Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies

Inclusion Criteria (cohorts 1, 2):

• Subjects with histologically confirmed, relapsed or refractory haematological malignancies Subjects will include but are not limited to the following:

Arm A : B-cell Non-Hodgkin lymphoma , T-cell Non-Hodgkin lymphoma , Small lymphocytic lymphoma (SLL) , Multiple myeloma (MM) Arm B: CLL (chronic lymphocytic leukaemia), Richter's syndrome , AML/secondary AML, ALL , High-risk myelodysplastic syndrome (MDS), CMML (chronic myelomonocytic leukemia) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

• Must have received at least 2 prior lines of therapy
• Documented active disease requiring treatment per respective NCCN/ESMO guideline that is relapsed or refractory defined as: Recurrence of disease after response to prior line(s) of therapy Or progressive disease after completion of the treatment regimen preceding entry into the study
• Adequate hematologic, hepatic and renal function
• Women should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential
• Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm donation during and after the conduct of the trial.

Exclusion Criteria (cohorts 1,2):

• Treatment with any investigational agents within 4 half-lives of said prior investigational agent(s), any other chemotherapy, immunotherapy or anticancer agents within 2 weeks, any hematopoietic growth factors (e.g., filgrastim; [G-CSF] or sargramostin [GM-CSF]) within 7 days of the first dose of investigational product or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days or Major surgery (excluding placement of vascular access) within 4 weeks (with regard to the first dose of study treatment on this protocol).

  • With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
  • Presence of, or history of, CNS lymphoma, leptomeningeal disease or spinal cord compression.
  • History of prior nonhematologic malignancy with exceptions mentioned in protocol
  • Undergone any procedures or experienced any of the conditions listed in protocol exclusion criteria currently or in the preceding 6 months
  • History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573.

Inclusion Criteria (cohort 3):

Men and women ≥18 years of age -Subjects with histologically confirmed, relapsed or refractory haematological malignancies, with at least one measurable lesion ≥ 1.5cm and where in the opinion of the treating Investigator, a clinical trial is the best option for next treatment based on prior response and/or tolerability to standard of care, e.g., but not limited to:

Arm A:

• B-cell Non-Hodgkin lymphoma
• T-cell Non-Hodgkin lymphoma
• Small lymphocytic lymphoma (SLL)
• Multiple myeloma (MM)

Arm B:

• CLL (chronic lymphocytic leukemia)
• Richter's syndrome
• AML/secondary AML
• ALL
• High-risk myelodysplastic syndrome (MDS) (according to revised International prognostic scoring system IPSS-R)
• CMML (chronic myelomonocytic leukaemia)

Exclusion criteria (cohort 3):

1. Treatment with any of the following:

   - Any other chemotherapy, immunotherapy or anticancer agents, including investigational agents, within 2 weeks of the first dose of study treatment

   • Any hematopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating factor; G-CSF], sargramostin [granulocyte-macrophage colony-stimulating factor; GM-CSF]) within 7 days of the first dose of study drug or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first dose of study drug
   • Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
2. Subjects with asecretory myeloma
3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
4. Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease or spinal cord compression.

5. History of prior nonhematologic malignancy except for the following:

   - Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician.

   - Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.

   - Adequately treated carcinoma in situ without current evidence of disease.

6. As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses (e.g., haemophilia or von Willebrand disease) or uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti- infective treatment within 2 weeks before first dose of study drug.
7. Known history of infection with human immunodeficiency virus (HIV).
8. Serological evidence of active Hepatitis B infection

9. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months:

   • coronary artery bypass graft
   • angioplasty
   • vascular stent - for the purposes of clarification, a subject who has had a cardiac stent or arterial stent currently or in the preceding 6 months will not be eligible for the study. However, a subject who has had a venous stent to prevent life-threatening conditions, currently or in the preceding

6 months, will be eligible for the study.

• myocardial infarction
• angina pectoris
• congestive heart failure (New York Heart Association Class ≥2)
• ventricular arrhythmias requiring continuous therapy
• atrial fibrillation, which is uncontrolled
• haemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding 10 Hyperuricemia >10 mg/dL. 11 Any of the following cardiac criteria:
• Resting corrected QT interval (QTcF) ≥ 470 msec obtained from a single electrocardiogram (ECG).
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block).
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.

Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study drug and through the DLT review period.

12 History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573.

13 Documented confirmation and treatment of adrenal gland insufficiency or pancreatitis.

14 Judgement by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.

15 Chronic use of systemic corticosteroids (prednisone or equivalent) >20mg/day whilst on study. Systemic corticosteroids at any dose, may be used during the screening period for symptom control, but must be tapered down, if necessary, to 20mg/day prior to dosing with AZD4573. Doses of systemic corticosteroid >20mg/day may be used during the study if clinically indicated (e.g., for treatment of an AE/SAE), but again, the dose must be tapered back down to no greater than 20mg/day upon resolution of the event, to avoid chronic use.

In addition, the following is considered a criterion for exclusion from the optional genetic research:

• Previous allogeneic bone marrow transplant