Clinical Trials Register

Summary
EudraCT Number:	2020-001642-18
Sponsor's Protocol Code Number:	D8230C00002
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2021-03-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Ireland - HPRA

A.2

EudraCT number

2020-001642-18

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

AZD4573 in Novel Combinations with Anti-cancer Agents in Patients with Advanced Haematological Malignancies.

A.3.2

Name or abbreviated title of the trial where available

D8230C00002

A.4.1

Sponsor's protocol code number

D8230C00002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04630756

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Centre
B.5.3	Address:
B.5.3.1	Street Address	not applicable
B.5.3.2	Town/ city	not applicable
B.5.3.3	Post code	not applicable
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	information.centre@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AZD4573
D.3.2	Product code	AZD4573
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZD4573
D.3.9.1	CAS number	2057509-72-3
D.3.9.2	Current sponsor code	AZD4573
D.3.9.3	Other descriptive name	AZ13810325
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Calquence
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Acalabrutinib
D.3.2	Product code	ACP-196
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACALABRUTINIB
D.3.9.1	CAS number	1420477-60-6
D.3.9.2	Current sponsor code	ACP-196
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Haematological Malignancies

E.1.1.1

Medical condition in easily understood language

Various cancers

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10066476
E.1.2	Term	Haematological malignancy
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A :
Assess the safety and tolerability, describe the DLTs, and identify the MTD and/or RP2D of AZD4573 when administered intravenously to participants with advanced relapsed/refractory haematological malignancies, in novel combinations with other anti-cancer agentsa
Part B:
Assess the efficacy of AZD4573 in novel combinations with other anti-cancer agents in participants with relapsed/refractory haematological malignancies

E.2.2

Secondary objectives of the trial

Part A and B:
-Assess the plasma/serum PK of AZD4573 and other anti-cancer agents when given in combination
Part B:
-Further assess efficacy of AZD4573 in novel combinations with other anti-cancer agents
-Assess the safety and tolerability of the RP2D of AZD4573 in novel combinations with other anti-cancer agents

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Genomics initiative research study (optional)
Tumour biopsy at disease progression (optional)

E.3

Principal inclusion criteria

1 Participant must be ≥ 18 years of age at the time of signing the informed consent.
2 Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
3 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.
- Participants with histologically confirmed, r/r DLBCL (Module 1) who have failed at least two prior therapies for the treatment of current disease, and are not eligible for curative or standard treatment options (including CAR-T cell therapy).
- Participants with histologically confirmed r/r MCL (Module 2) who have failed at least one prior therapy for the treatment of current disease and not be eligible for treatment with curative intent (e.g. allogenic haematopoietic cell transplantation [HCT]). Eligible patients include both BTKi-naïve and BTKi-exposed
4 Documented active disease requiring treatment that is relapsed or refractory as defined in the protocol, including.
5 Adequate haematological function (as defined in the protocol).
6 Adequate organ function at Screening (as defined in the protocol).
7 Uric acid level < upper limit of normal (ULN).

E.4

Principal exclusion criteria

Core
1.Participants with non-secretory myeloma
2.Unresolved non-haematological toxicities (except alopecia) from prior therapy>CTCAE Grade 1 at study treatment start
3.Presence or hist of central nervous system(CNS)lymphoma,leptomeningeal disease or spinal cord compression
4.Prior non-haematological malignancy except for the following
a)Malignancy treated with curative intent with no evidence of active disease for >one year before screening and thought at low risk of recurrence by treating physician b)Adequately treated lentigo maligna melanoma without evidence of disease or adequately controlled non-melanomatous skin cancer c)Adequately treated carcinoma in situ without evidence of disease
5.As judged by Investigator,severe or uncontrolled systemic disease (severe hepatic impairment, interstitial lung disease),unstable or uncompensated respiratory or cardiac conditions,uncontrolled hypertension,hist of or active bleeding diatheses,uncontrolled active systemic infection or IV anti infective treatment within two weeks before first dose of study drug
6.Known hist of infection with human immunodeficiency virus(HIV)
7.Serologic status reflecting active hepatitis B or C infection

Exclusion criteria related to acalabrutinib combinations (Module 1 and 2):
1.Participants must comply with Core excl. criteria
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,bowel obstruction,or gastric restrictions and bariatric surgery
3.Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment
4.Requires treatment with strong CYP3A inhibitors or inducers
5.Requires treatment with proton-pump inhibitors Participants who switch from proton-pump inhibitors to H2-receptor antagonists or antacids are eligible
6.Active Cytomegalovirus(CMV)infection (positive CMV immunoglobulin M[IgM] and positive PCR result)
7.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
8.Participants on dual antiplatelet and anticoagulant therapy(eg,aspirin and therapeutic doses of low molecular weight heparin)
9.Requires or receiving anticoagulation with vitK antagonists
10.Hist of or ongoing confirmed progressive multifocal leukoencephalopathy(PML)

E.5 End points

E.5.1

Primary end point(s)

Part A
•Adverse events
•Laboratory data
•vital signs
•ECG changes
Part B
•ORR- defined as the proportion of participants who have a tumor response (CR and PR).

E.5.1.1

Timepoint(s) of evaluation of this end point

As detailed in the Schedule of Activities (SoA)

E.5.2

Secondary end point(s)

Part A and B
•Plasma concentrations and derived PK parameters for AZD4573 summarized by cohort and dose level for the PK analysis set
•Plasma concentrations and derived PK parameters for acalabrutinib and its metabolite ACP-5862 summarized by cohort and dose level for the PK analysis set
Part B
•Endpoints based on revised response criteria for malignant lymphoma: CR rate, DoR, TTR, PFS
•OS
•Adverse events, laboratory data, vital signs, and ECG changes

E.5.2.1

Timepoint(s) of evaluation of this end point

As detailed in the Schedule of Activities (SoA)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability, MTD maximum tolerated dose, DLT dose-limiting toxicity, RP2D recommended Phase II dose

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Modular Phase I/II

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Modular

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

Korea, Republic of

United Kingdom

United States

France

Ireland

Italy

Poland

Spain

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The overall end of the study is defined as the date of the last visit of the last participant. In the event any participant remains on treatment following the end of the data collection for the primary analysis, the last visit of the study will be the date when the last participant permanently discontinued treatment with all investigational products.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

patients with incurrable diseases

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients still receiving AZD4573 after the data cut-off for the primary analysis will be able to continue receiving study treatment if, in the opinion of the Investigator, they are still deriving clinical benefit.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-05-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-13

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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