AMLM26/T3 INTERCEPT
A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics – Low-dose cytarabine (LDAC) + Venetoclax
Acute Myeloid Leukaemia
This is a combination drug treatment arm within the ALLG AMLM26 INTERCEPT trial platform, which is registered on ANZCTR with ID ACTRN12621000439842. The combination of Low dose cytarabine (LDAC) 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:
Venetoclax will be administered orally once daily (QD) Days 1–28, of a 28-day cycle, with a designated dose of 600 mg daily. Please note that Venetoclax dose ramp-up is required only for patients commencing therapy with bone marrow blasts of greater than or equal to 5%: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3 and 600 mg on day 4 onwards.
LDAC (20 mg/m2) is administered subcutaneously (SC) QD following administration of Venetoclax on Days 1-10 of every cycle
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 Low dose cytarabine 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 Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. ECOG 0-2
3. 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
4. Subject must have adequate liver function as demonstrated by below, unless considered to be due to leukemic organ involvement
a. aspartate aminotransferase (AST) less than or equal to 3.0 × Upper Limit Normal (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)
5. Female subjects must be either postmenopausal defined as:
a. Age greater than 55 years with no menses for 12 or more months without an alternative medical cause.
b. Age less than or equal to 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level greater than 40 IU/L.
OR
c. Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR
d. A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at Study Day 1 through at least 180 days after the last dose of study drug.
6. Male subjects who are sexually active with a WOCBP, even if the male subject has undergone a successful vasectomy, must agree from Study Day 1 through at least 180 days after the last dose of study drug to use condoms and his female partner(s) must use at least one of the contraceptive measures (as defined in the protocol for female study subjects of childbearing potential). Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug.
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. Prior use of venetoclax with LDAC/HMA is allowed unless demonstrated to be refractory to this combination. Prior venetoclax monotherapy is allowed.
3. Subject is HIV positive
4. 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 <10mg/day for GVHD management which is permitted)
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 (HBs antigen negative but HBc 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 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. Subjects 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 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%.
2. Prior use of venetoclax with LDAC/HMA is allowed unless demonstrated to be refractory to this combination. Prior venetoclax monotherapy is allowed.
3. Subject is HIV positive
4. 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 <10mg/day for GVHD management which is permitted)
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 (HBs antigen negative but HBc 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 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. Subjects 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 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%.
Dr. Carolyn Grove
Australasian Leukaemia & Lymphoma Group
Phase 1 / Phase 2
AMLM26/T3-INTERCEPT
ACTRN12624000006549