None listed
Conditions
Brief summary
The primary purpose of this trial is to evaluate the safety and efficacy of venetoclax in combination with chemotherapy for the treatment of acute myeloid leukaemia (AML) in elderly patients. Who is it for? You may be eligible to participate in this trial if you are aged 60 or over with monosomal karyotype, or aged 65 or over with any karyotype, and have been diagnosed with AML for which you have received no induction chemotherapy. Study details All participants enrolled in this trial will be administered Venetoclax in combination with modified-dose chemotherapy. The dose provided will depend on the time of enrolment - each sequentially enrolled group of participants will be administered with a slightly higher dose than the previous group, pending a review of the safety of the previous dose. Participants will have an induction treatment consisting of 14 days Venetoclax tablets, 5 days IV Cytarabine and 2 days IV Idarubicin. For participant achieving a response to treatment there will be up to 4 further cycles of 14 days Venetoclax, 2 days Cytarabine and 1 day Idarubicin or until adequate blood count recovery. Participants will be assessed through blood samples taken daily during initial hospitalisation and then at the end of each cycle of treatment, bone marrow samples taken 3 times during induction and then every other cycle as well as a physical exam every cycle in order for researchers to monitor whether the treatment is safe and whether it is effectively treating the AML. It is hoped that the findings of this trial will provide information on the optimal dose of Venetoclax in combination with chemotherapy for the safe and effective treatment of AML in elderly patients.
Interventions
Dosage for Cohort 1
Induction cycle: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-12, Idarubicin 12mg/m2/d IV bolus days 9-10
Continuation (4 cycles) for patients achieving CR, Cri, PR, PRm: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-9, Idarubicin 12mg/m2/d IV bolus day 8
Maintenance (max 7 cycles at discretion of physician and patient): Venetoclax 50mg oral tablet days 1-14 (of 28)
Venetoclax monitoring through empty bottl
Dosage for Cohort 1 Induction cycle: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-12, Idarubicin 12mg/m2/d IV bolus days 9-10 Continuation (4 cycles) for patients achieving CR, Cri, PR, PRm: Venetoclax 50mg oral tablet days 1-14 (of 28), Cytarabine 100mg/m2/d CIV days 8-9, Idarubicin 12mg/m2/d IV bolus day 8 Maintenance (max 7 cycles at discretion of physician and patient): Venetoclax 50mg oral tablet days 1-14 (of 28) Venetoclax monitoring through empty bottle return. Subsequent Cohorts Cytarabine and Idarubicin doses to remain the same for subsequent cohorts (up to 6). Venetoclax dosage increasing per cohort in increments of up to 100mg per day to a maximum possible dose of 800mg per day. Dose levels for each subsequent cohort to be determined following review by dose escalation committee.
Sponsors
Alfred Health
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. De novo, secondary or therapy-related AML (except Acute Promyelocytic Leukaemia) without prior exposure to induction chemotherapy (not including hydroxyurea, low-dose cytarabine eg ~20mg bd, hypomethylating agents or non-chemotherapy-based investigational agents) 2. Age greater than or equal to 65 3. Or Age greater than or equal to 60 and monosomal karyotype 4. ECOG performance status 0-1 5. Adequate hepatic function as defined by bilirubin less than or equal to 1.5 x the upper limit of normal (ULN, excluding Gilbert’s syndrome) and AST & ALT less than or equal to 2.5 x ULN (unless due to leukemic involvement) 6. Adequate renal function as defined by eGFR>50ml/min as assessed by eCCr =(140 – Age) x (Weight in kg) x [1.23 if Male, 1.04 if Female]/Serum Creatinine (micromol/L) 7. WCC less than 25 x 109/L (hydroxyurea allowable to reduce WCC prior to day 1 of study)
Exclusion criteria
1. Prior investigational anti-leukemia agents within 14 days of day 1 of study drug; demethylating agents within 14 days of day 1 of study drug; and hydroxyurea within 24 hrs prior to day 1 of study drug. 2. Prior exposure to Venetoclax or other BCL2 inhibitors 3. Prior anthracycline exposure for previous cancer 4. Any serious medical condition which the investigator feels may lead to an unacceptably high risk of treatment related death from 5+2 induction 5. Concurrent malignancy likely to affect treatment safety or study procedures 6. Known HIV infection 7. Uncontrolled viral hepatitis type B or C 8. Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following the date of last dose 9. Cardiac ejection fraction <45% 10. Subject has received the following within 7 days prior to the initiation of study treatment: *Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort; *Warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect). 11. Subject has received the following within 5 days prior to the initiation of study treatment: * CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin. 12. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment. 13. Subject has a history of other malignancies prior to study entry, with the exception of: *Adequately treated in situ carcinoma of the breast or cervix uteri; *Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; *Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. *Prior malignancy treated >4 years ago and no evidence of active disease
Outcome results
None listed