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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT04865419
Registration number
NCT04865419
Ethics application status
Date submitted
26/04/2021
Date registered
29/04/2021
Date last updated
22/05/2024
Titles & IDs
Public title
Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies
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Scientific title
A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies
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Secondary ID [1]
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2020-005106-25
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Secondary ID [2]
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D8241C00001
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Haematological Malignancies
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - AZD0466
Treatment: Drugs - Voriconazole
Experimental: Module 1: AZD0466 monotherapy - Participants will receive intravenous infusion of AZD0466 monotherapy once weekly during Cycle 1 (35 days), Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.
Experimental: Module 2: AZD0466 + Voriconazole - Participants may receive IV infusion of AZD0466 in combination with or without voriconazole during Cycle 1 (21 days), and Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.
Treatment: Drugs: AZD0466
AZD0466 powder for concentrate for solution for infusion will be administered by IV infusion.
Treatment: Drugs: Voriconazole
Voriconazole film-coated tablet will be administered orally.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 1]
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Assessment method [1]
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Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
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Timepoint [1]
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Until 28 days after last dose (Upto 3.5 Years)
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Primary outcome [2]
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Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 2]
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Assessment method [2]
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Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
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Timepoint [2]
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Until Day 19
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Primary outcome [3]
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Number of participants with Dose-limiting toxicity (DLT) [Module 1]
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Assessment method [3]
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Assessment of DLT to evaluate safety and tolerability of AZD0466 in participants with advanced haematological malignancies.
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Timepoint [3]
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35 days
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Secondary outcome [1]
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Module 1: Complete Response Rate (CR+CRi)
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Assessment method [1]
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To estimate the preliminary anti-tumor activity of AZD0466 by assessment of complete response rate [complete remission+complete remission with incomplete recovery (CR+CRi)] defined as the proportion of participants with a best response of CR or CRi.
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Timepoint [1]
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Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)
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Secondary outcome [2]
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Module 1: Time to Response (TTR)
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Assessment method [2]
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To estimate the preliminary antitumor activity of AZD0466 by assessment of TTR defined as the time from date of first dose until the date of first documented CR or CRi.
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Timepoint [2]
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Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)
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Secondary outcome [3]
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Module 1: Duration of Response (DoR)
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Assessment method [3]
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To estimate the preliminary antitumor activity of AZD0466 by assessment of DoR defined as the time from the date of first documented response (CR or CRi) until date of documented progression, relapse or failure or death due to any cause.
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Timepoint [3]
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Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)
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Secondary outcome [4]
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Module 1: Overall Survival (OS)
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Assessment method [4]
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To estimate preliminary anti-tumor activity of AZD0466 by assessment of OS defined as time from date of first dose until the date of death due to any cause.
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Timepoint [4]
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Day 1 until post treatment follow-up (28 days after last dose) and survival follow-up (every month after last dose) (up to 3.5 Years)
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Secondary outcome [5]
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Module 2: Area under the plasma concentration-curve (AUC) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole
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Assessment method [5]
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Assessment of AUC to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
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Timepoint [5]
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Cycle 1 Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)
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Secondary outcome [6]
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Module 2: Maximum observed plasma (peak) drug concentration (Cmax) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole
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Assessment method [6]
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Assessment of Cmax to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.
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Timepoint [6]
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Cycle 1: Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)
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Secondary outcome [7]
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Module 1 and Module 2: Plasma concentration of AZD4320
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Assessment method [7]
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Assessment of AZD4320 to characterise the PK profile of AZD0466 following intravenous administration (via PK profiles of the active moiety AZD4320 in plasma).
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Timepoint [7]
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Module 1: Cycle 1 Days 1-30 (Cycle length 21 days) to Cycle 3 Days 1-28, and beyond (Cycle length 28 days); Module 2: Cycle 1 Days 1-8, Days 15-19 (Cycle length 21 days), Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)
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Eligibility
Key inclusion criteria
- Diagnosis of acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL), or
intermediate or higher risk myelodysplastic syndrome (MDS; Part A only), which is
histologically proven based on criteria established by the World Health Organization
(WHO) as documented by medical records. for which there are limited treatment options
known to provide clinical benefit.
- 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 =8 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
defined criteria.
- White blood cell count must be <10 x 10^9/L prior to the first dose in Cycle 1, Day 1.
Treatment with hydroxyurea during screening and Cycle 1 to control white blood cell
count is permitted.
- Women of childbearing potential and men should use protocol defined contraceptive
measures.
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Minimum age
18
Years
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Maximum age
130
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
- 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.
- 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 uncontrolled infection with 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 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; any factors that increase the risk of
QTc prolongation or risk of arrhythmic events such 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; chemotherapy within =14 days or 5 half-lives prior to the first
dose of study treatment. 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; immunotherapies and
cellular therapies 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 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 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 plus of the specific drug 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 and heparin, which
cannot be stopped; 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.
Module 2:
• Patients for whom treatment with voriconazole is contraindicated per the local
prescribing information must not enter the study.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
11/06/2021
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
8/08/2023
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Sample size
Target
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Accrual to date
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Final
46
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Research Site - Melbourne
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Recruitment hospital [2]
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Research Site - Parkville
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Recruitment postcode(s) [1]
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3004 - Melbourne
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Recruitment postcode(s) [2]
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3050 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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State/province [2]
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Florida
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Country [3]
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United States of America
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Illinois
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Country [4]
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United States of America
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State/province [4]
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Ohio
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United States of America
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Texas
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France
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State/province [6]
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Pessac
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Country [7]
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Germany
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Aachen
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Germany
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Heidelberg
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Germany
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Kiel
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Country [10]
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Italy
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State/province [10]
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Bologna
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Country [11]
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Italy
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State/province [11]
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Meldola
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Country [12]
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Italy
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State/province [12]
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Rozzano
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Country [13]
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Korea, Republic of
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State/province [13]
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Busan
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
AstraZeneca
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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
antifungal voriconazole.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04865419
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Nitin Jain, MD, PhD
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Address
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The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 431 Houston, Texas 77030 United States of America
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Fax
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Email
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Contact person for public queries
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Address
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04865419
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