None listed
Conditions
Brief summary
This is an investigational combination treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. This treatment arm (Ivosidenib + Venetoclax) will be evaluated for its activity in a population of participants with progressive acute myeloid leukemia (AML). Who is it for? You may be eligible for to receive this treatment if you are a part of the AMLM26 Intercept trial which is registered on ANZCTR with ID ACTRN12621000439842 (ie if you are aged 18 or older, you have been diagnosed with progressive acute myeloid leukemia, and are currently in your first or second morphologic remission with a known and trackable minimal residual disease (MRD) marker.). If you are on the AMLM26 Intercept trial you may be eligible for this treatment option if your disease is worsening. The trial management committee will review your disease characteristics and determine your best treatment option(s) available on the trial. Study details Ivosidenib and Venetoclax are given orally. Ivosidenib 500mg once a day commencing day 15 of cycle one and taken continuously and Venetoclax administered days 1-14 of a 28 day cycle for 12 cycles. Patients with minimal residual disease will have a pilot safety run-in phase to confirm dose - investigating Venetoclax doses 800mg or 600mg daily. Once a tolerable dose is determined that dose will be used in a proof of concept phase.. Patients with morphologic relapse will enter directly into a proof of concept phase using a Venetoclax dose of 800mg daily with a dose ramp up in cycle 1. Participants will undergo a disease assessment at screening after cycle 1, cycle 2, cycle 3, cycle 6 and then 2 monthly until progression. This will require blood tests and bone marrow biopsies. Safety and tolerability of treatment will be assessed throughout the trial whilst you are receiving treatment. Health related quality of life during treatment will be assessed on the first treatment day of 3 consecutive cycles. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that Ivosidenib and Venetoclax will be well tolerated and may improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Interventions
The ALLG AMLM26 INTERCEPT trial is an adaptive trial allowing the testing of multiple new therapeutic options targeting various AML biomarkers in a staged manner. The Master Protocol outlines the overall study structure (this is detailed in ANZCTR entry ACTRN12621000439842). There will be separate domains for each AML biomarker being investigated. Each domain will have at least one investigational agent. Each investigational agent may be used on its own and/or in combination with other agents. Each option will be a different treatment arm within a domain. Separate Therapy-Specific Protocol Appendices will include treatment-specific information for each investigational agent including all of the treatment arms specific to that investigational agent. Each treatment arm may be targeted to a specific AML biomarker (domain) and/or may be used when patients have no targetable option available. This entry is for the investigational combination - Ivosidenib + Venetoclax. Ivosidenib and Venetoclax are both tablets that will be administered orally once a day up to 12 cycles, each 28 days in duration. Ivosidenib is taken with or without food and Venetoclax is taken after food. Ivosidenib is started on day 15 of the first cycle and taken continuously. Venetoclax is given days 1-14. As this agent has not yet been tested in patients with MRD progression, we will confirm the dose for patients with MRD progression in a pilot safety run-in phase. The first dose level explored will be 500mg daily ivosidenib day 15 onwards, and 800mg Venetoclax daily days 1 to 14. If not tolerable 500mg daily ivosidenib day 15 onwards, and 600mg Venetoclax daily days 1 to 14 will be investigated. Once the optimal dose is determined in the pilot phase for MRD progressors, enrolment onto a proof-of-concept phase will commence using the dose level deemed tolerable. Patients in the morphologic relapse will immediately be enrolled into the POC phase at a dose of 500mg daily ivosidenib day 15 onwards, and 800mg Venetoclax daily days 1 to 14 (utilising the recommended phase 2 dose determined by the sponsored phase 1b/II study (NCT03471260) to be most tolerable and effective).Patients with morphologic disease will undertake a dose ramp up of Venetoclax in cycle 1 only 100mg on Day 1, 200mg on day 2, 400mg on day 3 and 800mg on days 4to 14. Patients will be asked to complete a dose diary to confirm the tablets were taken. Patients will also be asked to return the ivosidenib and venetoclax bottles (with unused tablets or empty containers) to the hospital. This is to monitor compliance with the treatment.
Sponsors
Australasian Leukaemia & Lymphoma Group
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Meets inclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol(see ACTRN12621000439842 for details on the master protocol). 2. Presence of an IDH1 mutation in a bone marrow or peripheral blood sample taken no more than 42 days prior to cycle 1 day 1 of treatment on this treatment arm 3. ECOG 0-2 4. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection 5. Subject must have adequate liver function as demonstrated by: a. aspartate aminotransferase (AST) less than or equal to 3.0 × ULN b. alanine aminotransferase (ALT) less than or equal to 3.0 × ULN c. bilirubin less than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin) 6. Agrees to follow the recommended contraception procedures for this treatment domain
Exclusion criteria
1. Presence of any general exclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol) 2. QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms (except for right bundle branch block) 3. Prior allogeneic stem cell transplant within 30 days of post-transplant conditioning, or on immunosuppression for graft vs host disease (GVHD) (other than less than or equal to 10mg/day of prednisolone which is permitted). 4. Subject is HIV positive 5. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) 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) or patients who have past exposure to HepB (HepB Surface Antigen negative but core antibody positive and DNA negative) who do not require treatment may participate. 6. Treatment with any of the following within 7 days prior to the first dose of study drug: a. Steroid therapy for anti-neoplastic intent, or greater than 10mg/day prednisolone for graft versus host disease b. Moderate or strong CYP3A inducers c. Moderate or strong cytochrome CYP3A inhibitors are prohibited 7 days prior to cycle 1 day 1. They are prohibited during cycle 1 of the pilot safety run-in phase and during venetoclax dose ramp-up in all phases. At other times they may be used if required with caution and with appropriate dose modifications for venetoclax 7. Administration or consumption of any of the following within 3 days prior to the first dose of study drug: a. Grapefruit or grapefruit products b. Seville oranges (including marmalade containing Seville oranges) c. Star fruit 8. Treatment with prior anti-leukemic therapy within 14 days prior to the first dose of study drug. (except steroids see exclusion 5a) 9. Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Patients with fully excised BCC/SCC/CIN or other minor malignancy are not excluded. 10. Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation 11. Subject has radiation therapy within 4 weeks prior to the first study dose. 12. Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or gated cardiac blood pool scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is greater than or equal to 45%.
Outcome results
None listed