Clinical Trials Register

Summary
EudraCT Number:	2018-002572-41
Sponsor's Protocol Code Number:	D9103C00001
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-03-14
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

Germany - PEI

A.2

EudraCT number

2018-002572-41

A.3

Full title of the trial

A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab with Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Patients with unresected Stage I/II, lymph-node negative Non-small Cell Lung Cancer (PACIFIC-4/RTOG-3515)

Osimertinib cohort, Open-label, Single arm for patients with unresected stage I/II, lymph done negative NSCLC harboring a sensitizing EGFR Mutation

A.3.1

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

Study of durvalumab or placebo administered with radiation therapy for patients with early stage non-small cell lung Cancer

Study of osimertinib administered after radiation therapy in patients with early stage non-small cell lung cancer harboring an EGFR Mutation

A.3.2

Name or abbreviated title of the trial where available

PACIFIC-4/RTOG-3515

A.4.1

Sponsor's protocol code number

D9103C00001

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	Not applicable
B.5.3.2	Town/ city	Not applicable
B.5.3.3	Post code	Not applicable
B.5.3.4	Country	Sweden
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	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.3.9.3	Other descriptive name	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	Yes
D.2.1.1.1	Trade name	TAGRISSO
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	Osimertinib 80 mg
D.3.2	Product code	AZD9291
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	Osimertinib
D.3.9.1	CAS number	1421373-66-1
D.3.9.2	Current sponsor code	AZD9291
D.3.9.4	EV Substance Code	SUB176340
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	80
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	Yes
D.2.1.1.1	Trade name	TAGRISSO
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	Osimertinib 40 mg
D.3.2	Product code	AZD9291
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	Osimertinib
D.3.9.1	CAS number	1421373-66-1
D.3.9.2	Current sponsor code	AZD9291
D.3.9.4	EV Substance Code	SUB176340
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with unresected Stage I/II, lymph-node negative Non-small Cell Lung Cancer

E.1.1.1

Medical condition in easily understood language

Specific type of lung cancer called “Non-Small Cell Lung 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	LLT
E.1.2	Classification code	10029514
E.1.2	Term	Non-small cell lung cancer NOS
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

Applicable to main cohort:
To assess the efficacy of durvalumab with SoC SBRT compared to Placebo with SoC SBRT in terms of PFS in patients with a subset of T1 to T3N0M0 NSCLC

Applicable to osimertinib cohort:
To assess the efficacy of osimertinib following SoC SBRT in patients with T1 to T3N0M0 in terms of a 4-year PFS

E.2.2

Secondary objectives of the trial

Applicable to main cohort:
To assess the efficacy of durvalumab with SBRT (Stereotactic Body Radiation Therapy) compared to placebo with SBRT in terms of:
- PFS in patients with T1 to T3N0M0 NSCLC
- Overall Survival
- PFS24, TTP, TTDM, and PFS2

To assess the PK of durvalumab
To investigate the immunogenicity of durvalumab
To assess symptoms and health-related quality of life in patients treated with durvalumab with SBRT compared to placebo with SBRT using the EORTC QLQ-C30
To assess the safety and tolerability profile of durvalumab with SoC SBRT compared to placebo with SoC SBRT

Applicable to osi cohort:
-PFS by ICR according to RECIST 1.1
-OS, TTP, Time to CNS progression, PFS2
To assess the safety, tolerability, and compliance of a maximum of 3 years of osimertinib following SoC SBRT

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Applicable to both cohorts:
1. Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling and analyses
2. Age ≥18 years
3. Histologically or cytologically documented Stage I to II NSCLC, with clinical T1 to T3N0M0 Stage I/II disease and planned to receive definitive treatment with SBRT (Stereotactic Body Radiation Therapy).
Patients may be medically inoperable or are medically operable and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as definitive therapy
4. Planned SoC SBRT as definitive treatment
5. World Health Organization (WHO)/ECOG PS of 0, 1, or 2
6. Patients with central or peripheral lesions are eligible
7. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions
8. Staging studies must be done during screening (PET-CT within 10 weeks)
9. Submission of available tumor tissue or cell block samples from FNA

Main cohort (durvalumab) specific:
1. Life expectancy of at least 12 weeks
2. Body weight >30 kg
3. Adequate organ and marrow function required
4. Pulmonary Function Testing within 16 weeks of randomization

Osimertinib cohort specific:
1. Confirmation by local laboratory that the tumor harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R)
2. Adequate bone marrow reserve or organ function required

E.4

Principal exclusion criteria

Applicable to both cohorts:
1. Mixed small cell and non-small cell cancer
2. History of another primary malignancy with exceptions

Main cohort specific:
1. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort
2. History of allogeneic organ transplantation
3. History of active primary immunodeficiency or autoimmune disorders
4. History of non-infectious pneumonitis requiring steroids
5. Active infection including tuberculosis, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus
6. Prior exposure to immune-mediate therapy

Osimertinib cohort specific:
1. Patients currently receiving potent inducers of CYP3A4
2. Patients with known or increased risk factor for QTc prolongation
3. Treatment with any of the following:
-Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation
-Prior treatment with neoadjuvant or adjuvant EGFR TKI
-Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4
-Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib
4. Any of the following cardiac criteria
-Mean resting corrected QT interval >470 msec, obtained from 3 ECGs
-Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
-Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval
-Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD

E.5 End points

E.5.1

Primary end point(s)

Applicable to main cohort:
PFS in patients with subset of T1-T3N0M0 by BICR

Applicable to osimertinib cohort:
4-years PFS by ICR using RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

On-study tumor assessments occur 8 weeks after randomization (after start of SBRT for osimertinib cohort), then every 12 weeks through week 116, then every 16 weeks through 3 years after randomization (after start of SBRT for osimertinib cohort), then every 6 months thereafter
until objective disease progression.

E.5.2

Secondary end point(s)

Applicable to main cohort:
PFS in patients with T1 to T3N0M0 NSCLC
Overall Survival
PFS24, TTP, and TTDM using BICR assessments according to RECIST 1.1
PFS2 using local assessment
PK of durvalumab in serum
Presence of ADA for durvalumab
EORTC QLQ-C30: Change in symptoms, functioning, and global health
status/quality of life
Safety and tolerability: AEs, physical examinations, vital signs,
electrocardiograms, and laboratory findings

Applicable to osimertinib cohort:
AEs (graded by CTCAE version 5)
Laboratory studies: chemistry, hematology, and urinalysis
Clinical evaluations
ECG parametres
LVEF
WHO performance status
PFS using RECIST 1.1
OS
Site(s) of disease progression
Time to CNS progression
TTP
PFS2

E.5.2.1

Timepoint(s) of evaluation of this end point

Both cohorts:
OS: date of death
Lung cancer mortality: date of death due to lung cancer
TTP: date of progression (excluding deaths)
PFS2: the earliest of progression event subsequent to first subsequent
therapy or death

Main cohort:
PFS24: 24 months
TTDM: date of death or distant metastasis
Safety and tolerability: from randomization until 3 months after
treatment discontinuation

Osimertinib Cohort:
Time to CNS progression: date of Progression

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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
Symptoms and health-related quality of life
Healthcare resource utilization

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Above are applicable to main cohort. Osimertinib cohort is an open-label cohort (single-arm)

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Above are applicable to main cohort. Osimertinib cohort is a single arm (not placebo controlled)

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

Australia

Brazil

Canada

China

Israel

Japan

Korea, Republic of

Russian Federation

United Kingdom

United States

Belgium

France

Germany

Greece

Italy

Netherlands

Poland

Spain

Türkiye

E.8.7

Trial has a data monitoring committee

Yes

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 expected visit/contact of the last patient undergoing the study (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 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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

590

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

A legal representative may provide consent on behalf of a subject incapable of giving consent personally, where permitted by local regulations.

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

148

F.4.2.2

In the whole clinical trial

690

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 randomized to durvalumab monotherapy may undergo up to 24 months of retreatment
Patients who discontinue treatment after RECIST 1.1-defined PD will be followed up for survival
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be followed up with tumor assessments until RECIST 1.1-defined PD plus 1 or more follow-up scans or until death (whichever comes first) and followed for survival

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

2019-07-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-15

P. End of Trial
P.	End of Trial Status	Ongoing

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