg/m^2 administered IV daily. 3. For participants 65 years and older: Day 1 to Day 3: Ara-C 1g/m^2 administered IV twice a day. Consolidation Treatment will be administered to patients with less than 5% Bone Marrow blasts after 28 days of commencing induction treatment. Two cycles of treatment will be administered, with a 28 day gap between the cycles. For participants under 65 years: Days 1 to Day 7: 50 mg of Venetoclax administered orally once daily. Chemotherapy: Day 1 to Day 3: Ara-C (Cytarabine) 1.5g/m² twice a day administered IV. For participants 65 years and older: Days 1 to Day 7: 50 mg of Venetoclax administered orally once daily. Chemotherapy: Day 1 to Day 10: Low-dose cytarabine (LDAC) 20mg/m² is administered SC All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.