The purpose of the study is to the evaluate safety, tolerability, pharmacokinetics (PK), and
efficacy of AZD0466 as monotherapy in partciapants with advanced haematological malignancies
and also to assess drug-drug interaction (DDI) potential between AZD0466 and the azole
The study consists of 2 individual modules as: Module 1 (AZD0466 monotherapy), and Module 2
(DDI study of AZD0466 with voriconazole).
Eligible participants will be assigned to study treatments across Modules 1 and 2.
1. Module 1: AZD0466 monotherapy will include 2 parts- Part A dose escalation cohorts and
Part B dose expansion cohorts. Initiation of Part B will depend on the evaluation of
safety, tolerability, and PK in Part A.
2. Module 2: AZD0466 and voriconazole DDI study.
All participants will receive AZD0466, and administration will continue until disease
progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal
of consent, or other reasons to discontinue study treatment.
- Histologically confirmed acute myeloid leukaemia (AML) or acute lymphoblastic
leukaemia (ALL) for which there are limited treatment options known to provide
- Eastern cooperative oncology group performance status ≤2. Performance status must not
have deteriorated by ≥2 levels within 2 weeks after providing informed consent.
- Predicted life expectancy ≥12 weeks.
- Adequate organ function at screening as per the protocol defined criteria.
- Adequate cardiac function as demonstrated by LVEF > 50% on screening cardiac
multigated acquisition, magnetic resonance image or echocardiogram.
- Willing and able to participate in all required study evaluations and procedures
including receiving IV administration of study treatment and admission to the
hospital, when required, for administration of study treatment and monitoring.
- For inclusion in the genetic component of the study, participants must fulfil protocol
- White blood cell count must be <10 x 10^9/L. Treatment with hydroxyurea during
screening and Cycle 1 to achieve this level is permitted.
- Women of childbearing potential and men should use protocol defined contraceptive
- Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for
Adverse Events Grade ≥2. Participants with Grade 2 neuropathy or Grade 2 alopecia are
- Active idiopathic thrombocytopenic purpura.
- Stem cell transplant < 6 months prior to the first dose of study treatment.
- Active graft versus host disease.
- Active central nervous system (CNS) leukaemia/leptomeningeal disease/spinal cord
compression. Participants who have a history of CNS leukaemia must be free of CNS
leukaemia for >30 days prior to the first dose of study treatment, and the most recent
2 lumbar punctures must be negative for leukaemic cells, to be eligible.
- Active cytomegalovirus (CMV) infection (positive CMV Immunoglobulin M (IgM) and/or
positive polymerase chain reaction (PCR) result).
- Active infection including human immunodeficiency virus, Hepatitis B, Hepatitis C, or
severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).
- As judged by the Investigator: any evidence of severe or uncontrolled systemic
diseases, (eg, severe hepatic impairment, interstitial lung disease [bilateral,
diffuse, parenchymal lung disease]); current unstable or uncompensated respiratory or
cardiac conditions; Uncontrolled hypertension; history of, or active, bleeding
diatheses (eg, haemophilia or von Willebrand disease); uncontrolled active systemic
fungal, bacterial, or other infection.
- Any of the given cardiac criteria: history of cardiomyopathy, myocarditis or heart
failure; mean resting corrected QT interval (QTcF) ≥470 msec obtained from 3
electrocardiogram (ECGs), in the absence of a cardiac pacemaker; any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG; any
factors that increase the risk of QTc prolongation or risk of arrhythmic events such
as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT
syndrome, or unexplained sudden death under 40 years of age.
- History of another life-threatening malignancy ≤2 years prior to first dose of study
treatment with the exception of: malignancy treated with curative intent and with no
evidence of active disease present for more than 2 years before screening and
considered to be at low risk of recurrence by the treating physician; adequately
treated lentigo malignant melanoma without current evidence of disease or adequately
controlled non-melanomatous skin cancer; adequately treated carcinoma in situ without
current evidence of disease.
- Any of the mentioned procedures or conditions currently or in the 6 months prior to
the first dose of study treatment: coronary artery bypass graft; angioplasty; vascular
stent; myocardial infarction; angina pectoris; congestive heart failure (New York
Heart Association Class ≥2); ventricular arrhythmias requiring continuous therapy;
ventricular arrhythmias requiring continuous therapy; haemorrhagic or thrombotic
stroke, including transient ischaemic attacks or any other CNS bleeding.
- Treatment with any of the mentioned therapy: radiotherapy less than 3 weeks prior to
first study treatment; immunotherapy or chemotherapy within ≤21 days or 5 half-lives
prior to the first dose of study treatment. Treatment with one dose of cytarabine,
steroids, or 6-mercaptopurine is permitted prior to the first dose of study treatment
but these should be discontinued at least 2 days prior to the first dose of study
treatment. Treatment with hydroxyurea is permitted as previously outlined;
investigational drugs within ≤14 days or 5 half-lives (whichever is shorter) prior to
the first dose of study treatment; major surgery (excluding placement of vascular
access) ≤21 days, or minor surgical procedures ≤7 days, prior to the first dose of
study treatment. No waiting is required mentioned implantable port or catheter
placement; prescription or non-prescription drugs or other products known to be
sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or
CYP2D6, or reversible moderate or strong CYP3A inhibitors, which cannot be
discontinued within 5 half-lives of the first dose of study treatment and withheld
throughout the study until 14 days after the last dose of AZD0466; moderate or strong
mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5
half-lives plus 12 days of the drug prior to the first dose of study treatment and
withheld until 14 days after the last dose of AZD0466; concurrent anti-coagulation
therapy, including aspirin, which cannot be stopped; medications with known risk of
Torsades de Pointes within 5 half-lives of the first dose of study treatment and
continuing until 5 half-lives after the last dose of AZD0466; IV anti infection
treatment within 14 days before first dose of study treatment.
- History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs
with a similar chemical structure or class to AZD0466 or other BH3 mimetic.