Clinical Trials Register

Summary
EudraCT Number:	2019-002537-11
Sponsor's Protocol Code Number:	DART
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-13
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

Lithuania - SMCA

A.2

EudraCT number

2019-002537-11

A.3

Full title of the trial

Durvalumab (MEDI4736) After chemoRadioTherapy (DART) for NSCLC patients – a phase II translational and biomarker study investigating PDL1 positive and negative patients

A.3.1

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

Durvalumab (MEDI4736) After chemoRadioTherapy (DART) for NSCLC patients – a phase II translational and biomarker study investigating PDL1 positive and negative patients

A.3.2

Name or abbreviated title of the trial where available

DART (19-14434)

A.4.1

Sponsor's protocol code number

DART

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	Oslo University Hospital
B.1.3.4	Country	Norway
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Oslo University Hospital
B.5.2	Functional name of contact point	National Coordinating Investigator
B.5.3	Address:
B.5.3.1	Street Address	Ullernchausseen 70
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	0379
B.5.3.4	Country	Norway
B.5.4	Telephone number	4722934000
B.5.5	Fax number	4722935808
B.5.6	E-mail	ahh@ous-hf.no

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	Yes
D.2.1.1.1	Trade name	Imfinzi
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	Imfinzi
D.3.4	Pharmaceutical form	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	IMFINZI
D.3.9.4	EV Substance Code	SUB176342
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
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	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

Non-small cell lung cancer (NLCLC)

E.1.1.1

Medical condition in easily understood language

Non-small cell lung cancer (NLCLC)

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	10061873
E.1.2	Term	Non-small cell lung cancer
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 if patients with a high tumour mutational burden, TMB (>8.5 mutations per megabase) have a hazard ratio equal to or less than 0.55 as compared to patients with low TMB.

E.2.2

Secondary objectives of the trial

1. To investigate different levels of TMB in tumour tissue compared to blood samples, as predictors for development of clinical response
2. To characterise the transcriptome (RNA seq)
3. To investigate urine for predictive biomarkers (ctDNA, miRNA)
4. To evaluate if selected biomarkers correlate to progression-free survival and overall survival in PDL1 negative and positive patients receiving the PD-L1-inhibitor durvalumab after chemoradiation
5. To investigate the immunological response, tumour development (if present) and dynamics in the tumour micro-environment
6. To investigate if chemoradiation upregulates / changes PDL1 expression in the PDL1 negative / positive patients
7. To evaluate if biomarkers predict toxicity of this treatment in lung cancer patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study patients must fulfill all of the following criteria:
1. Locally-advanced, unresectable, stage 3 NSCLC (including PET-CT
and MRI-brain in the diagnostic work-up).
2. Capable of giving signed informed consent which includes
compliance with the requirements and restrictions listed in the informed
consent form (ICF) and in this protocol. Written informed consent and
any locally required authorization (European Union [EU] Data Privacy
Directive in the EU) obtained from the patient/legal representative prior
to performing any protocol-related procedures, including screening evaluations.
3. Diagnostic biopsy with PDL1 <1% in 50 patients PDL1 ≥1% in 50
patients
4. Adequate core or excisional biopsy
5. Age ≥ 18 years at time of study entry
6. Eastern Cooperative Oncology Group (ECOG performance status of 0,
1 or 2
7. Life expectancy of at least 12 weeks
8. Body weight >30 kg
9. Adequate normal organ and marrow function as defined below:
Hemoglobin ≥9.0 g/dL
Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)
Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
unless liver metastases are present, in which case it must be ≤5x ULN
Measured creatinine clearance (CL) >40 mL/min or Calculated
creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and
Gault 1976) or by 24-hour urine collection for determination of
creatinine clearance
10. Evidence of post-menopausal status or negative urinary or serum
pregnancy test for female pre-menopausal patients. Women will be
considered post-menopausal if they have been amenorrheic for 12
months without an alternative medical cause.
11. Women of childbearing potential should have a negative urine or
serum pregnancy test within 7 days prior to receiccing first dose of study
medication. if the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required. A woman is
considered WOCBP, i.e. fertile, following menarche and untill becoming
post-menopausal unkess permanently sterile. Permanent sterilisation
methods include hysterectomy, bilateral salpingectomy and bilateral
oophorectomy.
12. WOCBP should use an adequate method to avoid pregnancy
13.Males who are sexually active with women of childbearing potential
must agree to follow instructions for method(s) of contraception for a
period of 90 days (duration of sperm turnover) plus the time required for
the investigational drug to undergo five half-lives
14.Patient is willing and able to comply with the protocol for the
duration of the study including undergoing
treatment and scheduled visits and examinations including follow up.

E.4

Principal exclusion criteria

1. Non-small cell lung cancer disease suitable for curative surgery
2. Significant cardiac, pulmonary or other medical illness that would
limit activity or survival
3. Concurrent enrolment in another clinical study, unless it is an
observational (non-interventional) clinical study or during the follow-up
period of an interventional study during the last 2 weeks.
4. Any concurrent chemotherapy, Investigational product (IP), biologicor homonal therapy for cancer treatment. Concurrent use of hormonal
therapy for non-cancer related conditions (e.g. hormone replacement
therapy) is acceptable.
5. Major surgical procedure (as defined by the Investigator) within 28
days prior to the first dose of IP. Note: Local surgery of isolated lesions
for palliative intent is acceptable.
6. History of allogenic organ transplantation.
7. Active or prior documented autoimmune or inflammatory disorders
The following are exceptions to this criterion:
a. Patients with vitiligo or alopecia
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome)
stable on hormone replacement
c. Any chronic skin condition that does not require systemic therapy
d. Patients without active disease in the last 5 years may be included
but only after consultation with the study physician
e. Patients with celiac disease controlled by diet alone
8. Uncontrolled intercurrent illness, including but not limited to,
ongoing or active infection, symptomatic congestive heart failure,
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia,
interstitial lung disease, serious chronic gastrointestinal conditions
associated with diarrhea, or psychiatric illness/social situations that
would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give
written informed consent
9. History of other active cancer disease
10. History of active primary immunodeficiency or medical condition
requiring high doses (>30 mg prednisolone daily) of systemic steroids or
other forms of immunosuppressive therapy
11. Active infection including tuberculosis (clinical evaluation that
includes clinical history, physical examination and radiographic findings,
and TB testing in line with local practice), hepatitis B (known positive
HBV surface antigen (HBsAg) result), and hepatitis C. Patients with a
past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
positive for hepatitis C (HCV) antibody are eligible only if polymerase
chain reaction is negative for HCV RNA.
12. Current or prior use of immunosuppressive medication within 14
days before the first dose of durvalumab. The following are exceptions to
this criterion:
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra articular injection)
b. Systemic corticosteroids at physiologic doses not to exceed <<10
mg/day>> of prednisone or its equivalent
c. Steroids as premedication for hypersensitivity reactions (e.g., CT
scan premedication)
13. Receipt of live attenuated vaccine within 30 days prior to the first
dose of IP. Note: Patients, if enrolled, should not receive live vaccine
whilst receiving IP and up to 30 days after the last dose of IP.
14. Female patients who are pregnant or breastfeeding or male or
female patients of reproductive potential who are not willing to employ
effective birth control from screening to 90 days after the last dose of
durvalumab monotherapy.
15. Known allergy or hypersensitivity to any of the study drugs or any
of the study drug excipients.
16. Prior randomisation or treatment in a previous durvalumab clinical
study regardless of treatment arm assignment.
17. Judgment by the investigator that the patient is unsuitable to
participate in the study and the patient is unlikely to comply with study
procedures, restrictions and requirements.
18. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the
Study Physician.
19. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab
may be included only after consultation with the Study Physician.

E.5 End points

E.5.1

Primary end point(s)

Patients with high Tumour Mutational Burden, TMB (> 8.5 mutations per megabase) have a hazard ratio equal to or less than 0.55 as compared to patients with low TMB.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation is planned when all included patients are followed-up for two years after start of treatment.

E.5.2

Secondary end point(s)

1. Tumour Mutational Burden, TMB in tumor tissue and blood samples are associated and are predictive of clinical response
2. Specific RNA profiles predict response to treatment
3. Molecular profiles in urine predict response to treatment
4. Analysis of pre-treatment and under-treatment samples may identify biomarkers for predicting which patients will benefit from treatment with durvalumab after chemoratiation
5. The durvalumab treatment following chemoradiatio will induce T cell responses against antigens expressed in each patient´s tumor
6. A possible change in PDL1 status will be explored
7. The durvalumab treatment following chemoradiation has acceptable safety and tolerability in NSCLC patients, as assessed by Patient Reported Outcome measurements.

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation is planned when all included patients are followed-up for two years after start of treatment.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

All subjects will be followed for survival until the end of the study defined as the last expected visit of the last subject on study, approximately 10 years after the last subject discontinue treatment with investigational product or when the sponsor stops the study, whichever occurs earlier.

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

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

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

100

F.4.2.2

In the whole clinical trial

100

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)

The patients will be followed according to normal treatment of the condition

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

2020-04-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-27

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

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