A study investigating different combinations of Cytarabine, Midostaurin, Pracinostat and Venetoclax in elderly patients with Acute Myeloid Leukaemia to extend remission.
AMLM25: An ALLG Phase 2 study to Investigate Novel Triplets to Extend Remission with VENetoclax in Elderly (INTERVENE) Acute Myeloid Leukaemia
The Australasian Leukaemia and Lymphoma Group
208 participants
Aug 28, 2020
Interventional
Conditions
Summary
The purpose of this study is to investigate the combination and efficacy and safety of Low dose Cytarabine, Venetoclax, Midostaurin and Pracinostat in patients with acute myeloid Leukaemia (AML). Who is it for? You may be eligible for this study if you are an adult over 60 years of age who has been diagnosed with AML, with no previous chemotherapy treatment. Study details Participants in this study will receive the following treatments: Depending on which Part of the trial is open for recruitment, patients eligible after screening will be registered to either 1. Part 1 - The dose finding Run-in phase 2. Part 1A - Run in phase or 3. Part 2 - The randomised phase 2 study The Run-Phase patients will receive either: LDAC (Low dose cytarabine) + venetoclax + midostaurin or LDAC (Low dose cytarabine) + venetoclax + pracinostat The part 1A run in phase patients will receive venetoclax + azacitidine + midostaurin The Randomised Phase patients will receive: 1. LDAC + venetoclax (Tablets) + midostaurin (Tablets) a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax (Tablets) RP2D (ramp up in cycle 1 only) c. Midostaurin (Tablets) RP2D or 2. LDAC + venetoclax + pracinostat a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax (Tablets)RP2D (ramp up in cycle 1 only) c. Pracinostat (Tablets) RP2D or 3. LDAC + venetoclax a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax 600mg (Tablets)D1-28 (ramp up in cycle 1 only) All participants will undertake blood tests, bone marrow biopsies and questionnaires. This study aims to establish whether the combination of treatments, can control the disease more effectively for a longer duration.
Eligibility
Inclusion Criteria9
- Age, greater than or equal to 60 years.
- AML (excluding acute promyelocytic leukaemia and core binding factor AML) stratified by MRC 2010 criteria
- a. Non-adverse cytogenetic risk or
- b. Adverse cytogenetic risk (inclusive of failed cytogenetic analysis)
- ECOG performance status 0-2
- No prior treatment for AML (except hydroxyurea or thioguanine)
- Adequate liver function (AST or ALT less than 1.5x ULN and bilirubin les than or equal to 1.5x ULN*). *unless considered related to AML or Gilbert’s syndrome
- Adequate renal function as demonstrated by a Cockcroft Gault formula creatinine clearance of greater than 30mL/min.
- for venetoclax + azacitidine + midostaurin arm patients must be eligible to receive venetoclax + azacitidine on the Australian PBS
Exclusion Criteria35
- Any serious medical, psychological or social problem which the investigator feels may interfere with the procedures or evaluations of the study including:
- a. Malabsorption syndrome or other condition that precludes enteral route of administration
- b. Significant cardiovascular disability status of New York Heart Association Class greater than 2.
- c. Significant chronic respiratory disease that requires continuous oxygen
- WBC greater than 25x109/L. Hydroxyurea may be used to control the white blood cell count
- Acute promyelocytic leukaemia
- Core binding factor AML including t(8;21)(q22;q22) or inv(16)(p13. 1q22)/t(16;16)(p13.1;q22)
- Antecedent chronic myeloid leukaemia (CML) or CML in blast phase
- Antecedent myelofibrosis (including primary and secondary)
- Active CNS leukaemia
- Prior exposure to venetoclax, FLT3 inhibitors or pracinostat
- Exposure to other investigational agents within 30 days or 5 half lives
- Known hypersensitivity to any of the investigational agents
- History of other malignancy requiring active systemic treatment or which is likely to result in an expected survival time of less than 2 years
- Subject is known to be positive for HIV
- Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
- a. Clinically significant active systemic infection (viral, bacterial or fungal) requiring therapy
- 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) may participate
- Active bleeding or clinically relevant prolongation of APTT or INR
- QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms
- 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 cytochrome P450 3A (CYP3A inhibitors)
- c. Moderate or strong CYP3A inducers
- 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
- (For Pracinostat containing arm only) Current smokers (use of patches, chewing gums or vaping nicotine containing fluids is permitted). Patients who stopped smoking at least 8 days prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study.
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 4 months after stopping medication. Highly effective contraception methods include:
- a. Total abstinence (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 methods of contraception
- b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- c. Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
- d. Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
- e. Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.
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Interventions
This trial will be run in two parts. Depending on which Part of the trial is open for recruitment, patients eligible after screening will be registered to either 1. Part 1 - The dose finding Run-in phase or 2. Part 2 - The randomised phase 2 study Patients will be put into groups according to cytogenetic risk. If cytogenetic results are not available or not informative, patients will be allocated to the adverse risk group. Part 1 -The run-in phase will examine: 1. For non-adverse risk patients: Low dose Cytarabine (LDAC) + venetoclax + midostaurin LDAC 20mg/m2 subcutaneously on Days 1-10 Venetoclax either 400mg (tablets) daily on days 1-28 or 600mg (tablets) daily on Days 1-28 Midostaurin 50mg (tablets) daily o days 11-28 or 50mg (tablets) twice a day on days 11-28. The dose will depend on which group the patient is in and how well tolerated the different levels are. 2. For adverse risk patients: Low dose Cytarabine + venetoclax + pracinostat (This category includes patients with no cytogenetic analysis available at screening) LDAC 20mg/m2 subcutaneously on Days 1-10 Venetoclax either 400mg (tablets) daily on days 1-28 or 600mg (tablets) daily on Days 1-28 Pracinostat 45mg (tablets) daily on days 10,12,14,17,19,21 or 45mg (tablets) daily on days 10,12,14,17,19,21,24,26,28 Part 1A.– This run-in phase was introduced in place of the LDAC-venetoclax+/-pracinostat stratum which will closed to enrolment in May 2022. It will examine: 1. The combination of Azacitidine + venetoclax + midostaurin, initially in patients with adverse cytogenetics risk. 2. This combination will be expanded to include non-adverse risk patients upon completion of recruitment to the current phase 2 non-adverse stratum (LDAC + venetoclax + midostaurin vs LDAC + venetoclax). For all patients on Part 1A : Azacitidine + venetoclax + midostaurin Azacitidine 75mg/m2 subcutaneously on Days 1-9 Venetoclax 400mg (tablets) daily on days 1-28 Midostaurin 50mg (tablets) daily on days 10-28 or 50mg (tablets) twice a day on days 10-28. The dose will depend on which group the patient is in and how well tolerated the different levels are. If initial triplet dose levels are deemed intolerable, other dose schedules will be explored. These will include shorter durations of exposure of either midostaurin or pracinostat. In this manner, the run-in phase will determine the recommended phase 2 dose (RP2D) of Low dose Cytarabine + Venetoclax with midostaurin or pracinostat, as well as azacitidine + venetoclax with midostaurin. In Part 2 - phase 2, eligible patients will be stratified based on their karyotype and randomised 2:1 to either: Low dose Cytarabine + venetoclax + midostaurin (non-adverse karyotype) or Low dose Cytarabine + venetoclax + pracinostat (adverse karyotype) versus Low dose Cytarabine + venetoclax (comparator arm). Drug schedules: 1. Low dose Cytarabine + venetoclax + midostaurin a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax (Tablets) RP2D (will be gradually increased each day Day1-3/4) Depending on dose of Venetoclax the ramp up will be as follows. For the venetoclax 400mg dose level: • In cycle 1, venetoclax will be administered with a 3-day ramp up beginning with 100mg dose on Day 1, 200mg dose on Day 2, 400mg dose on Day 3. Venetoclax will continue at 400mg daily thereafter. For the venetoclax 600mg dose level: • In cycle 1, venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4. Venetoclax will continue at 600mg daily thereafter. c. Midostaurin (Tablets) RP2D 2. LDAC + venetoclax + pracinostat (Tablets) a. LDAC 20mg/m2 sc daily D1-10 of each cycle. b. Venetoclax RP2D (r(will be gradually increased each day Day1-3/4) Depending on dose of Venetoclax the ramp up will be as follows. For the venetoclax 400mg dose level: • In cycle 1, venetoclax will be administered with a 3-day ramp up beginning with 100mg dose on Day 1, 200mg dose on Day 2, 400mg dose on Day 3. Venetoclax will continue at 400mg daily thereafter. For the venetoclax 600mg dose level: • In cycle 1, venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4. Venetoclax will continue at 600mg daily thereafter. c. Pracinostat RP2D 3. LDAC + venetoclax a. LDAC 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax 600mg (Tablets) D1-28 (will be gradually increased each day Day1-4) Venetoclax will be administered with a 4-day ramp up beginning with 100mg on Day 1, 200mg on Day 2, 400mg on Day 3 and 600mg on Day 4. Each cycle will be 28 days in length. Intervention code [1] Treatment: Drugs Comparator / control treatment Low dose Cytarabine + venetoclax a. Low dose Cytarabine 20mg/m2 subcutaneously daily D1-10 of each cycle. b. Venetoclax 600mg (Tablets) D1-28 (ramp up in cycle 1 only) Control group Active
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ACTRN12619001655134