AMLM26/T1 INTERCEPT
AMLM26/T1 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics – Gilteritinib+ Venetoclax
Acute Myeloid Leukaemia
This is a combined drug treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. The combination of gilteritinib and 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:
The trial will commence with a safety run to determine the optimal dosing. Gilteritinib is given orally with or without food. Venetoclax is given orally after food. Venetoclax dose ramp-up is required only for patients commencing therapy with bone marrow blasts of greater than or equal to 5%. Each cycle will be 28-days in length
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 Gilteritinib 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.
Key inclusion criteria
1. Meets inclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. Presence of a FLT3 (ITD and/or TKD) or CBL mutation in a bone marrow or peripheral blood sample taken no more than 42-days prior to cycle 1 day 1 if 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
Key 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) >450ms (except for right bundle branch block)
3. Prior allogeneic stem cell transplantation within 30 days of post-conditioning or on immunosuppression for graft vs host disease (GVHD) (except for sole immunosuppression with prednisolone of less than or equal to 10mg/day for GVHD management 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
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 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 6a).
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%.
13. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject, which will require approval from the chief investigator.
2. QT-interval corrected according to Fridericia’s formula (QTcF) >450ms (except for right bundle branch block)
3. Prior allogeneic stem cell transplantation within 30 days of post-conditioning or on immunosuppression for graft vs host disease (GVHD) (except for sole immunosuppression with prednisolone of less than or equal to 10mg/day for GVHD management 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
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 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 6a).
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%.
13. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject, which will require approval from the chief investigator.
Dr. Carolyn Grove
Australasian Leukaemia & Lymphoma Group
Phase 1 / Phase 2
AMLM26/T1- INTERCEPT
ACTRN12624000082505