Clinical Trials Register

Summary
EudraCT Number:	2015-003639-37
Sponsor's Protocol Code Number:	D4198C00003
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-01-30
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

UK - MHRA

A.2

EudraCT number

2015-003639-37

A.3

Full title of the trial

A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

A.3.1

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

Study of MEDI4736, when used in combination with chemotherapy agents or AZD5069, as first or second line in metastatic Pancreatic Ductal Adenocarcinoma

A.4.1

Sponsor's protocol code number

D4198C00003

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	AstraZenenca
B.5.2	Functional name of contact point	Information Center
B.5.3.4	Country	United States
B.5.4	Telephone number	0018002369933
B.5.6	E-mail	information.center@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	MEDI4736
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: 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	AZD5069 40mg film-coated tablet
D.3.2	Product code	AZD5069
D.3.4	Pharmaceutical form	Film-coated tablet
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	AZD5069
D.3.9.1	CAS number	878385-84-3
D.3.9.2	Current sponsor code	AZD5069
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	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.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	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	AZD5069 10 mg film-coated tablet
D.3.2	Product code	AZD5069
D.3.4	Pharmaceutical form	Film-coated tablet
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	AZD5069
D.3.9.1	CAS number	878385-84-3
D.3.9.2	Current sponsor code	AZD5069
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	10
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

Adult patients (aged ≥18 years) with histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma who are treatment naive or have tumor progression following prior standard first-line 5-FU-containing or gemcitabine-containing chemotherapy.

E.1.1.1

Medical condition in easily understood language

Pancreatic Ductal Adenocarcinoma

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10033605
E.1.2	Term	Pancreatic cancer metastatic
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Cohort 1: To assess the safety, tolerability of Medi4736 in combination with nab-paclitaxel + gemcitabine
2. Cohort 2: To assess the safety, tolerability and ORR of MEDI4736 + AZD5069 in combination.

E.2.2

Secondary objectives of the trial

1.To further assess the efficacy of MEDI4736 +AZD5069 in terms of DoR, DCR, PFS, PFS3, PFS6, OS, OS6, and OS12.

2.To investigate the relationship between PD-L1 expression by IHC and efficacy parameters

3.To investigate the immunogenicity of MEDI4736 in combination with AZD5069.

4.To assess the PK of MEDI4736 and the combination of MEDI4736 and AZD5069.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 years at the time of screening.
2. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
3. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior systemic chemotherapy regimen or treatment-naïve patients
4. Life expectancy ≥ 12 weeks.
5. Eastern Cooperative Oncology Group 0 or 1
6. At least 1 lesion, not previously irradiated, that can be accurately measured at
baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements
-Patient should receive no more than 1 prior chemotherapy regimen or any other systemic therapy for recurrent/metastatic PDAC.
7. Adequate organ and bone marrow function as defined below:
 Hemoglobin ≥9 g/dL
 Albumin ≥3 g/dL
 Absolute neutrophil count ≥1500/mm3
 Platelet count ≥100000/mm3
 Serum bilirubin ≤1.5 × the upper limit of normal (ULN). 
ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥40 mL/min
8. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients
9. Mandatory tumor biopsy at screening

E.4

Principal exclusion criteria

1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
2. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
3. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
4. Receipt of last dose of an approved anticancer therapy within 21 days prior to the first dose of study treatment.
5. Major surgical procedure (as defined by the Investigator) within 21 days prior to the first dose of IP
6. Patients weighing less than 30 kg.
7. History of leptomeningeal carcinomatosis
8. Ascites requiring intervention
9. Brain metastases or spinal cord compression
10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
11. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736. with exceptions that Intranasal, inhaled, or topical steroids; or local steroid injections; Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions and chemotherapy induced nausea and vomiting.
12.Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736
13. History of organ transplant that requires use of immunosuppressive agents.
14. Active autoimmune disorders , or prior documented severe autoimmune or inflammatory disorders requiring immunosuppressive treatment
- Prior exposure to immune-mediated therapy
- Has received any potent and moderate cytochrome P450 (CYP)3A4 inhibitors, potent and moderate CYP3A4 inducers, P-glycoprotein substrates (digoxin and dabigatran), breast cancer resistance protein substrates (topotecan), sensitive CYP2B6 substrates (bupropion and efavirenz), warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment
15. Uncontrolled intercurrent illness
16. Other malignancy within 5 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, prostate cancer or ductal carcinoma in situ of the breast that has/have been surgically cured
17. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated from 3 ECG reports
18. History of active primary immunodeficiency.
19. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
20. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
22. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control (see Section 3.8).
23. Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies.
24. Any condition that, in the opinion of the Investigator, would interfere with evaluation of IP or interpretation of patient safety or study results.
25. Prior exposure to immune-mediated therapy or prior randomization or treament in previous MEDI4736 and/or tremelimumab clinical trials regardless of treatment arm assignment.

E.5 End points

E.5.1

Primary end point(s)

1. Objective response rate (Medi4736+AZD5069)
2. Calculation or derivation of safety variables

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression

2. Data from all cycles of treatment will be combined in the presentation of the safety data

E.5.2

Secondary end point(s)

1.Duration of Response, Disease control rate, Progression-free survival (PFS), Proportion of patients alive and PFS at 3, 6 & 12 months
2. ORR, DoR, DCR, Os, and PFS across PD-L1 expression using Investigator assessments according to RECIST 1.1
3.Presence of ADAs for MEDI4736
4.Concentration of MEDI4736 & AZD5069 in blood and noncompartmental PK parameters

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2 Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression. Biopsy for PD-L1 expression analysis taken at screening and at Week 4

3.Samples for immunogenicity assessment for MEDI4736 taken on day 1 of Cycles 1, 2, 3, 4, 7 and 3&6 months after last dose of IP

4 PK (Serum/Blood - MEDI4736&AZD5069), taken on day 1 of Cycles 1, 2, 3, 4, 7. and 3 months after last dose of IP for MEDI4736 only

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

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

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

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

United Kingdom

United States

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 subject last visit

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

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

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

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)

After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving MEDI4736 + AZD5069 combination therapy up to completion of a patient’s treatment period

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

2017-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-07-03

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