| Eligibility |
Inclusion Criteria (AZD5991 + venetoclax):
- Provision of signed and dated, written informed consent prior to any study-specific
procedures, sampling and analyses.
- Men and women 18 to 85 years of age, inclusive.
- Diagnosis of AML and histologically proven based on criteria established by the World
Health Organisation (WHO) as documented by medical records. Must have a measurable
blast infiltration in bone marrow which will serve as a response parameter
- Eastern Cooperative Oncology Group (ECOG) performance status of =2.
- Must have received at least 1 prior line of therapy and there must be no treatment
options available known to provide clinical benefit. Refer to National Comprehensive
Cancer Network (NCCN) guidelines.
- Documented active disease requiring treatment per respective NCCN 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.
- WBC =10,000 cells/mm3 (10 x 109/L); use of leukapheresis or hydroxyurea before study
drug initiation is allowed to achieve this entry criterion.
- Adequate hepatic and renal function at screening defined as:
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3.0 x upper
limit of normal (ULN).
- Bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin).
- Serum creatinine =1.5 times ULN and creatinine clearance =50 mL/min (measured or
calculated by Cockcroft and Gault equation [(140-Age) • Mass (kg)/(72 • creatinine
mg/dL) • multiply by 0.85 if female]).
- Lipase =1.5 x ULN and serum amylase =1.5 x ULN and no history of pancreatitis.
- 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 (AZD5991 + venetoclax):
- Treatment with any of the following:
- Any investigational agents from a previous clinical study within 4 half-lives or
14 days, whichever is the greater, of said prior investigational agent(s) with
regard to the first dose of study treatment on this protocol. Washout period not
required in subjects with aggressive disease who require treatment sooner.
- Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the
first dose of study treatment. Washout period not required in subjects with
aggressive disease who require treatment sooner.
- Any hematopoietic growth factors (eg, 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.
- Except for alopecia, any unresolved toxicities from prior therapy greater than CTCAE
Grade 1 at the time of starting study treatment.
- AML with known active central nervous system involvement.
- As judged by the Investigator, any evidence of severe or uncontrolled systemic disease
(eg, 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 (eg, hemophilia 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.
- Malabsorption syndrome or other condition that precludes enteral route of
administration.
- Chronic respiratory disease that requires continuous oxygen use.
- Known diagnosis of a hypercoagulable disorder other than malignancy
- Undergone any of the following procedures or experienced any of the following
conditions currently or in the preceding 6 months:
- angina pectoris
- supraventricular arrhythmias, including atrial fibrillation, which are
uncontrolled
- Myocarditis
- heart failure NYHA Class I or above
- Experienced any of the following conditions currently or at any previous timepoint
- Myocardial infarction (MI)
- coronary artery bypass graft
- angioplasty
- vascular stent
- Heart failure NYHA Class = 2
- Ventricular arrhythmias requiring continuous therapy
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTcF) = 450 msec applicable to both genders
obtained from 3 electrocardiograms (ECGs) (averaged)
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG eg, complete left bundle branch block, second to third degree AV
block, sinus node dysfunction with clinically significant sinus pause
- 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.
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.
- ST-wave depression and T-wave changes (e.g. inversion or flattened) in recent or
screening ECG
- CPK assay reading = ULN at screening
- Subjects with any troponin assay reading of =ULN during screening
- Left ventricular ejection fraction [LVEF] <55% with echocardiogram (ECHO) or
multi-gated acquisition scan (MUGA). Appropriate correction to be used, if a MUGA
is performed.
- History of severe allergic or anaphylactic reactions to BH3 mimetics or history of
hypersensitivity to active or inactive excipients of AZD5991.
- Received the following within 7 days before initiation of venetoclax:
- Strong or moderate cytochrome P450 3A (CYP3A) inducers
- Strong or moderate CYP3A inhibitors
- Pg-P inhibitors
- Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
containing Seville oranges) or star fruit within 3 days before the initiation of
venetoclax.
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