ALLG AMLM28/A2 (ADAPT): Achieving Durable remissions via Adaptive Pro-survival Targeting in acute myeloid leukaemia (AML)) – VEN/AZA/Pelcitoclax. A therapeutic arm of the ALLG AMLM28 ADAPT Study-Master Protocol.

Exclusion Criteria64

• A Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Presence of either of the following criteria in patients undergoing frontline Acute Myeloid Leukaemia (AML) treatment with Venetoclax and Azacitidine (VEN-AZA):
• a. Either mutated TP53, del17p or monosomy 17 at diagnosis. Patients eligible for this domain can enroll after completing 1-2 cycles of VEN-AZA (ADAPT-TP53), OR
• b. Morphologic remission with less than 5% bone marrow (BM) blasts but persistently detectable measurable residual disease (MRD) equal or greater than 0.1% after completing at least 3 cycles of VEN-AZA by flow cytometry. Patients should commence study therapy within 180 days from AML diagnosis (ADAPT-MRD).
• Adequate blood count parameters
• a. For patients in ADAPT-TP53:
• i. Platelet count equal or greater than 25 x109/L
• b. For patients in ADAPT-MRD:
• i. Platelet count equal or greater than 50 x109/L
• ii. Neutrophils equal or greater than 0.5 x109/L
• Adequate renal function as demonstrated by a creatinine clearance ?30 ml/min; calculated by the Cockroft Gault formula or measured by 24-hour urine collection.
• Adequate liver function as demonstrated by :
• a. Aspartate aminotransferase (AST) equal or less than 1.5 x Upper limit of Normal (ULN).
• b. Alanine aminotransferase (ALT) equal or less than 1.5 x ULN.
• c. Bilirubin equal or less than 1.5 xULN (unless considered due to Gilbert’s syndrome or AML).
• Coagulation profile: APTT and PT equal or less than 1.5 x ULN.
• Patient agrees to follow the recommended contraception procedures for this domain, see below:
• Female patients must be either:
• a) postmenopausal defined as:
• i. Older than 55 years of age with no menses for 12 or more months without an alternative medical cause.
• ii. 55 years of age or younger with no menses for 12 or more months without an alternative medical cause AND an FSH level over 40 IU/L.
• OR
• b) Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• OR
• c) Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at day 1 through at least 180 days after the last dose of study drug.
• Male patients who are sexually active, must agree, from day 1 through at least 180 days after the last dose of study drug, to practice the protocol specified Contraception outlined below. Male patients must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug.
• Females of childbearing potential must have negative results for pregnancy test performed:
• a) At Screening with a serum sample obtained within 7 days prior to the first study drug administration, and
• b) Patients with borderline pregnancy tests at Screening must have a serum pregnancy test equal or greater than 3 days later to document continued lack of a positive result.
• While participating in this research study, female patients should not become pregnant or breastfeed a baby. Male patients should not father a baby.
• Unless postmenopausal or permanently surgically sterile, a WOCBP must practice at least one of the following methods of birth control, on Study Day 1 (or earlier) through at least 180 days after the last dose of study drug.
• a) Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 1 month prior to Study Day 1. Also, subjects must use a barrier method during this study from initial study drug administration to 180 days after the last dose of study drug.
• b) Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 1 month prior to Study Day 1. Also, patients must use a barrier method during this study from initial study drug administration to 180 days after the last dose of study drug.
• c) Bilateral tubal occlusion/ligation or bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms success of the procedure.
• d) Vasectomized partner(s), provided the vasectomized partner verbally confirms receipt of medical assessment of the surgical success, vasectomy occurred more than 3 months prior to screening, and is the sole sexual partner of the WOCBP trial participant.
• e) Intrauterine device (IUD).
• f) Intrauterine hormone-releasing system (IUS).
• g) True abstinence: Refraining from heterosexual intercourse 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].
• Male patients who are sexually active with a WOCBP, even if the male patients has undergone a successful vasectomy, must agree:
• a) 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 patients of childbearing potential).
• b) Additionally, male subject agrees not to donate sperm from Study Day 1 through at least 180 days after the last dose of study drug.
• A patient will not be eligible for this treatment arm participation if any of the following criteria apply:
• White Cell Count (WCC) greater than 15 x10^9/L. Hydroxyurea and/or thioguanine may be used for cytoreduction.
• Active Central Nervous System (CNS) leukaemia.
• The patient is unable to swallow tablets, or has malabsorptive issues that in the investigator’s opinion will interfere with absorption of study drugs.
• 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: patients 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.
• QT-interval corrected according to Fridericia’s formula (QTcf) >450ms.
• Patient unable to have a 5-day washout prior to commencing first dose of study drug:
• a. Strong or moderate cytochrome P450 (CYP)3A inducers such as Rifampin, carbamazepine, phenytoin and St John’s wort
• b. Strong or moderate CYP3A inhibitors such as posaconazole, voriconazole, fluconazole, ketoconazole, clarithromycin, fosaprepitant, aprepitant. They are prohibited during cycle 1 of the safety run-in phase. At other times they may be used
• if required with caution and with appropriate dose modifications for Venetoclax.
• Patient unable to have a 3-day interval prior to the first dose of study drug from:
• a. Grapefruit or grapefruit products, seville oranges (including marmalade containing Seville oranges), star fruit
• Treatment with prior anti-leukemic therapy (not including VEN-AZA) within 14 days prior to the first dose of study drug.
• History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of <2 years.
• The patient is human immunodeficiency virus (HIV) positive.
• Known hypersensitivity to the investigational agent.
• The patient has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation.
• Patient requiring medical treatment with antiplatelet or anticoagulants, or herbal supplement that affects platelet function within 7 days prior to the first dose of study drug.
• Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patient 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 equal or greater than 45%.
• Patient has significant chronic respiratory disease that requires continuous oxygen.
• Active bleeding or history of major bleeding (Grade 3+) within the last 12 months.