Clinical Trials Register

Summary
EudraCT Number:	2016-004787-20
Sponsor's Protocol Code Number:	MED3-201601
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:	2017-07-05
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2016-004787-20

A.3

Full title of the trial

An Open Label, Randomized Phase 2 Clinical Trial of Nivolumab investigating Effiacy and safety of Nivolumab given once prior to, concurrent to the radiotherapy (RT) and as maintenance therapy over 12 months in patients with advanced resectable HNSCC after surgery (NadiHN)

Offene, randomisierte Phase-II-Studie bei Patienten mit resektablem fortgeschrittenem Plattenepithelcarcinom des Kopf-Hals-Bereichs (Stadium III ohne Risikofaktor), die die Effektivität und Sicherheit von Nivolumab in Kombination mit einer adjuvanten Strahlentherapie versus der Effektivität einer alleinigen Strahlentherapie untersucht

A.3.1

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

Offene, randomisierte Phase-II-Studie bei Patienten mit operablem fortgeschrittenem Plattenepithelcarcinom des Kopf-Hals-Bereichs (Stadium III ohne Risikofaktor), die die Verträglichkeit und Wirksamkei von Nivolumab in Kombination mit einer adjuvanten Strahlentherapie mit der Wirksamkeit einer alleinigen Strahlentherapie vergleicht.

A.3.2

Name or abbreviated title of the trial where available

NadiHN

A.4.1

Sponsor's protocol code number

MED3-201601

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	Rheinische Friedrich-Wilhelms-Universität Bonn
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	Studienzentrale Studienzentrum Bonn (SZB)
B.5.2	Functional name of contact point	Marius Krauthausen
B.5.3	Address:
B.5.3.1	Street Address	Venusberg-Campus 1
B.5.3.2	Town/ city	Bonn
B.5.3.4	Country	Germany
B.5.4	Telephone number	004922828711775
B.5.5	Fax number	004922828716039
B.5.6	E-mail	marius.krauthausen@ukbonn.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	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	Nivolumab
D.3.2	Product code	BMS-936558-01
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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.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

Patients with resectable advanced stage HNSCC (T1–T4 N0-N2 M0) with intermediate risk (resection margins > 5 mm, no perineural invasion and no extracapsular evasion) for whom definite RT post surgery would be standard of care.

E.1.1.1

Medical condition in easily understood language

Patients with resectable advanced stage HNSCC (T1–T4 N0-N2 M0) with intermediate risk for whom definite RT post surgery would be standard of care.

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10060121
E.1.2	Term	Squamous cell carcinoma of head and neck
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 analyze response of intermediate risk HNSCC patients after surgery to treatment with nivolumab plus radiotherapy versus radiotherapy alone.

E.2.2

Secondary objectives of the trial

• To assess overall survival in response to experimental treatment versus standard treatment
• To assess safety of nivolumab plus radiotherapy compared to radiotherapy alone
• To assess quality of life of experimental treatment versus standard treatment

Exploratory Objectives:
• Identification of antigens recognized by the immune system under nivolumab plus radiotherapy compared to radiotherapy alone
• To identify immunological biomarker for treatment response and prognosis

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed squamous cell carcinoma of the head and neck region (oral cavity, pharynx, larynx), T1–T4 N0-N2 M0, with intermediate risk and curative intent for which post operative adjuvant radiation therapy would be standard of care. No presence of the following risk factors: extracapsular growth of the lymph nodes or positive margins; (in these cases an adjuvant post operation platinum based chemoradiation therapy is recommended). Close margins (< 5 mm) of the main specimen or focally positive margins of the main specimen are permitted if subsequent margins are negative. Additionally, close margins (< 5 mm) of the main specimen are allowed under certain circumstances, see inclusion criteria (3).
2. CT scan or MRI (MRI in the case of contrast agent allergy) of the neck and thorax within 80 days prior to randomization (preoperative or postoperative). CT of the abdomen (or ultrasound abdomen) within 80 days prior to randomization (preoperative or postoperative).
3. Margin(s) of resection > 5 mm; margins < 5 mm are only allowed if a) subsequently confirmed as a negative margin or b) the close margin adjoins a clear anatomical border (e.g. bone). Similary, patients whose tumors had focally positive margins in the main specimen are eligible if margins from reexcised samples in the region of the positve margin are negative.
4. Males and Females  18 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status 1.
5. Documentation of p16-positive or p16-negative disease to determine human papillomavirus (HPV) status of tumor for SCCHN.
6. Be free of signs of remaining cancer.
7. Tumor tissue must be available for PD-L1 expression analysis (Randomisation < 1 % versus ≥ 1 % expression of PD-L1) and other biomarker correlative studies.
8. Immunosuppressive doses of systemic medication, such as steroids or absorbed topical steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks before study drug administration.
9. Have adequate organ function
10. Screening laboratory values must meet the following criteria (using CTCAE v4):
• WBC 2000/μL
• Neutrophils 1500/μL
• Platelets 100 x103/μL
• Hemoglobin  9.0 g/dL
• Serum creatinine 1.5 x ULN or creatinine clearance (CrCl) > 40 mL/min
• AST/ALT 3 x ULN
• Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
11. Subjects must have resting baseline O2 saturation by pulse oximetry of ≥ 92 % at rest.

E.4

Principal exclusion criteria

1. Histologically confirmed recurrent or metastatic carcinoma or primary of the nasopharynx or salivary gland or non-squamous histologies (e.g. mucosal melanoma) are not allowed.
2. One of the following risk factors: extracapsular growth of the lymph nodes, or positive margins (post operative adjuvant platinum based chemoradiation therapy recommended).
3. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
4. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
5. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
6. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
7. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
8. Patient is the recipient of an organ/bone marrow transplant
9. Positive test for Hepatitis B virus surface antigen (HB sAg) or active Hepatitis C (presence of HCV RNA in case of positive HCV antibody) or positive testing for HIV (HIV antibodies).
10. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
11. History of allergy to study drug components.
12. History of severe hypersensitivity reaction to any monoclonal antibody.
13. Prisoners or subjects who are involuntarily incarcerated.
14. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
15. Current pregnancy or lactating females.
16. Females of childbearing potential, who are not using and not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized/hysterectomized or there are any other criteria sufficiently reliable by the investigator in individual cases.
17. The subject received an investigational drug within 30 days prior to inclusion into this study.
18. The subject is unwilling to provide informed consent or unwilling or unable to follow the procedures outlined in the protocol.
19. The subject is mentally or legally incapacitated.

E.5 End points

E.5.1

Primary end point(s)

Disease free survival measured from time of randomization to first signs of local recurrence, regional or distant metastasis, second primary or death, whichever comes first.

E.5.1.1

Timepoint(s) of evaluation of this end point

36 month after randomization

E.5.2

Secondary end point(s)

• Overall survival, measured from time of randomisation to death of any cause
• Adverse events (graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, V 4.0)
• Quality of Life will be evaluated by standardized questionnaires QLQ-C30, EQ-5D and head and neck specific module QLQ-H&N35

Exploratory endpoints:
• Immunological monitoring will consist of serum biomarkers, including but not limited to T cell response, characterization of immune cell subsets in peripheral blood, soluble PD-L1, soluble PD-L2, IL-2, inflammatory factors, rheumatoid factors.

E.5.2.1

Timepoint(s) of evaluation of this end point

36 month after randomization,
over all survival will by assessed by long-term follow-up till death of any cause

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

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.2.3.1

Comparator description

Radiotherapy

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

LVLS

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:

176

F.1.3

Elderly (>=65 years)

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

176

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)

none

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

2017-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-05

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials