Clinical Trials Register

Summary
EudraCT Number:	2017-000105-20
Sponsor's Protocol Code Number:	0316-ASG
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-04-11
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

Germany - PEI

A.2

EudraCT number

2017-000105-20

A.3

Full title of the trial

Neoadjuvant anti PD-1 immunotherapy in resectable non-small cell lung cancer

Neoadjuvante anti-PD-1 Immuntherapie bei operablem nichtkleinzelligen
Lungenkrebs

A.3.1

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

Administration of an anti-cancer therapy, which is based on release of brakes in the natural immune response, in patients which are planned to subsequently undergo surgery for removal of their non-small cell lung cancer

Verabreichung einer Krebs-Therapie, welche auf dem Lösen von Bremsen der natürlichen Körperabwehr basiert, bei Patienten deren nichtkleinzelliger Lungenkrebs anschließend in einer Operation entfernt werden soll

A.3.2

Name or abbreviated title of the trial where available

NEOMUN

A.4.1

Sponsor's protocol code number

0316-ASG

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	AIO-Studien-gGmbH
B.1.3.4	Country	Germany
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	MSD SHARP & DOHME GMBH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AIO-Studien-gGmbH
B.5.2	Functional name of contact point	Dr. Aysun Karatas
B.5.3	Address:
B.5.3.1	Street Address	Kuno-Fischer-Straße 8
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	14057
B.5.3.4	Country	Germany
B.5.4	Telephone number	004930814534431
B.5.5	Fax number	004930322932926
B.5.6	E-mail	info@aio-studien-ggmbh.de

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	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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.3.4	Pharmaceutical form	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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.3	Other descriptive name	MK-3475
D.3.9.4	EV Substance Code	SUB91641
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	25
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)	Yes
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.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 (NSCLC), resectable

E.1.1.1

Medical condition in easily understood language

non-small cell lung cancer (NSCLC), removable by surgery

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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10029520
E.1.2	Term	Non-small cell lung cancer stage IIIA
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029518
E.1.2	Term	Non-small cell lung cancer stage II
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

- feasibility and safety of a neoadjuvant application of pembrolizumab
- antitumor activity of pembrolizumab with regard to clinical and pathologic tumor response

E.2.2

Secondary objectives of the trial

- impact of neoadjuvant pembrolizumab on patient survival
- explore potential predictive biomarkers for pembrolizumab efficacy
- immune cell imaging

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Cooperation and willingness to complete all aspects of the study
2. Signed and dated written informed consent must be given prior to study inclusion
3. Histological or cytological confirmed NSCLC.
4. Clinical stage II-IIIA according to the TNM classification, 7th edition.
stage IIIa: T1/T2 N2 (IIIa1-3 Robinson classification)
5. Adequate disease staging by PET/CT performed and resectability established.
6. At least 1 measurable lesion according to RECIST 1.1
7. Age ≥ 18 years
8. ECOG performance status 0 - 1
9. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in in the protocol, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in protocol, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Adequate bone marrow function, liver and renal function:
a. Absolute neutrophil count ≥ 1.5 x 10^9/L
b. Thrombocytes ≥ 100 x 10^9/L
c. Hemoglobin ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of assessment)
d. INR < 1.4 ULN and PTT < 40 seconds during the last 7 days before therapy
e. Bilirubin < 1.5 x upper limit of normal
f. AST (GOT) and ALT (GPT) < 2.5 x ULN
g. Albumin ≥ 2.5 mg/dL
h. Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl):
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
12. Adequate lung and cardiac function for intended lung resection according to German S3 guideline

E.4

Principal exclusion criteria

1. Anticancer treatment during the last 30 days prior to start of treatment, including systemic therapy, radiotherapy or major surgery
2. Participation in a clinical trial within the last 30 days prior to study treatment
3. History of allogeneic tissue/solid organ transplant
4. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
5. Evidence of interstitial lung disease.
6. cT4 tumor
7. Symptomatic acute cardiovascular or cerebrovascular disease
8. Known active HBV, HCV or HIV infection
9. Has any other active infection requiring systemic therapy.
10. Patients with active tuberculosis
11. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-Programmed cell death-ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
12. A diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
13. Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1
14. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. [Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, he/she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.]
15. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study.
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment. [Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.]
17. Has known hypersensitivity to pembrolizumab or any of constituents of the product.
18. Other active malignancy requiring treatment
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
19. Lactating or pregnant women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (allowed methods of contraception, meaning methods with a rate of failure of less than 1% per year are implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner). Women of childbearing potential must have a negative pregnancy test (serum β-hCG) at Screening.
20. Any psychiatric illness that would affect the patient’s ability to understand the demands of the clinical trial
21. Patient has already been recruited in this trial
22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

E.5 End points

E.5.1

Primary end point(s)

The trial design will be a phase II trial, with descriptive outcome assessments of:
• frequency and severity of adverse events including peri- and post-operative complications (grade 2-4 AEs according to NCI-CTCAE V4.03)
• number of patients treated in compliance with protocol
• Tumor response evaluation
Clinical response parameters:
o response rates (∆ tumor size / lymph node size), according to RECIST 1.1 criteria
o ∆ PET-activity (standardized uptake value [SUV])
Pathologic response parameters:
o Pathologic regression grading according to Junker criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

after relevant data for the respective endpoint has been collected and cleaned or at the end of study

E.5.2

Secondary end point(s)

• disease free survival
• overall survival
• prognostic value of tumor shrinkage
• prognostic value of inflammatory infiltrates in and around the resected tumor
• serum- and tumor tissue cytokine concentrations
• multi-OMICS tissue analysis approach for markers and mechanisms

E.5.2.1

Timepoint(s) of evaluation of this end point

after relevant data for the respective endpoint has been collected and cleaned or at the end of study

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

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

LSLV

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

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.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 completion of study at the End-of-Treatment-Visit, patients will generally be treated at the discretion of the investigator according to medical routine.

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

2017-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-05

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