Clinical Trials

Core Inclusion Criteria:

• Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, and analyses. Informed consent includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • If a patient declines to participate in optional exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study.
• Patient must be aged ≥ 8 years, at the time of signing the informed consent. In some countries parental consent may be required in addition to an assent form for patients who are 18 years of age.
• Diagnosis of AML or ALL and histologically proven based on criteria established by the World Health Organization (WHO) as documented by medical records.
• Patients must have received at least one prior line of therapy, and an established standard of care with proven benefit, and for which the patient is eligible, must not be available at the time of enrolment.
• Documented active disease requiring treatment that is relapsed or refractory defined as:
  • Recurrence/relapse of disease after response to prior line(s) of therapy;
  • Progressive disease (refractory) on/after completion of the treatment regimen preceding entry into the study.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Performance status must not have deteriorated by ≥ 2 levels within 2 weeks after providing informed consent.
• Predicted life expectancy ≥ 8 weeks.
• 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.
• Adequate organ function at screening as per the protocol defined criteria.
• Adequate cardiac function as demonstrated by left ventricular ejection fraction (LVEF) > 50% on screening cardiac multigated acquisition (MUGA), magnetic resonance imaging (MRI), or echocardiogram (ECHO).
• 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.
• All patients must consent to and undergo both pretreatment and on-treatment fresh bone marrow aspirates and biopsies
• For inclusion in the genetic component of the study, participants must fulfil protocol defined criteria.
• Women of childbearing potential must be willing to use highly effective contraceptive measures, should not be breastfeeding and must have a negative pregnancy test (serum) prior to start of dosing, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
  • Women under 50 years of age would be considered postmenopausal if they have been amenorrhoeic for the last 2 months following the cessation of exogenous hormonal treatments and have serum follicle-stimulating hormone and luteinising hormone levels in the postmenopausal range for the institution;
  • Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Men should be willing to use barrier contraception (i.e., condoms) and refrain from sperm donation during and after the conduct of the trial. If not done previously, storage of sperm before receiving AZD0466 will be advised to male patients with a desire to have children.

Additional Inclusion Criteria Module 1:

Expansion Cohort B1

• Patients must have a diagnosis of AML with a prior history of MPN which is histologically proven based on criteria established by the WHO as documented by medical records.
• Patients must have received ≤ 2 prior lines of treatment for AML; prior treatment with venetoclax is permitted. A line of treatment is defined as a recognised regimen, as per local or national guidelines, of which the patient has received at least one dose, following which they have relapsed or had refractory disease.

Expansion Cohort B2

• Patients must have a histologically proven diagnosis of AML which is based on criteria established by WHO as documented by medical records with a TP53 mutation. TP53 status already determined in accordance with local/institutional practice can be used for enrolment but needs to be confirmed centrally. Patients with AML who have had a prior history of MPN are ineligible.
• Patients must have received ≤ 3 prior lines of treatment for AML; prior treatment with venetoclax is permitted. A line of treatment is defined as a recognised regimen, as per local or national guidelines, of which the patient has received at least one dose, following which they have relapsed or had refractory disease as defined in Appendix J.

Expansion Cohort B3

• Patients must have a diagnosis of AML which is histologically proven based on criteria established by WHO as documented by medical records. Patients with AML with TP53 mutation (as described in B2) or AML who have had a prior history of MPN are ineligible.
• Patients must have been previously treated with venetoclax (either as monotherapy or in combination) and have received ≤ 3 prior lines of treatment. A line of treatment is defined as a recognised regimen, as per local or national guidelines, of which the patient has received at least one dose, following which they have relapsed or had refractory disease.

Expansion Cohort B4

• Patients must have a diagnosis of acute lymphoblastic leukaemia (ALL) which is histologically proven based on criteria established by WHO as documented by medical records. Patients with T-ALL or B-ALL are eligible for inclusion.
• Patients must have received ≤3 prior lines of treatment. A line of treatment is defined as a recognised regimen, as per local or national guidelines, of which the patient has received at least one dose, following which they have relapsed or had refractory disease.

Exclusion Criteria:

• 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 eligible.
• Active idiopathic thrombocytopenic purpura.
• Haemopoietic stem cell transplant < 100 days prior to the first dose of study treatment.
• Immunosuppression for graft versus host disease (GVHD) or GVHD prophylaxis within 4 weeks prior to the first dose of study treatment. The following are permitted:
  • topical steroids for GVHD may continue indefinitely;
  • systemic steroids for GVHD up to 2 weeks prior to the first dose of study treatment;
  • if systemic steroids are being used for primary malignancy control, they may be continued up until 2 days prior to the first dose of study treatment.
• 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.
• Known history of infection with human immunodeficiency virus (HIV).
• Known serologic status reflecting active hepatitis B or C infection.
  • Patients who are anti-HBc antibody positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrolment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive will be excluded;
  • Patients who are hepatitis C antibody positive will need to have a negative PCR result before enrolment. Those who are hepatitis C PCR positive will be excluded.
• Known uncontrolled infection with cytomegalovirus (CMV).
• Patients should be tested for severe acute respiratory syndrome coronavirus-2 (SARS-‑CoV-2) and those with active infection detected either using either molecular or antigen tests in accordance with local testing guidelines will be excluded.
• As judged by the Investigator:
  • any evidence of severe or uncontrolled systemic diseases (e.g., 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 (e.g., haemophilia or von Willebrand disease);
  • uncontrolled active systemic fungal, bacterial, or other infection.
• Any of the given cardiac criteria:
  • Patients with history of myocarditis within one year of study entry, or heart failure New York Heart Association Functional Classification Class 3 or 4;
  • Mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 electrocardiogram (ECGs), in the absence of a cardiac pacemaker;
  • Abnormalities in rhythm, conduction or morphology of resting ECG that pose an unacceptable risk to the subject in the opinion of the enrolling physician;
  • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as 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.  The following are permitted:
  • Myelodysplastic syndrome or myeloproliferative neoplasm (including chronic myelomonocytic leukaemia [CMML]);
  • 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;
  • 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;
  • Anticancer agents within ≤ 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. Some anticancer agents may be strong CYP3A inducers or inhibitors, and should be withheld accordingly;
  • Treatment with high-dose steroids for primary malignancy control is permitted, but must be discontinued at least 2 days prior to the first dose of study treatment;
  • Treatment with hydroxyurea is permitted during screening until the start of Cycle 2, and should be stopped once the white blood cell count falls <10 × 10^9/L during study treatment:
    • Patients who relapse while on maintenance-type ALL therapy or are receiving maintenance therapy for disease stabilisation should have therapy discontinued at least 7 days prior to first dose of study treatment.
  • Immunotherapies and cellular therapies such as chimeric antigen receptor T cell therapy (CAR-T) within 4 weeks prior to the first dose of study treatment;
  • 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 following 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, which cannot be discontinued within 5 half-lives prior to the first dose of study treatment and withheld throughout the study until 14 days after the last dose of AZD0466;
  • Reversible CYP3A inhibitors which cannot be discontinued within 5 half-lives prior to 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 of the specific drug plus 12 days 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 and heparin, which cannot be stopped.  Heparin for vascular line management is allowed;
  • Medications with known risk of Torsades de Pointes, which cannot be discontinued within 5 half-lives of the first dose of study treatment and withheld until 14 days 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.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Judgement by the Investigator or Medical Monitor that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Lactating, breastfeeding, or positive pregnancy test for women of childbearing potential.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

Eligibility last updated 12/22/21. Questions regarding updates should be directed to the study team contact.