None listed
Conditions
Brief 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) and venetoclax (IC-VEN). For patients older than 65 years of age, a modified regimen combining a reduction of IC and venetoclax will be provided. A total of 390 patients will be recruited across participating sites. It is hoped this study will: Determine whether adding venetoclax to 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.
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, 100 mg. Venetoclax will be administered over a period of 9 days, with a single dose each day as specified.
Induction Treatment
For participants under 65 years:
Induction Cycle 1.
Day before the start of the main treatment: 100 mg of Venetoclax administered orally.
First day of main treatment: 200 mg of Venetoclax administe
The intervention is Venetoclax in combination with a reduced intensive chemotherapy regimen in induction and consolidation therapy. Venetoclax is supplied as an oral tablet, 100 mg. Venetoclax will be administered over a period of 9 days, with a single dose each day as specified. Induction Treatment For participants under 65 years: Induction Cycle 1. Day before the start of the main treatment: 100 mg of Venetoclax administered orally. First day of main treatment: 200 mg of Venetoclax administered orally. Days 1 to Day 7 of treatment period: 400 mg of Venetoclax administered orally once daily. Chemotherapy: 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: Day before the start of the main treatment: 200 mg of Venetoclax administered orally. First day of main treatment: 400 mg of Venetoclax administered orally. Days 1 to Day 7 of treatment period: 600 mg of Venetoclax administered orally once daily. Chemotherapy: 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. For participants under 65 years: 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. 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: 400 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: 400 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.
The intervention is Venetoclax in combination with intensive chemotherapy regimen in induction and consolidation therapy. Venetoclax is supplied as an oral tablet, 50 mg. Venetoclax will be administered over a period of 12 days, with a single dose each day as specified. Prophylaxis treatment with Posaconazole must commence 5 days prior to treatment with Venetoclax and continue at least 12 days of administration to ensure overlap with Venetoclax. Posaconazole to be administered as per institution
The intervention is Venetoclax in combination with intensive chemotherapy regimen in induction and consolidation therapy. Venetoclax is supplied as an oral tablet, 50 mg. Venetoclax will be administered over a period of 12 days, with a single dose each day as specified. Prophylaxis treatment with Posaconazole must commence 5 days prior to treatment with Venetoclax and continue at least 12 days of administration to ensure overlap with Venetoclax. Posaconazole to be administered as per institutional guidelines. Induction Treatment For participants under 65 years: Induction Cycle 1. Five days before the start of the main treatment: 50 mg of Venetoclax administered orally. 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: 50 mg of Venetoclax administered orally. 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 four options available: 1. FLAG-Ida-Ven (Fludarabine-Cytarabine (Ara-C)-Idarubicin-Venetoclax) Days 1 to Day 7 of treatment period: Filgrastim 5mcg/kg daily administered subcutaneously (SC). Pegfilgrastim 6mg may be given 24 hours after completing chemotherapy instead of continuing daily filgrastim. Day 2 to Day 6 of treatment period: Fludarabine 30mg/m^2 administered IV daily. (Patients over the age of 60 years will receive 20mg/m^2 administered IV daily. Day 2 to Day 6 of treatment period: Cytarabine 1.5g/m^2 administered IV 4 hours after Fludarabine administration. (Patients over the age of 60 years will receive 0.5-1g/m^2 of Cytarabine). Day 4 to Day 6 of treatment period: Idarubicin 6mg/m^2 administered as an IV bolus daily. Day 1 of treatment period: Venetoclax 100mg administered orally Day 2 of treatment period: Venetoclax 200mg administered orally Day 3 to day 7 of treatment period: Venetoclax 400mg administered orally (dose adjustment required for Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) interactions). 2. FLAG-Ida (Fludarabine-Cytarabine (Ara-C)-Idarubicin) Days 1 to Day 7 of treatment period: Filgrastim 5mcg/kg daily administered subcutaneously (SC). Pegfilgrastim 6mg may be given 24 hours after completing chemotherapy instead of continuing daily filgrastim. Day 2 to Day 6 of treatment period: Fludarabine 30mg/m^2 administered IV daily. Day 2 to Day 6 of treatment period: Cytarabine 2g/m^2 administered IV 4 hours after Fludarabine administration. (Patients over the age of 60 years will receive 1g/m^2 of Cytarabine). Day 4 to Day 6 of treatment period: Idarubicin 8mg/m^2 administered as an IV bolus daily. 3. IDAC-AMSA (Intermediate-dose Cytarabine (Ara-C)-Amsacrine) 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. 4. IDAC (Intermediate-dose Cytarabine (Ara-C)) 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: 1) Platelets equal or greater than 100x10^9/L, 2) Neutrophils counts equal or less than 1.0x10^9/L, and 3) Resolution of non-haematological toxicities equal or less than Grade 2. Up to two cycles of treatment will be administered, with a 28 day gap between the cycles. Prophylaxis treatment with Posaconazole must commence 5 days prior to treatment with Venetoclax and continue at least 12 days of administration to ensure overlap with Venetoclax. Posaconazole to be administered as per institutional guidelines. For participants younger than 65 years of age: Days 1 to Day 7: 50 mg of Venetoclax administered orally once daily. Chemotherapy: Day 1 to Day 3: Ara-C (Cytarabine) 1.5g/m^2 twice a day administered IV. (Patients 60 years of age or older will be administered 1g/m^2) For participants 65 years of age 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.
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
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.
Sponsors
Australasian Leukaemia and Lymphoma Group
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years and over. 2. 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. 3. Consented to the ALLG National Blood Cancer Registry (NBCR). 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 inclusive . 5. 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. 6. 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 7. Cardiac ejection fraction greater than 45% by echocardiogram (ECHO) or gated blood pool scan (GHPS). 8. No prior treatment for AML (Note: hydroxyurea, cytarabine (1-2 doses only), and/or thioguanine for cytoreduction is allowed). 9. White Cell Count (WCC) less than 25 x109/L (cytoreductive agents as specified above permitted for management of high WCC). 10. No contraindication to the use of the investigational product venetoclax. 11. 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 1. Age 18 years and over. 2. 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. 3. Consented to the ALLG National Blood Cancer Registry (NBCR). 4. ECOG performance status 0-2 inclusive. 5. 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. 6. 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 7. Cardiac ejection fraction greater than45% by echocardiogram (ECHO) or gated blood pool scan (GHPS). 8. No prior treatment for AML (Note: hydroxyurea, cytarabine (1-2 doses only), and/or thioguanine for cytoreduction is allowed). 9. White Cell Count (WCC) less than25 x109/L (cytoreductive agents as specified above permitted for management of high WCC). 10. No contraindication to the use of the investigational product venetoclax. 11. 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. 12. 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 criteria
1. Secondary AML with prior history of myeloproliferative neoplasm. 2. AML, post-cytotoxic therapy as defined by the World Health Organisation (WHO)2022 (cytotoxic therapy and/or large-field radiation therapy). 3. Evidence of central nervous system (CNS) leukaemia. 4. Prior treatment for AML (except for cytoreduction specified above) or prior exposure to Venetoclax or another BCL-2 inhibitor. 5. Prior treatment with a hypomethylating agent for myelodysplastic syndrome. 6. Unrelated malignancy with an expected survival of less than 3 years. 7. 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. 8. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation. 9. 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 (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. 10. Patient has received the following within 7 days prior to the initial of study treatment a. Strong or moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin and St John’s wort 11. Patient has received the following within 5 days prior to the initial study treatment a. Strong or moderate CYP3A inhibitors such as posaconazole, voriconazole, fluconazole, ketoconazole, clarithromycin, fosaprepitant, aprepitant 12. Administration or consumption of any of the following within 3 days prior to the first dose of Venetoclax: a. Grapefruit or grapefruit products, seville oranges (including marmalade containing Seville oranges), star fruit 13. 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. 14. Women who are pregnant or lactating.
Outcome results
None listed