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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04630756




Registration number
NCT04630756
Ethics application status
Date submitted
2/09/2020
Date registered
16/11/2020

Titles & IDs
Public title
AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood Cancer
Scientific title
A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Haematological Malignancies
Secondary ID [1] 0 0
2020-001642-18
Secondary ID [2] 0 0
D8230C00002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Haematological Malignancies 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - AZD4573
Treatment: Drugs - Acalabrutinib

Experimental: Module 1: Part A and Part B - Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively.

In Part B, participants will receive the RP2D of AZD4573 from Part A.

Experimental: Module 2: Part A and Part B - Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2.

Part B of Module 2 will be determined from the data emerging from Part A.


Treatment: Drugs: AZD4573
AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly (as monotherapy for Module 2 only) and in combination with orally administered acalabrutinib twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 weeks, with a dose ramp-up. Subsequent cycles are 21 days (3 weeks) with once weekly dosing of AZD4573 in combination with acalabrutinib twice daily continuously (in Module 1 and Module 2, period 2).

Treatment: Drugs: Acalabrutinib
Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Module 1 Part A : Number of participants with serious and non-serious adverse events
Timepoint [1] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Primary outcome [2] 0 0
Module 2 Part A : Number of participants with serious and non-serious adverse events
Timepoint [2] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Primary outcome [3] 0 0
Module 1 Part B: Overall response rate (ORR) of AZD4573 in combination with acalabrutinib
Timepoint [3] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [1] 0 0
Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via CR rate
Timepoint [1] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [2] 0 0
Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via duration of response (DoR)
Timepoint [2] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [3] 0 0
Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Time to Response (TTR)
Timepoint [3] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [4] 0 0
Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Progression free survival (PFS)
Timepoint [4] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [5] 0 0
Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Overall survival (OS)
Timepoint [5] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [6] 0 0
Module 1 Part B: Number of participants with serious and non-serious adverse events
Timepoint [6] 0 0
From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months)
Secondary outcome [7] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma pharmacokinetics (PK) (Cmax) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [7] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1
Secondary outcome [8] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUC0-t) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [8] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1
Secondary outcome [9] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUClast) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [9] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1
Secondary outcome [10] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUCinf) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [10] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1
Secondary outcome [11] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma PK (tmax) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [11] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1
Secondary outcome [12] 0 0
Module 1 Part A and Part B; Module 2 Part A: Plasma PK (t1/2) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination
Timepoint [12] 0 0
Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1

Eligibility
Key inclusion criteria
Inclusion Criteria - Core

* Participant must be = 18 years of age at the time of signing the informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of = 2.
* Must have received at least one prior line of therapy for the treatment of current disease and a clinical study is the best option for next treatment based on prior response and/or tolerability.
* Documented active disease requiring treatment that is r/r defined as: Recurrence of disease after response to at least one prior line(s) of therapy or Progressive disease after completion of or on the treatment regimen preceding entry into the study or Disease that did not achieve an objective response (overall response of CR or PR).
* Adequate haematological function.
* Adequate organ function at Screening.
* Uric acid level < upper limit of normal (ULN).

Inclusion Criteria - Module 1

- Participants with histologically confirmed, r/r DLBCL, or r/r MZL, for whom a clinical study is the best option for next treatment based on response and/or tolerability to prior lines of therapy.

PART A

• Participants with r/r DLBCL, including subtypes such as DLBCL not otherwise specified [NOS], high-grade B cell lymphoma [HGBCL], primary mediastinal large B-cell lymphoma [PMBCL], or large B cell lymphoma transformed from indolent B-cell lymphomas (including but not limited to Richter Syndrome, transformed Follicular Lymphoma, transformed MZL), or r/r MZL: participants with r/r MZL are eligible as well. In case fresh tumor biopsy is not available, archival tumor samples are acceptable, if done with 24 months

PART B • Participants with r/r de novo r/r DLBCL only, fresh tumor biopsy, done at screening or within 60 days before planned 1st dosing, unless there was any anticancer treatment given after tumor biopsy, but prior initiated study treatment.

* Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy.
* Participants must have failed at least two prior therapies for the treatment of current disease. Participants shall not be eligible for curative treatment options, and have no standard therapy available (including CAR-T cell therapy).
* Adequate haematologic function at screening: No growth factor support within 14 days prior to the date of the screening laboratory assessment; No transfusions within 7 days prior to the date of the screening laboratory assessment.
* Optional tumour biopsy on study: Participants are also encouraged to consent to and undergo an optional tumour biopsy at disease progression to support correlative biomarker studies.
* All participants must be willing and able to provide mandatory baseline bone marrow biopsy/aspirate.

Inclusion Criteria - Module 2

- Participants with histologically confirmed r/r MCL for whom a clinical study is the best option (in the opinion of the investigator) for next treatment based on response and/or tolerability to prior lines of therapy.

PART A

* Participants with r/r MCL:

* Diagnosis must be confirmed by biopsy and be immunohistologically characterised.
* Tumour tissue must also be available for sending to AstraZeneca for pathology testing.
* Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
* Participants must have failed at least one prior therapy for the treatment of current disease and not be eligible for treatment with curative intent (e.g. allogenichaematopoietic cell transplantation [HCT]). Eligible participants include both BTKi-naïve and BTKi-exposed.
* Adequate haematologic function at screening: No growth factor support within 14 days prior to the date of the screening laboratory assessment; No transfusions within 7 days prior to the date of the screening laboratory assessment.
* Optional tumour biopsy on study: Participants are also encouraged to consent to and undergo an optional tumour biopsy at disease progression to support correlative biomarker studies.
* All participants must be willing and able to provide mandatory baseline bone marrow biopsy/aspirate.
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria - Core

* Participants with non-secretory myeloma.
* With the exception of alopecia, any unresolved non-haematological toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment.
* Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease, or spinal cord compression.
* History of prior non-haematological malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease for >1 year before Screening and felt to be at low risk for recurrence by treating physician; Adequately treated lentigo maligna melanoma without evidence of disease or adequately controlled non-melanomatous skin cancer; Adequately treated carcinoma in situ without current evidence of disease.
* Any evidence of severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial lung disease), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses or uncontrolled active systemic fungal, bacterial, viral, or other infection, or IV anti infective treatment within two weeks before first dose of study drug.
* Known history of infection with human immunodeficiency virus (HIV).
* Serologic status reflecting active hepatitis B or C infection.
* Any of the following cardiac criteria: Resting QT interval corrected using Fridericia's formula (QTcF) = 470 msec obtained from a single electrocardiogram (ECG); any clinically important abnormalities in rhythm (except for participants with a pacemaker in place), conduction or morphology of resting ECG); 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-assessment period (Part A) or during the scheduled ECG assessments.
* History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of study treatment.
* Documented confirmation and ongoing treatment of adrenal gland insufficiency or pancreatitis.
* History, within the previous 6 months prior to first dose, of: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure (New York Heart Association Class = 2); ventricular arrhythmias requiring continuous therapy; atrial fibrillation, which is judged as uncontrolled by the treating physician; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.

Module 1

* Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, bowel obstruction, or gastric restrictions and bariatric surgery.
* Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
* Requires treatment with strong CYP3A inhibitors or inducers.
* Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
* Serologic status reflecting active hepatitis B or C infection.
* Active Cytomegalovirus (CMV) infection.
* Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
* Participants on dual antiplatelet and therapeutic anticoagulant therapy.
* Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
* History of or ongoing confirmed progressive multifocal leukoencephalopathy

Module 2

* Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery.
* Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
* Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
* Requires treatment with strong CYP3A inhibitors or inducers.
* Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
* Serologic status reflecting active hepatitis B or C infection.
* Active CMV infection.
* Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
* Participants on dual antiplatelet and therapeutic anticoagulant therapy.
* History of or ongoing confirmed progressive multifocal leukoencephalopathy

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/02/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Clayton
Recruitment hospital [2] 0 0
Research Site - Nedlands
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment postcode(s) [2] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas
Country [3] 0 0
United States of America
State/province [3] 0 0
Utah
Country [4] 0 0
Canada
State/province [4] 0 0
Quebec
Country [5] 0 0
France
State/province [5] 0 0
Lille Cedex
Country [6] 0 0
Ireland
State/province [6] 0 0
Dublin
Country [7] 0 0
Ireland
State/province [7] 0 0
Galway
Country [8] 0 0
Korea, Republic of
State/province [8] 0 0
Seoul
Country [9] 0 0
Poland
State/province [9] 0 0
Kraków
Country [10] 0 0
Spain
State/province [10] 0 0
Barcelona
Country [11] 0 0
Spain
State/province [11] 0 0
Palma de mallorca
Country [12] 0 0
United Kingdom
State/province [12] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AstraZeneca
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Parexel
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Available to whom?
When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04630756