Clinical Trials Register

Summary
EudraCT Number:	2016-002244-16
Sponsor's Protocol Code Number:	NRG-HN002
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-07-06
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

Ireland - HPRA

A.2

EudraCT number

2016-002244-16

A.3

Full title of the trial

A Randomized Phase II Trial for Patients with p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer

A.3.1

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

A phase II clinical trial for patients with cancer of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls) that is non-smoking associated and is positive for the p16 biomarker.

A.4.1

Sponsor's protocol code number

NRG-HN002

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	Irish Clinical Oncology Research Group CLG, trading as Cancer Trials Ireland
B.1.3.4	Country	Ireland
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	NRG Oncology
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Irish Clinical Oncology Research Group CLG, trading as Cancer Trials Ireland
B.5.2	Functional name of contact point	Clinical Program Leader
B.5.3	Address:
B.5.3.1	Street Address	60 Fitzwilliam Square
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	2
B.5.3.4	Country	Ireland
B.5.4	Telephone number	+35316677211
B.5.5	Fax number	+35316697869
B.5.6	E-mail	Verena.Murphy@cancertrials.ie

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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.2.1.2	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	Cisplatin
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	Cisplatin
D.3.9.3	Other descriptive name	CISPLATIN
D.3.9.4	EV Substance Code	SUB07483MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locoregionally advanced oropharyngeal cancer

E.1.1.1

Medical condition in easily understood language

Cancer of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls)

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10031096
E.1.2	Term	Oropharyngeal 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

Primary Objective:
● To select the arm(s) achieving a 2-year progression-free survival rate of ≥ 85% without unacceptable swallowing toxicity at 1 year.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
● To determine patterns of failure (locoregional relapse versus distant) and survival (overall and progression-free) at 6 months and 2 years;
● To determine acute toxicity profiles at the end of radiation therapy and at 1 and 6 months;
● To determine late toxicity profiles at 1 and 2 years;
● To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years;
● To determine the predictive value of 12-14 week, post-treatment FDG-PET/CT for locoregional control and PFS at 2 years;
● To determine the predictive value of blood and tissue biomarkers for disease outcomes at 2 years;
● To determine swallowing recovery per videofluoroscopy imaging at 2 years.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

> Step 1: Registration

1. Pathologically (histologically/cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma&basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation&should be sufficient to estimate the size of the primary (for T stage).

2. Clinically or radiographically evident measurable disease at the primary site or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted&considered as non-therapeutic nodal excisions.

3. Immunohistochemical (IHC) staining for p16 must be performed on tissue&this tissue must be submitted for central review. Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue if formalin-fixed paraffin-embedded cell block material is available for p16 IHC. FNA specimens prepared with adequate p16 testing in this manner are acceptable to submit for central review. If the p16 preparation is not adequate, additional specimens will be required to establish p16 status.

4. Clinical stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th ed.) including no distant metastases based on the following diagnostic workup:
● General history&physical examination within 56 days prior to registration;
● Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 70 days prior to registration;
● One of the following combinations of imaging is required within 56 days prior to registration:
a) A CT scan of the neck (with contrast) & a chest CT scan (with or without contrast);
b) or an MRI of the neck (with contrast) & a chest CT scan (with or without contrast);
c) or a CT scan of neck (with contrast) & a PET/CT of neck and chest (with or without contrast);
d) or an MRI of the neck (with contrast) & a PET/CT of neck and chest (with or without contrast).
Note: A CT scan of neck and/or a PET/CT performed for the purposes of radiation planning may serve as both staging&planning tools.

5. Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years. Please refer to the protocol for details of pack-years calculation.

6. Zubrod Performance Status of 0-1 within 56 days prior to registration;

7. Age ≥ 18;

8. The trial is open to both genders;

9. Adequate hematologic function within 14 days prior to registration, defined as follows:
● Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
● Platelets ≥ 100,000 cells/mm3;
● Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve
Hgb ≥ 8.0 g/dl is acceptable.

10. Adequate renal function within 14 days prior to registration, defined as follows:
● Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula as described in protocol section 3.2.10.

11. Adequate hepatic function within 14 days prior to registration defined as follows:
● Bilirubin < 2 mg/dl;
● AST or ALT < 3 x the upper limit of normal.

12. Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential;

13. Patients who are HIV positive but have no prior AIDS-defining illness&have CD4 cells of at least 350/mm3 are eligible. HIV-positive patients must not have multi-drug resistant HIV infection or other concurrent AIDS-defining conditions. Patients must not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or antihepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C antibody positive). However, patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).

14. The patient must provide study-specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review.

15.Patients who speak English (or read one of the languages for which a translation is available (see protocol Section 10.2) must consent to complete the mandatory dysphagia-related patient reported instrument (MDADI). Please refer to the protocol section 3.2.15 for additional details.

> Step 2: Randomization

16. p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear&cytoplasmic staining of tumor cells), confirmed by central pathology review; (see protocol Section 10.1 for details).

E.4

Principal exclusion criteria

> Step 1: Registration

1. Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas;

2. Carcinoma of the neck of unknown primary site origin (even if p16 positive);

3. Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane;

4. Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the clavicle;

5. Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles;

6. Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. In other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed.

7. Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers;

8. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible);

9. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable;

10. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;

11. Severe, active co-morbidity defined as follows:
● Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
● Transmural myocardial infarction within the last 6 months;
● Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
● Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration;
● Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol other than those requested in protocol section 3.2.10.
● Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition with immune compromise greater than that noted in protocol section 3.1.13; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements
may also exclude immuno-compromised patients.

12. Pregnancy; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

13. Prior allergic reaction to cisplatin.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) at 2 years.

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression free survival (PFS) is defined as from time of randomization to local-regional failure, distant metastasis or deaths due to any causes. PFS rates will be estimated for all treatment arms using the Kaplan-Meier method (1958).One sample binomial test will be used to test the 2-year PFS for each arm. Multivariate analysis will be performed using the Cox proportional hazards model.

The interim analysis time will be 1.56 years from the start of study (6 months for site IRB approval,0.56 years for accrual,6-month follow up).

Interim reports (containing information about accrual rate,pretreatment characteristics of patients accrued&the frequency&severity of adverse events) will be prepared biannually until the final analysis has been accepted for presentation or publication.

E.5.2

Secondary end point(s)

● Local-regional failure at 6 months and 2 years;
● Distant metastasis at 6 months and 2 years;
● Overall survival at 6 months and 2 years;
● Acute toxicities (≥ grade 3, CTCAE, v. 4) at the end of radiation therapy and at 1 and 6 months;
● Late toxicities at (≥ grade 3, CTCAE, v. 4) 1 and 2 years;
● Patient-reported swallowing outcomes at 6 months and 1 and 2 years;
● Post-treatment FDG-PET/CT;
● Translational research.

E.5.2.1

Timepoint(s) of evaluation of this end point

For the secondary endpoints listed in protocol section 13.2.2, OS rates will be estimated using the Kaplan-Meier method (1958) and the failure rates for the experimental treatment will be compared against the control using a log rank test. The cumulative incidence method will be used to estimate locoregional and distant failure rates and the failure rates for the experimental treatment will be compared against the control using a failure specific log rank test. Failure for local-regional failure and distant metastasis endpoints is defined in protocol section 13.6.1.

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

Yes

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

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 plus Chemotherapy vs Radiotherapy alone

E.8.2.4

Number of treatment arms in the trial

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

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

United States

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

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:

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

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

F.4.2.2

In the whole clinical trial

296

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 will be treated according to standard after care per institutional guidelines.

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

2016-09-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-12

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

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