Clinical Trials Register

Summary
EudraCT Number:	2013-000044-25
Sponsor's Protocol Code Number:	1143-201
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-04-22
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

France - ANSM

A.2

EudraCT number

2013-000044-25

A.3

Full title of the trial

A Phase I/II randomized study to determine the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of Debio1143 combined with concurrent Chemo-Radiation Therapy in patients with locally advanced squamous cell carcinoma of the head and neck.

A.3.1

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

Study to evaluate the safety, antitumour activity and determine the maximum tolerated dose of Debio 1143 combined with Chemo-Radiation Therapy in patients with advanced head and neck cancer.

A.4.1

Sponsor's protocol code number

1143-201

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	Debiopharm S.A.
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Debiopharm S.A.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Debiopharm S.A.
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Chemin Messidor 5-7
B.5.3.2	Town/ city	Lausanne
B.5.3.3	Post code	1002
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41213210111
B.5.5	Fax number	+41213210169
B.5.6	E-mail	info@debiopharm.com

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	Debio 1143
D.3.2	Product code	Debio 1143
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	Debio1143
D.3.9.3	Other descriptive name	Debio1143
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	20
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with locally advanced squamous cell carcinoma of the head and neck

E.1.1.1

Medical condition in easily understood language

Patients with advanced head and neck cancer

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	14.1
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

Part A : To determine the maximum tolerated dose (MTD) of Debio1143 in combination with concurrent CRT in patients with LA-SCCHN.
Part B: To evaluate the anti-tumour activity of Debio1143 in comparison with placebo when added to standard concurrent CRT in patients with LA-SCCHN

E.2.2

Secondary objectives of the trial

Part A: 1. safety of Debio1143 in combination with concurrent CRT 2. anti-tumour activity of the recommended dose of Debio1143 in combination with concurrent CRT 3.explore PK of Debio1143 and cisplatin when administered in combination with radiation therapy, and explore the potential for drug-drug interactions.4. explore pharmacodynamic biomarkers of Debio1143 activity with concurrent CRT 5.explore PK/PD, PK/efficacy, PK/safety, PD/efficacy and PD/safety and pharmacogenetic factors 6.To explore pharmacogenomic, and tumour pharmacogenetic factors. Part B: 1. safety of the recommended dose of Debio1143 o in combination with concurrent CRT 2. To explore PD biomarkers of Debio1143 activity with concurrent CRT 3. To explore predictive biomarkers of response in the field of pharmacogenomics, tumour profiling, blood transcriptome and proteome. 4. To explore the PK of Debio1143 with CRT.5. To explore PK/PD, PK/efficacy, PK/safety, PD/efficacy and PD/safety and pharmacogenetic factors.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Willing and able to sign a written informed consent;
2.Male or female ≥18 ≤75 years of age.
3.Histologically confirmed diagnosis of previously untreated LA-SCCHN (Stage III, IVa and IVb according to the American Joint Committee on Cancer Staging System) of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx;
4.Tumour HPV negative status for oropharynx cancer patients, determined by p16 IHC;
5.Smokers (> 10 packs/year);
6.Availability of pre-treatment tumour sample (optional for Phase I; mandatory for Phase II [10-20 tumour slides]);
7.Measurable disease by the RECIST 1.1 criteria;
8.Negative medical history of Hepatitis B and Hepatitis C;
9.Women of child-bearing potential:
a.Negative serum pregnancy test at screening;
b.Agreement to use appropriate contraception methods from study entry to 6 months after the last day of treatment. Agreement to use contraception methods from her male partner.
10.Male patients agree to use contraception methods from study entry to 6 months after the last day of treatment;
11.ECOG performance status 0 or 1
12.Subjects must have adequate haematological, renal and hepatic function; calculated creatinine clearance ≥ 60 mL/min as determined by the modified method of Cockcroft and Gault or by the EDTA method, absolute neutrophil count ≥1 500/μL, platelets ≥100 000/μL, haemoglobin ≥ 10 g/dL, aspartate (AST) and alanine transaminase (ALT) less than 3 times the upper limit of the normal range (ULN), total bilirubin ≤ 2.0 mg/dL, serum albumin >35 g/L.
13.QTcF interval ≤ 450 ms
14.Left ventricular ejection fraction (LVEF) within the institutional normal ranges as measured by echocardiogram (ECHO) or multigated acquisition (MUGA) scan;
15.No prior treatment with IAP inhibitors.
16.No use or requirement for use of aspirin or aspirin containing products with
> 100 mg of aspirin per day;
17.No history of gastrointestinal bleeding within 1 year;
18.No active rheumatoid arthritis, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation.

E.4

Principal exclusion criteria

1.Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers;
2.Squamous cell cancer involving cervical neck nodes but from unknown primary site;
3.Metastatic disease;
4.Any prior or current treatment for invasive head and neck cancer of any kind. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent;
5.Weight loss of >10% during the last month;
6.Not compensated liver cirrhosis (Child-Pugh class C);
7.Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, major abdominal surgery, significant bowel obstruction, ulcerative colitis, Crohn’s disease);
8.Impaired bone turnover (serum C-terminal telopeptide [CTX] <300 pg/mL;1
9.Concurrent treatment with any other systemic anti-cancer therapy that is not specified as part of the protocol regimen;
10.Concomitant treatment with any drug on the prohibited medication list (provided separately);
11.Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;
12.History of another malignancy within the last 5 years, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma. History of non-invasive lesion or in-situ carcinoma, including in the head and neck region that was successfully treated with surgery, photodynamic or laser, will be permitted;
13.Peripheral neuropathy ≥ grade 2;
14.Clinical hearing loss (to be confirmed by audiogram in doubtful cases);
15.If female, pregnant or lactating;
16.History of allergic reactions to appropriate antiemetics (e.g. 5-HT3 antagonists) to be administered with chemotherapy;
17.The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations.

E.5 End points

E.5.1

Primary end point(s)

Part A: Occurrence of DLTs. Part B: Proportion of patients achieving Locoregional Control (LRC) at 18 months from the end of chemo-radiation therapy.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of Part A and Part B

E.5.2

Secondary end point(s)

For Part A only:
1.Locoregional control rate at 6 months, one year and 18 months after completion of chemo-radiation therapy;
2.Progression free survival (PFS) rate at one year, 18 months and 2 years as of initiation chemo-radiation therapy (PFS is defined as the time from randomization to the first radiologic confirmation of disease progression or death from any cause, whichever come first);
3.Distant relapse rate at six months, one year, 18 months and 2 years after completion of chemo-radiation therapy;
4.Evaluation of the compliance to the study treatment and cisplatin dose density;
5.Pharmacokinetic parameters (Cmax, AUC0-t, AUC∞, λz, t½, MRT, Ctrough, tmax, CL/F, Vss/F, AUC, PTF, RAUC) of Debio1143 alone and in combination with cisplatin and radiotherapy. The potential for drug-drug interactions and for accumulation upon repeated dosing will be explored;
6.Pharmacokinetic parameters ( AUC(0-t), AUC∞ Cmax, CL, Vss, t1/2) of cisplatin in combination with Debio 1143 and radiotherapy;
7.Exploration of PK/PD, PK/Efficacy, PK/safety, PD/efficacy and PD/safety relationships as well as pharmacogenetics factors that may influence PK;
8.Exploration of pharmacogenomic factors.
For Part A and B:
1.Change in vital signs and ECOG Performance Status (PS);
2.Incidence of SAEs;
3.Incidence and severity of AEs, graded according to NCI-CTCAE version 4 criteria;
4.Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4 criteria;
5.Incidence of late toxicity (e.g.; dysphagia, chronic swallowing dysfunctions, speech problems, , cervical fibrosis) 1 year and at 2 years as of initiation of chemo-radiation therapy;
6.Incidence of treatment discontinuations and treatment modifications due to AEs;
7.Tumour response (by RECIST): Best overall response, Disease control, and Response Rate, after 10 weeks and 6 months from the end of chemo-radiation therapy;
8.Disease specific survival rate one year and at 2 years as of initiation of chemo-radiation therapy;
9.Overall survival rate at one year and at 2 years ;
10.Exploration of pharmacodynamic biomarkers of Debio 1143 activity in serum, PBMCs and saliva;
For Part B only:
1.Complete Response Rate (by RECIST version 1.1) at six months after completion of chemo-radiation therapy;
2.Locoregional control rate at 6 months and one year after completion of chemo-radiation therapy;
3.Progression free survival rate at one year and at 2 years as of initiation of chemo-radiation therapy;
4.Distant relapse rate at six months, one year and 18 months after completion of chemo-radiation therapy;
5.Duration of the feeding tube dependence;
6.Exploration of predictive biomarkers of response to Debio 1143 in plasma, blood and tumour tissue;
7.Exploration of Debio1143 PK in combination with CRT, and if applicable PK/PD, PK/efficacy, PK/safety relationships and pharmacogenetic factors that may affect Debio1143 PK.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of Part A and Part B

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

to determine MTD

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Chemo-Radiation Therapy

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

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

Switzerland

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

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

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

F.4.2.2

In the whole clinical trial

116

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)

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

2013-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-16

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

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