Primary Objective:Assess the safety and explore the biologically effective dose (BED) and/or the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) of AZD4573 in patients with relapsed or refractory haematological…
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Brief title
Condition
- Lymphomas NEC
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Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety parameters:
Frequency, severity, and relationship to study drug of any treatment-emergent
adverse events or abnormalities of laboratory tests; DLTs; vital signs; ECGs;
serious adverse events (SAEs); and adverse events leading to discontinuation of
study treatment.
Pharmacokinetic parameters:
The following PK sampling timepoints applies to those patients enrolled into
Cohorts 2A/B and 3A/B: schedules can be found in protocol synopsis.
The timing of these samples may be adjusted, dependent upon ongoing PK analysis
and interpretation. PK parameters to be estimated include maximum concentration
(Cmax), area under the curve (AUC), half-life clearance and volume of
distribution. Additional parameters may be calculated as appropriate.
Surplus plasma samples may be analysed for potential metabolites of AZD4573.
The data from this sample analysis may be pooled and these data will be
exploratory and the results of any analysis may not be available at the end of
the study. The results of this analysis if undertaken may not be reported in
the final clinical study report (CSR).
For Cohorts 1-3, ECGs will be collected for central analysis according to the
schedule below:
• Screening (Single ECG only)
• Cycles A-D and Cycle 1, Day 1 (triplicate ECGs):
* Pre-dose (up to 2 hours prior to infusion) and 1, 2, 4, 7 (7 for Cohort 2
only), 8 (8 for Cohort 3 only), 10, and 24 hours (i.e., Day 2) after starting
the infusion (triplicate ECG will only be taken at each dosing day during which
a patient is receiving a dose to which the patient was not exposed to
previously, otherwise single ECGs apply).
• Cycles 2-8: On Day 1 of each cycle, within 30 minutes after the end of
infusion (Single ECG only)
• Safety-follow up visit (Single ECG only)
Pharmacodynamic and Biomarker Parameters:
Whole blood samples for immediate on-site peripheral blood mononuclear cell
(PBMC) isolation will be collected from all patients at screening and Day 1 of
each new dose (i.e., any dose which the patient had not been previously exposed
to).
The timing of these samples may be adjusted dependent upon ongoing PK and
pharmacodynamic analysis and interpretation.
For each new dose, samples will be collected at the following time points:
• Pre-dose (up to 2 hours prior to infusion), 2, 4, 7 (7 for Cohort 2 only), 8
(8 for Cohorts 3 to 5 only) and 24 hours after starting the infusion.
Additional Exploratory Biomarker Parameters:
Archival tumour tissue (blocks or slides) will be required, if available, from
all enrolled patients. Additional bone marrow aspirate from
samples taken at screening, and/or any time on study (i.e., disease
assessment/confirmation of complete response), will be used for exploratory
biomarker testing.
An optional bone marrow aspirate collection or tumour biopsy is requested at
disease progression.
For all patients in Arm B (e.g., patients with AML, ALL, CLL, who are likely to
have significant levels of tumour cells in their peripheral blood) an
additional whole blood sample for exploratory biomarkers will be taken at:
• Screening
• Pre-dose for Cycle A (up to 2 hours prior to infusion)
• Cohort 3B only: Pre-dose on Cycle B, Day 1 and Cycle C, Day 1 (up to 2 hours
prior to infusion)
• Cohort 3B only: Pre-dose, Cycle 1 Day 1 (up to 2 hours prior to infusion)
• Disease progression
These tissues (i.e., blood, archived tumour tissue, bone marrow aspirates and
tumour biopsies) will be used to assess potential biomarkers of response and/or
resistance (and if appropriate, pharmacodynamic responses) to AZD4573.
Additional plasma samples will be collected from all patients, to assess
exploratory biomarkers at the timepoints below:
• Screening
• For each dose during ramp-up Cycles A-D:
* Pre-dose (within 2 hours before start of dosing)
* 4 hours after start of the infusion (± 30 minutes)
* 10 hours after start of the infusion (± 1 hour)
* 24 hours (i.e., Day 2) after start of infusion (± 1 hour)
• Samples also to be taken at 96 hours ( 2/+12 hours) post start of infusion
and pre-dose the following infusion (within 4 hours) if patient has increases
in LFTs/bilirubin (defined as any elevated transaminases of Grade 3 or above or
fulfilling potential Hy*s Law criteria) and chemistry panel testing is being
performed
For any elevated LFTs/bilirubin that is observed with subsequent dosing with
AZD4573, liver safety biomarker sampling should be performed using the
timepoints outlined above (exception of screening sample not required).
Efficacy parameters:
• Overall response rate (ORR)
• Duration of response (DOR)
• Progression-free survival PFS)
• Overall survival (OS)
• Minimal residual disease (MRD) for applicable histologies/disease indications
(e.g., CLL)
Secondary outcome
n.a.
Background summary
Cyclin-dependent kinases (CDKs) represent a family of closely related
serine/threonine kinases that bind to their cognate regulatory
subunits, known as cyclins, to form active heterodimeric complexes. Several
CDK/cyclin complexes play crucial roles in regulating cell cycle progression
(CDK1, 2, 4, 6), however more recently they have also been implicated in
transcription and mRNA processing (Lim and Kaldis 2013).
Regulation of transcription is a complex process governed in part through
activity of CDK9 (Bywater et al. 2013). Following successful transcription
initiation, RNA polymerase II (RNAP2) pauses downstream of the transcription
start site, which serves as a checkpoint and allows for the rapid, synchronous
activation of genes and integration of multiple regulatory signals before
proper elongation can proceed (Gilchrist et al. 2010, Adelman and Lis. 2012).
To release RNAP2 from this pause and permit subsequent elongation, multiple
CDK9-mediated phosphorylation events are required. First, phosphorylation of
the elongation repressive complex DRB Sensitivity Inducing Factor-Negative
Elongation Factor (DSIF-NELF) results in the dissociation of NELF from RNAP2
while converting DSIF to a positive elongation factor. CDK9 also phosphorylates
the carboxyl-terminal domain (CTD) of RNAP2, which is comprised of 52
heptapeptide repeats (YSPTSPS), at the serine 2 (Ser2) position in the final
step before elongation can proceed (Sanso and Fisher 2013).
As an integral node of the transcription regulatory network, CDK9 represents a
potential target for cancer therapy. Short-term inhibition of CDK9 results in
transient transcriptional repression and rapid downregulation of genes with
short-lived mRNAs and labile proteins (Booher et al. 2014). This therefore
provides a therapeutic opportunity to treat tumours preferentially dependent on
target key driver oncogenes which are rapidly turned over without having broad
toxicity related to general transcriptional repression. Two such genes are
Myeloid Cell Leukaemia 1 (MCL1) and MYC (Yang et al. 1996, Stewart et al. 2010,
Hann and Eisenman 1984). Mcl-1 is an anti-apoptotic member of the B-cell
Lymphoma-2 (Bcl-2) family, and its amplification and overexpression have been
linked to increased survival of and chemotherapy resistance in various cancers.
c-Myc is a proto-oncogenic transcription factor that coordinates diverse
transcription programs and is overexpressed through amplification or genomic
rearrangement in multiple indications. Given the pivotal role played by Mcl-1
and c Myc in tumour cell growth and survival and tumour maintenance, depletion
of these oncoproteins in specific tumour contexts results in rapid cell death
and tumour regressions. CDK9 therefore represents an intriguing target to
indirectly and transiently reduce the level of these oncoproteins through
transcription regulation to drive oncogene addicted tumour cells toward cell
death, while sparing normal cells and tissues not dependent on these and other
short half-life pro-tumour survival proteins.
Several multi-CDK inhibitors have been progressed in clinical trials, including
Dinaciclib which is able to reduce levels of Mcl-1 in relapsed/refractory
chronic lymphocytic leukaemia (rrCLL) patients and induce clinical responses
attributed to CDK9 inhibition (Flynn et al. 2015). However, a more potent and
selective CDK9 inhibitor which has appropriate pharmacokinetics for tuneable
target engagement and an optimal dose/schedule, leading to improved efficacy as
single agent or in combination and/or therapeutic index, is warranted.
AZD4573 (formerly known as AZ13810325) is a potent inhibitor of CDK9 with
nanomolar potency against the enzyme (IC50 <4 nM) and selectivity over other
CDK family members (>5.8 fold). AZD4573 decreases pSer2RNAP2 levels linked to
reduction of Mcl-1 and c-Myc and rapid and preferential induction of apoptosis
in a broad range of human cancer cell lines derived from haematological
malignancies. AZD4573 demonstrates significant antitumour activity in vivo
associated with transient CDK9 inhibition across a range of tumour xenograft
models as single agent when dosed intermittently and also demonstrated improved
depth and duration of response when combined with a number of standard of care
or other targeted agents in vivo.
The purpose of this study is to assess the safety, tolerability,
pharmacokinetics (PK), pharmacodynamics (PDx) and preliminary antitumour
activity of AZD4573 in patients with relapsed or refractory haematological
malignancies.
Study objective
Primary Objective:
Assess the safety and explore the biologically effective dose (BED) and/or the
maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) of
AZD4573 in patients with relapsed or refractory haematological malignancies
Secondary Objective:
• Assess the plasma pharmacokinetics (PK) of AZD4573
• Assess preliminary tumour response/activity of AZD4573
Exploratory Objectives:
• Assess the pharmacodynamics (PDx) of AZD4573.
• Assess biomarkers that may correlate with AZD4573 mechanism of action,
including response and/or resistance to AZD4573.
Exploratory analyses may be performed retrospectively after completion of the
clinical trial itself. Where available prior to finalisation, results from
exploratory analyses will be reported in the Clinical Study Report (CSR).
Where testing is performed after the study has completed, these results may be
added in a CSR addendum.
Study design
This study is a multicentre, open-label, first in human, non-randomised, phase
1, dose-escalation study including an intra-patient ramp-up.
The study consists of two, parallel dose escalation arms, namely:
• Patients with relapsed or refractory haematological malignancies (all comers
excluding AML/ALL/high-risk MDS/CMML/CLL and Richter*s syndrome), herein
referred to as Arm A.
• Patients with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and
Richter*s syndrome, herein referred to as Arm B.
Patients in Arm B are most likely to have significant levels of tumour cells in
their peripheral blood and may have an increased risk of TLS due to disease
burden.
The intention where feasible is for both Arm A and Arm B to follow the same
ramp-up and dose escalation steps, unless otherwise indicated by the review of
ongoing and emerging safety/efficacy data.
The ramp-up period is defined as Cycles A-D, in which each ramp-up dose is a
new cycle. The target dose is defined as starting at Cycle 1 following the
ramp-up period. See the dosing schedules table in protocol synopsis.
A Safety Review Committee (SRC) which includes the Principal Investigators, is
in place and is tasked with the review of the available safety data (adverse
events and available PK/PD data) prior to the SRC making decisions on opening
next cohorts or changing the dose schedule. Refer to the current version of the
SRC charter for specifics. All decisions are and will be documented in writing
in the form of meeting minutes.
Given the potential for those subjects in Arm B to have an increased risk of
TLS due to disease burden, Arm A Cohort 1 was started
At the time of protocol amendment 7.0, Cohorts 1A and 1B are completed.
As of the IB data cut-off of 20 July 2019, no patients had yet been enrolled
under the 4-week DLT period. If additional data are required on safety,
tolerability or efficacy then cohort expansions at these doses/schedules may be
opened or alternative doses/schedules explored, but the dose will be below 18
mg.
All available data from completed and ongoing cohorts will be used to explore
safe and efficacious dose and schedules. Modelling may be used at the end of
the study to support a Recommended Phase II Dose (RP2D).
The maximum tolerated dose (MTD) was originally defined as the highest dose
level for which < 33% of the patients experience a DLT during the 8-week DLT
review period; for cohorts with a 4-week DLT assessment period (Cohort 3) the
definition is < 25% to reflect the shorter period of DLT evaluation. A
biologically effective dose (BED) may be determined in addition to, or instead
of, a MTD.
As per the latest IB data cut-off (20 July 2019), 30 patients have been dosed
with AZD4573 as monotherapy (Cohort 1A [9], Cohort 1B [5], Cohort 2A [10],
Cohort 2B [6]).
Intervention
Intravenous injection of AZD4573 with monitoring afterwards, patients divided
in different arms. Dose of IV injection modified in cohort-system as stated in
the protocol.
Study burden and risks
This is the first time the study drug AZD4573 is used on humans. The study drug
may cause side effects. Findings based on animal studies, which may potentially
be observed in humans, and based on early findings in humans in this study are
summarized below. Side effects can vary from mild to very serious and may vary
from person to person. The patient may experience none, some, or all of those
listed. It is also possible that unexpected side effects might occur.
• Tumour Lysis Syndrome (TLS)
This is a complication that can occur during the treatment of cancer, where
large amounts of tumor cells are killed off (lysed) by the treatment. TLS can
result in nausea and vomiting, but more seriously in, acute kidney failure,
seizures, irregular heartbeat and death. The patient will be closely monitored
for signs of TLS and given treatment to prevent serious complications, the
patient may need to remain in the hospital for longer than specified above as
per study doctor*s decision., so the doctor needs to follow the patient
closely. If the patient experiences TLS after dosing, the patient may need to
remain in hospital longer than 2 days as per study doctor decision.
• Diarrhoea
The patient may experience diarrhoea, at the time of, and in the hours
immediately after being given AZD4573. The study doctor will give the patient
treatment to prevent this, as well as ensuring the patient stays well hydrated
with intravenous fluids.
• Decrease in white blood cells
This means the patient has an increased risk for episodes of fever mostly
caused by infections (bacterial, fungal, viral infections).
• Decreases in red blood cells and platelets
A decrease in platelets in the blood results in easy bruising, bleeding from
the gums or blood in the stools. It can also lead to life- threatening bleeding
anywhere in the body (which you will be monitored for). A decrease in red blood
cells can result in dizziness and can make the patient feel tired.
• Effects on liver enzymes (an enzyme is a type of protein) and/or bilirubin
(bilirubin is a yellow/orange substance in the blood made by normal breakdown
of red blood cells)
Treatment with AZD4573 may cause an increase in blood levels of some liver
enzymes and/or bilirubin. These increases usually are not associated with
clinical symptoms and return to pre-treatment levels within 1 week, and most of
the time within 3 days. It is not known whether these increases in liver
enzymes and/or bilirubin can damage patients' liver in the long term. Liver
enzymes and bilirubin levels will be monitored closely by the study doctor. If
patients are affected by liver enzyme and/or bilirubin increases their doctor
will discuss with them whether or not to continue with AZD4573 treatment based
on their individual circumstances.
• Effects on pancreas enzyme levels
Transient changes in pancreas enzyme (enzymes are proteins that accelerate
chemical reactions) tests results indicate abnormal pancreas function. This is
usually without any symptoms. If you have any symptoms (e.g. pain) associated
with pancreas enzyme elevations, you may need to undergo an ultrasound and/or a
computer tomography (CT)-scan, because there may be an inflammation of your
pancreas.
• Effects on adrenal gland function.
Initial changes to the adrenal gland function usually occur without any
symptoms.The adrenal gland function will be tested regularly.
• Effects on the gastrointestinal system
Nausea and vomiting are common with AZD4573, your study doctor will give you
treatment to help prevent and treat this. It is important that you remain well
hydrated. You may experience bowel inflammation and possible weight loss.
• Possible effect on the heart
There has been a single case of possible mild heart attack in a patient taking
AZD4573 that fully recovered. It is not known whether AZD4573 caused this. No
other patients have experienced a heart attack whilst receiving AZD4573. Heart
rate increase has also been noted in some patients; again, it is not known
whether AZD4573 causes this. Your heart will be monitored closely during the
course of the study by means of ECG and blood tests. Patients should inform
their study doctor immediately if they experience any chest pain or
palpitations.
• Concomitant mediation
AZD4573 can interact in the body with other concomitant drugs the patient might
take, therefore these should be avoided (the study doctor will be able to
provide further advice on this).
The physician will closely monitor the patients' health and if possible will
treat the patient to minimize the symptoms. If needed the dose of AZD4573 will
be changed. If needed the dose of the study drug will be changed.
There may be risks involved in taking this study drug AZD4573 that have not yet
been discovered. There is always a risk involved in taking an investigational
drug. If the patient suffers any side effects or injuries, or the condition
gets worse, the patient needs to tell the study doctor immediately so he can
receive appropriate care.
Other risks and discomforts:
Blood draws
There is a small risk of side effects from drawing blood for the tests that the
patient will have throughout the study. Drawing blood from a vein may cause
local pain, bruising, fainting, and very rarely, infection at the site of the
blood draw.
Injection site reaction
There is a small risk of side effects from receiving study drug directly into
the vein by infusion, which may cause local pain, bruising, blood clot or
infection at the site of injection.
Electrocardiogram (ECG)
After an ECG test, the 12 self-adhesive electrodes are removed from the skin.
The patient may have mild irritation, slight redness, and itching at the places
on the skin where the recording patches are placed. The patient may also have
to have his chest shaved for this procedure.
Bone marrow biopsy and aspiration
The bone marrow biopsy and aspiration will be done at the hospital by a trained
doctor. It may be done under local anaesthesia because bone marrow aspiration
can cause brief but sharp pain. The patient will be fully awake during the
procedure, but the aspiration and biopsy site will be numbed to reduce pain. If
the patient feels anxious about pain, he may be given an IV medication so that
the patient is either completely or partially sedated (asleep) during the bone
marrow exam.
If this is the case, plan to have someone drive the patient home. Contact the
doctor if the patient has:
• Bleeding that soaks through the bandage and does not stop with direct pressure
• A persistent fever
• Worsening pain or discomfort
• Swelling at the procedure site
• Increasing redness or drainage at the procedure site
Tumour Biopsy
A tumour biopsy in blood cancer can either be a bone marrow biopsy or a needle
biopsy of lymph nodes. The lymph node biopsy will be done at the hospital by a
trained doctor. The biopsy takes about 10 to 15 minutes.
There are risks involved with any type of surgical procedure. Notable risks
from a lymph node biopsy include:
• tenderness around the biopsy site
• infection
• bleeding
• numbness caused by incidental nerve damage. Any numbness normally disappears
within a couple of weeks.
Pain and tenderness can last for a few days after a biopsy. Contact the doctor
if patients show signs of an infection or complications,
including:
• fever
• chills
• swelling
• intense pain
• bleeding or discharge from the biopsy site
Echocardiogram (ECHO)
An ECHO, or ultrasound of the heart, is a non-invasive procedure that takes
about 30 minutes and provides an image of the structures of the heart. During
the ECHO, electrodes will be placed onto the chest. Then a transducer (a device
that looks like a computer mouse) will be applied. You may feel slight pressure
on the chest from
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Age
Inclusion criteria
1. Provision of signed and dated, written informed consent prior to any
study-specific procedures, sampling and analyses.
2. Men and women >=18 years of age
3. Patients with histologically confirmed, relapsed or refractory
haematological malignancies, with at least one measurable lesion >= 1.5 cm and
where in the opinion of the 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:
o B-cell Non-Hodgkin lymphoma
o T-cell Non-Hodgkin lymphoma
o Small lymphocytic lymphoma (SLL)
o Multiple myeloma (MM) , Arm B:
o CLL (chronic lymphocytic leukaemia)
o Richter*s syndrome
o AML/secondary AML
o ALL
o High-risk myelodysplastic syndrome (MDS) (according to revised International
prognostic scoring system IPSS- R)
o CMML (chronic myelomonocytic leukaemia),
NOTE: AML/ALL patients must have pathologically confirmed first or second
relapsed or primary refractory AML using the World Health Organization (WHO)
definition or European LeukemiaNet (ELN) recommendations. A bone marrow blast
count of >5% will be sufficient in the appropriate setting of a patient with a
prior diagnosis of AML/ALL.
NOTE: AML patients with APL (acute promyelocytic leukaemia FAB subtype M3) will
be excluded
NOTE: Patients >70 years of age with untreated AML who are considered unfit for
intensive treatment or who refuse intensive treatment, may be considered
eligible for the study, upon consultation and agreement between the Sponsor and
the Investigator.
NOTE: Patients with DLBCL subtypes such as Richter's syndrome, Transformed
Follicular Lymphoma, Primary Mediastinal Lymphoma and High-grade lymphomas
[e.g. double-hit]) are also eligible to be included in the Cohort 2A DLBCL
expansion.
4. Eastern Cooperative Oncology Group (ECOG) performance status of <=2.
5. Must have received at least 2 prior lines of therapy for the treatment of
current histology and a clinical trial is best option for next treatment based
on prior response and/or tolerability to standard of care. Refer to National
Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology
(ESMO) guidelines of each respective histology for guidance. NOTE: For some
disease indications, for example Richter*s syndrome, failure of one therapy
(e.g., R-CHOP) would be sufficient to consider a patient for enrolment in a
study with an Investigational agent. Disease indications, where there may be no
standard of care or standard of care options have been exhausted after failure
of first line therapy, these patients may be discussed and considered by
Sponsor and Investigator on a case by case basis for enrolment into the study
and decisions to enrol such patients documented in writing.
6. Documented active disease requiring treatment per respective NCCN/ESMO
guideline that is relapsed or refractory defined as:
o Recurrence of disease after response to prior line(s) of therapy
o or progressive disease after completion of the treatment regimen preceding
entry into the study
7. Adequate haematologic function (Note: does not apply to acute leukaemias,
CLL, Richter*s syndrome or high-risk MDS), defined as:
o Absolute neutrophil count (ANC) >=1000 cells/mm3 (1.0 x 109/L)
o Platelet count >=50,000 cells/mm3 (50 x 109/L) or >=35,000 cells/mm3 (35 x
109/L) with bone marrow involvement., NOTE: For AML/ALL/MDS/CMML/CLL/Richter*s
syndrome, patients with platelet counts < 10 x 10^9/L and/or neutropenia <0.1 x
10^9/L may be enrolled. , NOTE: For AML/CMML patients, WBC must be
<25,000/µl. Treatment with hydroxyurea (HU) prior to study entry and during
ramp-up to achieve this level is permitted in AML patients, as long as there is
8-24 hours between the start of AZD4573 and use of HU.
8. Adequate hepatic and renal function at screening defined as:
o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
<=2.5 x upper limit of normal (ULN) except for those patients with liver
involvement/infiltration due to disease
Note: If LFTs are elevated for any patient at study entry, investigator sites
are to document, if known, the reason for LFT elevation (i.e., confirmed
disease infiltration of the liver, or to document if unknown cause for
elevation).
Patients with elevated LFTs at study entry must be discussed with the Sponsor
prior to any decision on dosing with AZD4573.
o Bilirubin <=1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or
of non-hepatic origin)
o Serum creatinine <=2.0 mg/dL OR <=1.5 x ULN (local reference), INR <1.5OR
creatinine clearance >=50 mL/min as measured or calculated by Cockcroft and
Gault equation [(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by
0.85 if female])
9. Uric acid level < 5 mg/dl at the time of treatment initiation. (applies to
all AZD4573 infusions) NOTE: TLS prophylaxis/management with rasburicase or
allopurinol, and IV fluid is permitted at any time during screening and
treatment. Rasburicase and allopurinol must not be co administered.
10. Lipase <=1.5 x ULN and serum amylase <=1.5 x ULN and no history of
pancreatitis.
11. Heart function: EF>40% by echocardiogram or multi-gated acquisition scan
(MUGA) at baseline (left ventricular ejection fraction [LVEF] >40%).
Appropriate correction to be used, if a MUGA is performed.
12. 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 by
fulfilling one of the following criteria at screening:
o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at
least 12 months following cessation of all exogenous hormonal treatments
o Documentation of irreversible surgical sterilisation by hysterectomy,
bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
13. 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 AZD4573 will be advised to
male patients with a desire to have children.
14. Willing and able to participate in all required evaluations and procedures
in this study protocol including receiving intravenous administration of study
drug and being admitted, when required, for at least 24 hours during study drug
administration, and willing and able to provide mandatory baseline bone marrow
biopsy/aspirate.
Host genetics research study (optional):
For inclusion in the optional genetic component of the study, patients must
fulfil the following additional criteria:
• Provision of signed, written, and dated informed consent for genetic
research. If a patient declines to participate in the genetic component of the
study, there will be no penalty or loss of benefit to the patientt. The patient
will not be excluded from other aspects of the study described in this
protocol, so long as they consented to the main study.
• Whole blood transfusion given within 120 days of genetic sample collection
should be leukocyte depleted. Bone marrow aspirate/tumour biopsy on study
(optional):
For inclusion in the optional bone marrow aspirate / tumour biopsy component of
the study, patients must fulfil the following additional criteria:
1. Provision of signed, written, and dated informed consent for a bone marrow
aspirate or tumour biopsy on study. If a patient declines to participate in the
bone marrow aspirate/tumour biopsy component of the study, there will be no
penalty or loss of benefit to the patient. The patient will not be excluded
from other aspects of the study described in this protocol, so long as they
consented to the main study. Any additional bone marrow aspirate (i.e. from
second draw) will be collected and sent to sponsor for exploratory biomarker
testing
2. P
Exclusion criteria
1. Treatment with any of the following:
o Any other chemotherapy, immunotherapy or anticancer agents, including
investigational agents, within 2 weeks of the first dose of study treatment
o Any haematopoietic 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
o Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of study treatment
Any full-dose level anti-coagulation treatment sufficiently prior to treatment
that INR is <1.5 (DVT/PE prophylaxis dose is allowed)
o
2. Patients with asecetory mylema
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 nonhaematologic malignancy except for the following:
o 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.
o Adequately treated lentigo maligna melanoma without current evidence of
disease or adequately controlled nonmelanomatous skin cancer.
o 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., 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.
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:
o coronary artery bypass graft
o angioplasty
o vascular stent - for the purposes of clarification, a patient 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 patient who has had a venous stent to
prevent life-threatening conditions, currently or in the preceding 6 months,
will be eligible for the study.
o myocardial infarction
o angina pectoris
o congestive heart failure (New York Heart Association Class >=2)
o ventricular arrhythmias requiring continuous therapy
o atrial fibrillation, which is uncontrolled
o haemorrhagic or thrombotic stroke, including transient ischemic attacks or
any other central nervous system bleeding
10. Hyperuricaemia >10 mg/dL.
NOTE: If hyperuricaemia of any kind is present at screening, standard of care
(SoC) therapy should be administered (including IV fluid and rasburicase or
allopurinol). Rasburicase and allopurinol must not be co administered.
11. Any of the following cardiac criteria:
o Resting corrected QT interval (QTcF) >= 470 msec obtained from a single
electrocardiogram (ECG).
o Any clinically important abnormalities in rhythm (except for patients with a
pace maker in place), conduction or morphology of resting ECG (e.g., complete
left bundle branch block, third degree heart block).
o 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 patient should not participate in
the study if the patient 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 20 mg/day prior to dosing with AZD4573. Doses of systemic
corticosteroid > 20 mg/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 20 mg/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
In addition, the following is considered a criterion for exclusion from the
optional genetic research:
• Previous allogeneic bone marrow transplant
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000817-22-NL |
| CCMO | NL62394.018.17 |