Clinical Trials Register

Summary
EudraCT Number:	2015-005741-31
Sponsor's Protocol Code Number:	AIO-YMO/TRK-0415
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:	2016-07-18
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

2015-005741-31

A.3

Full title of the trial

Fostering efficacy of anti – PD-1 – treatment: Nivolumab plus radiotherapy in advanced
NSCLC

Förderung der Wirksamkeit einer anti-PD-1-Behandlung (Immuntherapie Nivolumab) in Kombination mit Strahlentherapie zur Behandlung des fortgeschrittenen nicht-kleinzelligen Lungenkarzinoms (NSCLC)

A.3.1

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

Fostering efficacy of anti – PD-1 – treatment: Nivolumab plus radiotherapy in advanced
NSCLC

A.3.2

Name or abbreviated title of the trial where available

FORCE

A.4.1

Sponsor's protocol code number

AIO-YMO/TRK-0415

A.5.4

Other Identifiers

Name:

BMS study number

Number:

CA209-430

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	Bristol-Myers Squibb GmbH & Co.KGaA
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	AIO-Studien-gGmbH
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	004930322939226
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	Opdivo (R)
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
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	Nivolumab
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	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.4	EV Substance Code	SUB122750
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	10
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	Yes
D.3.11.13.1	Other medicinal product type	Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains.

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

metastatic non-squamous Non-Small Cell Lung Cancer (Lung adenocarcinoma metastatic and Large cell lung cancer metastatic)

metastasiertes nicht-squamöses nicht-kleinzelliges Lungenkarzinom (metastasiertes nicht-kleinzelliges Adenokarzinom der Lunge und metastasiertes großzelliges Lungenkarzinom)

E.1.1.1

Medical condition in easily understood language

metastatic non-squamous Non-Small Cell Lung Cancer (Lung adenocarcinoma metastatic and Large cell lung cancer metastatic)

metastasiertes nicht-squamöses nicht-kleinzelliges Lungenkarzinom (metastasiertes nicht-kleinzelliges Adenokarzinom der Lunge und metastasiertes großzelliges Lungenkarzinom)

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	10069730
E.1.2	Term	Large cell lung cancer metastatic
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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10064049
E.1.2	Term	Lung adenocarcinoma 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

The primary objective is to investigate clinical efficacy of a nivolumab-radiotherapy combination treatment..

Das primäre Studienziel ist die Untersuchung der Wirksamkeit einer Kombination aus Nivolumab und palliativer Strahlentherapie in Patienten mit metastasiertem nicht-squamösem NSCLC.

E.2.2

Secondary objectives of the trial

Secondary objectives:
• information on safety and tolerability of nivolumab in combination with radiotherapy by measurement of incidence and severity of AEs and specific laboratory abnormalities in all treated subjects by subject subgroups
• further efficacy data will in patients without necessity of radiotherapy
• information on individual, patient reported and investigator-assessed quality of life
• To explore immune related RECIST criteria as an evaluation method for clinical benefit of nivolumab and nivolumab/radiotherapy
Exploratory objectives:
• Tissue collection and blood sampling whilst course of disease to explore potential predictors of response to nivolumab
• To address the role of radiotherapy in the context of immune modulation, several aspects of radiation planning and treatment are planned to be explored

Sekundär:
• Informationen über die Sicherheit und Verträglichkeit von Nivolumab in Kombination mit einer Strahlentherapie durch Messung der Häufigkeit und Schwere von AEs und Veränderungen spezifischer Laborwerte bei allen behandelten Patienten und in Subgruppen
• weiterer Wirksamkeitsdaten bei Patienten ohne Notwendigkeit einer Strahlentherapie
• Informationen über individuelle, von Patienten berichtete und vom Prüfarzt bewertete, Lebensqualität
• Prüfung, ob die immuntherapie-bezogenen RECIST-Kriterien eine geeignete Evaluierungsmethode des klinischen Nutzens einer Nivolumab-Monotherapie bzw. einer Nivolumab-Strahlen-Kombinationstherapie sind
Explorativ:
• Sammlung von Gewebe- und Blutproben im Verlauf der Behandlung, um mögliche Prädiktoren für das Krankheitsansprechen nach Nivolumabgabe zu untersuchen
• Bestimmung der Rolle der Strahlentherapie im Kontext der Immunmodulation wobei verschiedene Aspekte der Planung und Durchführung der Strahlentherapie erforscht werden sollen

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years at time of study entry.
2. ECOG performance status 0-1.
3. Patients with metastatic non-squamous non-small cell lung cancer after failure of platinum-based doublet chemotherapy and
a) no necessity of radiotherapy (group B) or
b) the necessity of radiotherapy of a metastatic bone lesion or soft tissue lesion (group A)
4. Patients must have measurable disease by CT or MRI per RECIST 1.1 criteria.
5. For each patient a formalin fixed, paraffin-embedded tumor tissue block (archival or recent) or a minimum of 15 unstained slides of tumor sample (2-3 µm sections; slices must be recent and collected on slides provided by the sponsor) must be available for biomarker (PD-L1) evaluation. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient.

E.4

Principal exclusion criteria

1. Patients who require ongoing treatment with more than 10‑mg of prednisone (or steroid equivalent, excluding inhaled or topical steroids) daily.
2. Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
3. Patients with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders, (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.)
4. Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
5. Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required or anticipated to be required during the study period.
6. Brain metastases mandating active treatment in terms of WBI (whole brain irradiation or stereotactic brain irradiation).
7. Subjects with brain metastases are eligible if metastases have been treated and treatment has been completed at least 12 weeks before inclusion in this study for group B and 2 weeks for group A. Moreover, there must be no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with stable/asymptomatic brain metastases that do not require local therapy with irradiation (whole brain irradiation or stereotactic brain irradiation) can be included. In ambiguous cases, consultation with the LKP or any authorized person ist advised
8. Known activating EGFR mutation or a known ALK translocation.

E.5 End points

E.5.1

Primary end point(s)

• ORR according to RECIST 1.1 criteria

• objektive Ansprechrate (ORR) nach RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

approx. 36 months after FPI, approx. 6 months after LPI

ca. 36 Monate nach FPI, ca. 6 Monate nach LPI

E.5.2

Secondary end point(s)

• PFS
• PFS and ORR using assessment according to irRECIST
• OS
• 1 year OS rate
• Descriptive subgroup analyses of efficacy in relation to PD-L1 expression levels (e.g. cut-off 1%, 5%, 10%)
• Treatment Emergent Adverse Events according to CTC 4.03
• Frequency of abnormal laboratory parameters
• QoL [FACT-L]

• Progressionsfreies Überleben (PFS) nach RECIST 1.1
• PFS und ORR Bestimmung nach nach immuntherapie-bezogenden RECIST-Kriterien
• Gesamtüberleben (OS)
• 1-Jahres-Gesamtüberlebensrate
• Deskriptive Subgruppenanalysen der Wirksamkeit in Bezug auf PD-L1-Expressions des Tumors (z.B. Schwellenwert 1%, 5%, 10%)
• Behandlungsspezifische unerwünschte Ereignisse nach CTC 4.03
• Häufigkeit anormaler Laborparameter
• QoL [FACT-L]

E.5.2.1

Timepoint(s) of evaluation of this end point

approx. 48 months after FPI

ca. 48 Monate nach FPI

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

Yes

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.8.6 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

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

End of study (EoS) is defined as the 31 DEC 2020.

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

130

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)

further treatment is at the discretion of the treating physican
In the event that patients show continued clinical benefit from treatment with nivolumab at EOS date and/ or at EOT in case of study termination, the decision to continue treatment shall be based on the marketing authorization of nivolumab and the clinical judgment of the investigator/treating physician (also applies in cases of premature study termination).

die weitere Behandlung liegt im Ermessen des Arztes
Für den Fall, dass der Patient zum Zeitpunkt der Beendigung der klinischen Prüfung und/oder Beendigung der Studienteilnahme von der Behandlung mit Nivolumab weiterhin profitiert, kann nach Ermessen des Prüfers die Therapie mit Nivolumab gemäß der Zulassung fortgeführt werden (gilt auch für vorzeitige Beendigung der Studie)

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

2016-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-14

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