Clinical Trials Register

Summary
EudraCT Number:	2020-000209-10
Sponsor's Protocol Code Number:	D8731C00002
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-10-21
Trial results	View 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

Netherlands - Competent Authority

A.2

EudraCT number

2020-000209-10

A.3

Full title of the trial

A Phase II, Open-label Study to Assess the Efficacy, Safety, and Tolerability of AZD4635 in Combination with Durvalumab and in Combination with Cabazitaxel and Durvalumab in Patients Who Have Progressive Metastatic Castrate-Resistant Prostate Cancer (AARDVARC)

A.3.1

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

Phase II two-arm study of AZD4635 in combination with durvalumab and in combination with cabazitaxel and durvalumab in patients with mCRPC

A.3.2

Name or abbreviated title of the trial where available

AARDVARC

A.4.1

Sponsor's protocol code number

D8731C00002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04495179

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 Center
B.5.3	Address:
B.5.3.1	Street Address	USA
B.5.3.2	Town/ city	USA
B.5.3.3	Post code	USA
B.5.3.4	Country	United States
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.3.2	Product code	AZD4635
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	Not applicable
D.3.9.1	CAS number	1321514-06-0
D.3.9.2	Current sponsor code	AZD4635
D.3.9.3	Other descriptive name	SSP002388X, SPD559
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	25
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	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	Durvalumab
D.3.2	Product code	MEDI4736
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	Durvalumab
D.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
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	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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: 3
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	Jevtana
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-aventis groupe
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	Cabazitaxel
D.3.4	Pharmaceutical form	Concentrate and solvent for 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	Cabazitaxel
D.3.9.1	CAS number	183133-96-2
D.3.9.4	EV Substance Code	SUB31282
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	40
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

Progressive Metastatic Castrate-Resistant Prostate Cancer

E.1.1.1

Medical condition in easily understood language

Prostate Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10036909
E.1.2	Term	Prostate cancer metastatic
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

To determine the efficacy (as assessed by radiographic progression free survival [rPFS]) of AZD4635 plus durvalumab and separately of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC.

E.2.2

Secondary objectives of the trial

*To evaluate the safety and tolerability of each treatment regimen
*To determine the efficacy of AZD4635 plus durvalumab and separately of AZD4635 plus durvalumab plus cabazitaxel by assessment of overall survival, objective response rate, duration of response, prostate-specific antigen response in participants with mCRPC
*Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel
*To determine the efficacy of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC, by adenosine signaling gene expression in high and low subgroups in each arm separately
*To determine the effects of AZD4635 plus durvalumab and separately of AZD4635 plus durvalumab plus cabazitaxel on pain and other prostate cancer-related symptoms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Participant must be 18 years of age inclusive at the time of signing the informed consent.
2 Histologically confirmed adenocarcinoma of the prostate.
3 Known castrate-resistant disease.
4 Evidence of disease progression ≤6 months.
5 Body weight >30 kg at screening.
6 Willingness to adhere to the study treatment-specific contraception requirements.
7 Adequate bone marrow reserve and organ function.
8 Adequate organ function for Arm A as demonstrated by all of the following laboratory values:
− Alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases.
− Aspartate aminotransferase (AST) ≤2.5 × ULN if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases
− Total bilirubin (TBL) ≤1.5 × ULN − TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin
9 Participants in Arm A must have received the following prior therapy:
− Maximum of 3 lines of therapy in the mCRPC setting
− Prior therapy with one or more NHAs (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory settings
− Prior therapy with one or more lines of taxanes (eg, docetaxel and/or cabazitaxel)
− Alternatively, must be taxane-ineligible
− Prior therapy can be in either the hormone-sensitive or the hormone-refractory setting
10 Adequate organ function for Arm B as demonstrated by all of the following laboratory values:
− AST and/or ALT ≤1.5 × ULN
− TBL ≤ ULN − TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin
11 Participants in Arm B must have received the following prior therapy:
− Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory settings
− Received no prior cytotoxic chemotherapy other than docetaxel for prostate cancer except for estramustine and except adjuvant/neo-adjuvant treatment completed >3 years ago.
− Prior therapy with only one NHAs (eg, abiraterone acetate or enzalutamide; prior apalutamide is not permitted) for treatment of mCRPC in either hormone-sensitive or hormone-refractory settings.
− Be suitable to receive concomitant Granulocyte-colony stimulating factor during all cycles of cabazitaxel.
− Participants who meet inclusion criteria for Arm B will be allocated preferentially to that arm until recruitment to that arm is completed.

E.4

Principal exclusion criteria

1 Active brain metastases or leptomeningeal metastases.
2 There must be no requirement for immunosuppressive doses of systemic corticosteroids for at least 2 weeks prior to study enrollment.
3 History of pneumonitis, second malignancy that is progressing and/or received active treatment ≤3 years before the first dose of study intervention, and hypersensitivity to polysorbate-80 if allocated to cabazitaxel.
4 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases.
5 Creatinine clearance <40 mL/min (calculated by Cockcroft-Gault equation).
6 Prior exposure to immune-mediated therapy.
7 History of allogeneic organ transplantation.-
8 Active or prior documented autoimmune or inflammatory disorders
9 History of active primary immunodeficiency.
10 Active infection including tuberculosis
11 Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
12 Ongoing treatment with warfarin (Coumadin).
13 Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study intervention.

E.5 End points

E.5.1

Primary end point(s)

rPFS, defined as the time from first dose to radiographic progression as assessed by the Investigator per RECIST v1.1 (soft tissue) and Prostate Cancer Working Group 3 criteria (PCWG3) (bone) or death from any cause, whichever occurs first.

E.5.1.1

Timepoint(s) of evaluation of this end point

•Arm A: RECIST and PCWG3 measurements will be made every 8 weeks (±1 week) for the first 24 weeks relative to the start of study treatment (Cycle 1, Day 1) and every 12 weeks (±1 week) thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond disease progression).”
•Arm B: RECIST and PCWG3 measurements will be made every 9 weeks (±1 week) for the first 27 weeks relative to the start of study treatment (Cycle 1, Day 1)
and every 12 weeks (±1 week) thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond disease progression).”

E.5.2

Secondary end point(s)

- Adverse events/serious adverse events (AEs/SAEs) collected to the last safety follow-up visit.
- Overall survival
- Objective response rate
- Duration of response
- Prostate-specific antigen response
- AZD4635, durvalumab and cabazitaxel plasma concentration and derived PK parameters.
- Radiographic progression free survival within the adenosine signaling gene expression subgroup
- Change from baseline in worst pain, average pain and pain interference in the daily activities scales of the BPI-SF.
- Time to pain progression based on BPI-SF Item 3 “worst pain in 24-hours”.
- Change from baseline in the FAPSI-6 as derived from 6 items, FAPSI-8, as derived from 8 items within the FACT-P and the PCS, as derived from the 12 items in the prostate-specific module of the FACT-P.

E.5.2.1

Timepoint(s) of evaluation of this end point

•RECIST and PCWG3 measurements will be made every 8 ± 1 weeks (Arm A) or 9 ±1 weeks (Arm B) for the first 24 weeks (Arm A) or 27 weeks (Arm B) relative to the start of study treatment and every 12 ±1 weeks thereafter until RECIST 1.1 defined disease progression
•OS:will be determined every 3 months from disease progression until data cut off or death
•PK:will be measured at limited time points up to follow up
•PSA assessment at baseline and at the start of each new treatment cycle (every 4 weeks for arm A and every 3 weeks for first 10 cycles and then every 4 weeks arm B), at end of treatment, and at progression
•BPI-SF and FACT-P assessments will be measured at limited time points up to follow up
•Safety data will be collected from time of informed consent through to safety follow up

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker assessment

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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

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.8.2.4

Number of treatment arms in the trial

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

Korea, Republic of

United States

Belgium

Denmark

France

Germany

Netherlands

Spain

United Kingdom

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

Last visit of the last patient.

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

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

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)

Intervention after the end of the study will be at the discretion of the Investigator.

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

2020-10-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-18

P. End of Trial
P.	End of Trial Status	Completed

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