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Clinical Trial Results:
A Phase I/II randomized study to determine the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of Debio 1143 combined with concurrent Chemo-Radiation Therapy in patients with locally advanced squamous cell carcinoma of the head and neck

Summary
EudraCT number	2013-000044-25
Trial protocol	FR
Global end of trial date	28 Apr 2022

Results information
Results version number	v1(current)
This version publication date	26 Mar 2023
First version publication date	26 Mar 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1143-201

ISRCTN number

US NCT number

NCT02022098

WHO universal trial number (UTN)

Sponsor organisation name

Debiopharm International, S.A.

Sponsor organisation address

Case postale 5911, Chemin Messidor 5-7, Lausanne, Switzerland, 1002

Public contact

Clinical Department, Debiopharm S.A., +41 213210111, clinicaltrials@debiopharm.com

Scientific contact

Clinical Department, Debiopharm S.A., +41 213210111, clinicaltrials@debiopharm.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Apr 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Apr 2022

Was the trial ended prematurely?

Main objective of the trial

Part A: To determine the maximum tolerated dose (MTD) of Debio1143 in combination with concurrent chemoradiotherapy (CRT) in subjects with locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Part B: To evaluate the anti-tumour activity of Debio1143 in comparison with placebo when added to standard concurrent CRT in subjects with LA-SCCHN.

Protection of trial subjects

Written approval of the study protocol and the informed consent was obtained from the independent ethics committee (IEC), prior to initiation of the study. The study was conducted in accordance with local regulations, Good Clinical Practice (GCP), International Council for Harmonisation (ICH) notes for GCP (ICH/CPMP/135/95), and ethical principles that have their origin in the Declaration of Helsinki and its amendments.

Background therapy

Concomitant chemo-radiation therapy (CRT) including cisplatin, 100 mg/m^2, 1-hour intravenous (IV) infusion, once on Day 2 in each 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction radiotherapy (RT) of 2 gray (Gy), daily for 5 days per week up to 7 weeks.

Evidence for comparator

Actual start date of recruitment

16 Sep 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 105

Country: Number of subjects enrolled

Switzerland: 5

Worldwide total number of subjects

110

EEA total number of subjects

105

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Parts A and B of the study were conducted at 23 study centres in France and Switzerland from 16 September 2013 to 28 April 2022.

Screening details

A total of 110 subjects were enrolled, 14 subjects into Part A and 96 subjects were randomised into Part B. Out of 96 randomised subjects from Part B, 95 received Debio 1143 or matching placebo.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Double blind for Part B only.

Are arms mutually exclusive

Yes

Part A: Debio 1143 100 mg + CRT

Arm description

Subjects were assigned Debio 1143 100 milligram (mg), oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion, once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

Other name

Xevinapant

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

100 mg administered orally, once daily for 14 days in a 21-day cycle for 3 cycles.

Part A: Debio 1143 200mg + CRT

Arm description

Subjects were assigned Debio 1143 200 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion, once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

Other name

Xevinapant

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

200 mg administered orally, once daily for 14 days in a 21-day cycle for 3 cycles.

Part A: Debio 1143 300mg + CRT

Arm description

Subjects were assigned Debio 1143 300 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion, once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

Other name

Xevinapant

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

300 mg administered orally, once daily for 14 days in a 21-day cycle for 3 cycles.

Part B: Debio 1143 200mg + CRT

Arm description

Subjects were assigned Debio 1143 200 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

Other name

Xevinapant

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

200 mg administered orally, once daily for 14 days in a 21-day cycle for 3 cycles.

Part B: Placebo + CRT

Arm description

Subjects were assigned Debio 1143 matching placebo, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Debio 1143 matching placebo administered orally, once daily for 14 days in a 21-day cycle for 3 cycles.

Number of subjects in period 1	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Started	5	6	3	48	48
Completed	2	5	1	19	8
Not completed	3	1	2	29	40
Subject lost to follow-up	-	-	-	1	1
Subject non-compliance	-	-	-	1	-
Subject not in physical capacity for end of study	-	-	1	-	-
Adverse event	-	1	1	4	3
Investigator Decision	-	-	-	2	-
Reason not specified	-	-	-	5	1
Disease Progression	-	-	-	11	18
Withdrawal of Consent	-	-	-	2	4
Subject followed in another hospital	1	-	-	-	-
Did not enter extended efficacy follow-up	-	-	-	2	4
Death	-	-	-	1	8
Progressive disease	2	-	-	-	-
Prohibited Medication	-	-	-	-	1

Baseline characteristics

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Reporting group title

Part A: Debio 1143 100 mg + CRT

Reporting group description

Reporting group title

Part A: Debio 1143 200mg + CRT

Reporting group description

Reporting group title

Part A: Debio 1143 300mg + CRT

Reporting group description

Reporting group title

Part B: Debio 1143 200mg + CRT

Reporting group description

Subjects were assigned Debio 1143 200 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Reporting group title

Part B: Placebo + CRT

Reporting group description

Reporting group values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT	Total
Number of subjects	5	6	3	48	48	110
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58.20 ( 11.10 )	64.17 ( 3.19 )	63.67 ( 5.86 )	56.4 ( 7.06 )	59.1 ( 6.28 )	-
Gender categorical
Units: Subjects
Female	1	1	0	11	7	20
Male	4	5	3	37	41	90
Race
Units: Subjects
White	5	6	3	48	44	106
Asian	0	0	0	0	1	1
Not Reported	0	0	0	0	3	3
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	1	0	1
Not Hispanic or Latino	5	6	3	47	44	105
Missing	0	0	0	0	4	4

End points

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Reporting group title

Part A: Debio 1143 100 mg + CRT

Reporting group description

Reporting group title

Part A: Debio 1143 200mg + CRT

Reporting group description

Reporting group title

Part A: Debio 1143 300mg + CRT

Reporting group description

Reporting group title

Part B: Debio 1143 200mg + CRT

Reporting group description

Subjects were assigned Debio 1143 200 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Reporting group title

Part B: Placebo + CRT

Reporting group description

Primary: Part A: Percentage of Subjects Experiencing Dose-Limiting Toxicities (DLTs)

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End point title

Part A: Percentage of Subjects Experiencing Dose-Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLT was defined as the occurrence of life-threatening toxicities and/or specific severe laboratory abnormalities or treatment related adverse events (AEs). It is defined by any of the following: Common Terminology Criteria (CTC) Grade 4 neutropenia that is uncomplicated (not associated with fever >38.5°C lasting ≥ 7 days; CTC Grade 3 or 4 neutropenia concomitant with fever >38.5ºC or Grade ≥3 infection; thrombocytopenia <25,000/μL lasting ≥ 5 days or <50,000/μL with bleeding or requiring platelets transfusion; CTC Grade ≥3 non-haematologic toxicity (except untreated nausea, untreated vomiting, or untreated diarrhoea); CTC grade 2/higher ototoxicity, worsening of renal function, grade 3 or higher decrease in cardiac left ventricular function, grade 4 skin or mucosal reactions; Cisplatin and/or Debio 1143 treatment delay >2 weeks for related adverse event (AE) occurring during the DLT period. Safety population included all subjects who received any dose of Debio 1143 or cisplatin or RT.

End point type

Primary

End point timeframe

From first dose of study drug up to Week 9

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the primary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: percentage of subjects
number (not applicable)	20.0	33.3	66.7

No statistical analyses for this end point

Primary: Part B: Percentage of Subjects Achieving Locoregional Control (LRC) at 18 Months From the End of Chemo-Radiation Therapy (CRT)

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End point title

Part B: Percentage of Subjects Achieving Locoregional Control (LRC) at 18 Months From the End of Chemo-Radiation Therapy (CRT) ^[3]

End point description

LRC at a time point is defined as absence of locoregional relapse up to and including that time point, where locoregional relapse is defined as progressive disease at the site of the primary tumour or the locoregional lymph nodes. Intention-to-treat (ITT) population included all subjects who were randomised to treatment.

End point type

Primary

End point timeframe

From the end of CRT (Week 9) up to 18 months

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the primary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	48
Units: percentage of subjects
number (confidence interval 95%)	54.2 (39.2 to 68.6)	33.3 (20.4 to 48.4)

Part B: Debio 1143 200 mg vs Placebo

Comparison groups

Part B: Debio 1143 200mg + CRT v Part B: Placebo + CRT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0232 ^[4]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.74

Confidence interval

level

95%

sides

2-sided

lower limit

1.15

upper limit

6.53

Notes
[4] - P-value was calculated using logistic regression stratified for the randomization factors of nodal involvement, cancer localization and human papillomavirus (HPV)-16 status.

Secondary: Part A: Number of Subjects Experiencing at Least One Treatment Emergent Adverse Event (TEAE), Grade 3 or Above TEAE, and Serious Adverse Event (SAE)

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End point title

Part A: Number of Subjects Experiencing at Least One Treatment Emergent Adverse Event (TEAE), Grade 3 or Above TEAE, and Serious Adverse Event (SAE) ^[5]

End point description

An adverse event (AE) is any untoward medical occurrence in a clinical trial subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A TEAE is any new, undesirable medical occurrence or change of an existing condition in a subject that occurs during or after first investigational medicinal product administration (Debio 1143/cisplatin/RT), whether or not considered to be drug-related. A SAE is any untoward medical occurrence that, at any dose, results in death; is life threatening (i.e., puts subject at immediate risk of death); requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect. TEAEs were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. Safety population=All subjects who received any dose of Debio 1143/cisplatin/RT.

End point type

Secondary

End point timeframe

Up to 30 days after EOT (approximately 13 weeks for subjects who completed the 9-week treatment period)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: subjects
TEAE	5	6	3
Grade 3 or Above TEAE	5	5	3
SAE	3	2	3

No statistical analyses for this end point

Secondary: Part A: Number of Subjects With Treatment Discontinuations and Treatment Modifications due to AEs

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End point title

Part A: Number of Subjects With Treatment Discontinuations and Treatment Modifications due to AEs ^[6]

End point description

Safety population included all subjects who received any dose of Debio 1143 or cisplatin or RT.

End point type

Secondary

End point timeframe

Up to 30 days after EOT (approximately 13 weeks for subjects who completed the 9-week treatment period)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: subjects
Treatment Discontinuations	1	1	1
Treatment Modifications	1	0	0

No statistical analyses for this end point

Secondary: Part A: Percentage of Subjects With Tumour Response: Best Overall Response

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End point title

Part A: Percentage of Subjects With Tumour Response: Best Overall Response ^[7]

End point description

Best overall response was defined as best response recorded from start of study treatment until disease progression (PD)/recurrence was documented, a new systemic therapy was started or analysis cut-off, whichever occurred first. PD criteria for target lesions: At least 20% increase in sum of diameters of lesions, referring smallest sum on study, in addition to relative increase of 20%, sum should be an increase of at least 5 mm. Appearance of one/more new lesions is also considered progression. Per protocol (PP) population=all subjects who had measurable disease, according to Response Evaluation Criteria in Solid Tumours (RECIST) and underwent a baseline disease assessment and at least one post-baseline assessment, but excluded those who fulfilled any of following conditions: Violation of clinically relevant criteria; Administration of non-permitted concomitant treatments; Did not receive at least 70% of planned Debio 1143/RT dose; Did not receive at least 100 mg/m^2 of cisplatin.

End point type

Secondary

End point timeframe

Up to the disease progression or recurrence or end of study for Part A (up to 24.9 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	5	3
Units: percentage of subjects
number (not applicable)
Complete response	40	80	100
Partial response	40	0	0
Progressive disease	20	20	0

No statistical analyses for this end point

Secondary: Part A: Maximum Observed Plasma Concentration (Cmax) for Debio 1143 and D-1143-MET1

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End point title

Part A: Maximum Observed Plasma Concentration (Cmax) for Debio 1143 and D-1143-MET1 ^[8]

End point description

Geometric coefficient of variation (CV) reported in this endpoint is geometric CV%. Pharmacokinetic (PK) population included all subjects who underwent the specific PK assessments who did not have a major protocol deviation that may have had an impact on the PK outcome. Number analysed 'n' indicates the number of subjects with data available for analyses at the specified time point.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 1.5 (only for Days 1, 2), 2, 3, 4, 6, 8 and 24 hours post dose on Days 1,2 and 9 of Cycle 1 (1 Cycle = 21 days)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: nanograms/millilitre (ng/ml)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1: Debio 1143 (n= 5,5,2)	1029.18 ( 32.48 )	2519.12 ( 42.84 )	4000.15 ( 104.38 )
Cycle 1 Day 1: D-1143-MET-1 (n=5,5,2)	735.55 ( 22.39 )	1416.11 ( 30.76 )	1238.62 ( 35.47 )
Cycle 1 Day 2: Debio 1143 (n= 5,5,2)	914.25 ( 88.32 )	2938.54 ( 38.45 )	4704.93 ( 0.75 )
Cycle 1 Day 2: D-1143-MET-1 (n=5,5,2)	892.59 ( 86.01 )	1557.80 ( 43.67 )	1910.24 ( 10.01 )
Cycle 1 Day 9: Debio 1143 (n= 4,4,3)	1646.92 ( 34.17 )	1548.99 ( 30.02 )	3998.26 ( 71.13 )
Cycle 1 Day 9: D-1143-MET-1 (n=4,4,3)	1139.68 ( 33.42 )	2202.85 ( 51.24 )	1674.55 ( 59.87 )

No statistical analyses for this end point

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to the Last Quantifiable Concentration (AUC0-t) for Debio 1143 and D-1143-MET1

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End point title

Part A: Area Under the Plasma Concentration-time Curve From Administration up to the Last Quantifiable Concentration (AUC0-t) for Debio 1143 and D-1143-MET1 ^[9]

End point description

Geometric CV reported in this endpoint is geometric CV%. PK population included all subjects who underwent the specific PK assessments, who did not have a major protocol deviation that may have had an impact on the PK outcome. Number analysed ‘n’ indicates the number of subjects with data available for analyses at the specified time point. 99999= not reported due to no available data, standard deviation (SD) cannot be calculated for 1 subject.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 1.5 (only for Days 1, 2), 2, 3, 4, 6, 8 and 24 hours post dose on Days 1,2 and 9 of Cycle 1 (1 Cycle = 21 days)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: hour×nanograms/millilitre (h×ng/ml)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1: Debio-1143 (n=5,5,2)	5297.53 ( 39.89 )	10399.11 ( 39.10 )	17983.33 ( 12.22 )
Cycle 1 Day 1: Debio-1143-MET-1 (n=2,4,2)	8324.46 ( 1.61 )	15346.86 ( 37.27 )	15674.82 ( 31.63 )
Cycle 1 Day 2: Debio-1143 (n=5,5,2)	4974.63 ( 82.85 )	14911.070 ( 46.03 )	22492.67 ( 13.88 )
Cycle 1 Day 2: Debio-1143-MET-1 (n=0,3,2)	99999 ( 99999 )	21576.38 ( 18.03 )	26061.66 ( 26.34 )
Cycle 1 Day 9: Debio-1143 (n=4,5,3)	7723.25 ( 15.91 )	6693.57 ( 45.50 )	21283.34 ( 20.23 )
Cycle 1 Day 9: Debio-1143-MET-1 (n=3,3,1)	12509.81 ( 43.66 )	27287.56 ( 79.05 )	31200.00 ( 99999 )

No statistical analyses for this end point

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to Infinity (AUC∞) for Debio 1143 and D-1143-MET1

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End point title

Part A: Area Under the Plasma Concentration-time Curve From Administration up to Infinity (AUC∞) for Debio 1143 and D-1143-MET1 ^[10]

End point description

Geometric CV reported in this endpoint is geometric CV%. PK population included all subjects who underwent the specific PK assessments, who did not have a major protocol deviation that may have had an impact on the PK outcome. Number of subjects analysed indicates the number of subjects with data available for analysis for this endpoint. 99999= SD cannot be calculated for 1 subject or not reported due to no available data.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours post dose on Day 1 of Cycle 1 (1 Cycle = 21 days)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part A.

End point values	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT
Number of subjects analysed	5	6	3
Units: h×ng/ml
geometric mean (geometric coefficient of variation)
Debio-1143 (n=5,5,2)	5551.59 ( 40.13 )	11084.39 ( 38.97 )	19002.11 ( 10.06 )
D-1143-MET-1 (n=1,2,0)	9110.00 ( 99999 )	14129.76 ( 22.20 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Part B: Progression-Free Survival (PFS)

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End point title

Part B: Progression-Free Survival (PFS) ^[11]

End point description

PFS is defined as the time elapsed between treatment initiation and tumour progression or death from any cause, whichever occurs first. Progression for target lesions: At least 20% increase in sum of diameters of lesions, referring the smallest sum on study, in addition to relative increase of 20%, sum should be an increase of at least 5 mm. Appearance of one/more new lesions is also considered progression. 99999= The median PFS and upper limit was not reached due to insufficient number of events. ITT population included all subjects who were randomised to treatment.

End point type

Secondary

End point timeframe

Up to the tumour progression or death or end of study for Part B (up to 52.1 months)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	48
Units: months
median (confidence interval 95%)	99999 (37.4 to 99999)	16.9 (7.5 to 36.1)

Part B: Debio 1143 200 mg vs Placebo

Comparison groups

Part B: Debio 1143 200mg + CRT v Part B: Placebo + CRT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0019 ^[12]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.67

Notes
[12] - P-value was calculated using cox model stratified for the randomization factors of nodal involvement, tumor localization and HPV-16 status.

Secondary: Part B: Duration of Locoregional Control (LRC)

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End point title

Part B: Duration of Locoregional Control (LRC) ^[13]

End point description

Locoregional control is defined as the absence of PD or recurrence at the site of the primary tumour or locoregional lymph nodes. Duration of LRC is defined as the as the time from treatment initiation to the occurrence of locoregional relapse. PD criteria for target lesions: At least 20% increase in sum of diameters of lesions, referring the smallest sum on study, in addition to relative increase of 20%, sum should be an increase of at least 5 mm. Appearance of one/more new lesions is also considered progression. 99999=The median duration of LRC was not reached due to insufficient number of events. ITT population included all subjects randomised to treatment.

End point type

Secondary

End point timeframe

From end of CRT up to the disease progression or recurrence or end of study for Part B (up to 50 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	48
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (14.9 to 99999)

Part B: Debio 1143 200 mg vs Placebo

Comparison groups

Part B: Debio 1143 200mg + CRT v Part B: Placebo + CRT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0893 ^[14]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

1.13

Notes
[14] - P-value was calculated using cox model stratified for the randomization factors of node involvement, tumor localization and HPV-16 status.

Secondary: Part B: Time to Distant Relapse

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End point title

Part B: Time to Distant Relapse ^[15]

End point description

Time to distant relapse duration is defined as the time elapsed between treatment initiation and the distant relapse. Distant relapse at a time point is defined as PD in a location other than the site of the primary tumour or locoregional lymph nodes at any assessment up to and including that time point. PD criteria for target lesions: At least 20% increase in sum of diameters of lesions, referring the smallest sum on study, in addition to relative increase of 20%, sum should be an increase of at least 5 mm. Appearance of one/more new lesions is also considered progression. 99999=The median duration was not reached due to insufficient number of events. ITT population included all subjects randomised to treatment.

End point type

Secondary

End point timeframe

Up to the disease progression or end of study for Part B (up to 50 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	48
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Part B: Debio 1143 200 mg vs Placebo

Comparison groups

Part B: Debio 1143 200mg + CRT v Part B: Placebo + CRT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2858 ^[16]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

1.58

Notes
[16] - P-value was calculated using cox model stratified for the randomization factors of node involvement, tumor localization and HPV-16 status.

Secondary: Part B: Overall Survival (OS)

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End point title

Part B: Overall Survival (OS) ^[17]

End point description

Overall survival is defined as the duration between the first dose date of Debio 1143 and the date of death due to any cause. ITT population included all subjects randomised to treatment. 99999=The Median duration was not reached due to insufficient number of events.

End point type

Secondary

End point timeframe

Up to the death or end of study for Part B (up to 71.3 months)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	48
Units: months
median (confidence interval 95%)	99999 (40.3 to 99999)	36.1 (21.8 to 46.7)

Part B: Debio 1143 200 mg vs Placebo

Comparison groups

Part B: Placebo + CRT v Part B: Debio 1143 200mg + CRT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0101 ^[18]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

0.84

Notes
[18] - P-value was calculated using cox model stratified for the randomization factors of node involvement, tumor localization and HPV-16 status.

Secondary: Part B: Number of Subjects Experiencing at Least One TEAE and Grade 3 or Above TEAE

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End point title

Part B: Number of Subjects Experiencing at Least One TEAE and Grade 3 or Above TEAE ^[19]

End point description

An AE is any untoward medical occurrence in a clinical trial subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A TEAE is any new, undesirable medical occurrence or change of an existing condition in a subject that occurs during or after the first investigational medicinal product administration (Debio 1143, cisplatin or RT), whether or not considered to be drug-related. TEAEs were graded according to NCI-CTCAE version 4. Safety population included all subjects who received any dose of Debio 1143 or placebo or cisplatin or RT.

End point type

Secondary

End point timeframe

Up to 30 days after EOT (approximately 13 weeks for subjects who completed the 9-week treatment period)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	47
Units: subjects
TEAE	48	47
Garde 3 or Above TEAE	42	40

No statistical analyses for this end point

Secondary: Part B: Number of Subjects Experiencing Any Late Toxicity

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End point title

Part B: Number of Subjects Experiencing Any Late Toxicity ^[20]

End point description

Safety population included all subjects who received any dose of Debio 1143 or placebo or cisplatin or RT.

End point type

Secondary

End point timeframe

From 30 days after EOT until EOS (up to 52 months)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was the key secondary endpoint only for part B.

End point values	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Number of subjects analysed	48	47
Units: subjects	39	33

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part A: Up to 30 days after EOT (approximately 13 weeks for subjects who completed the 9-week treatment period); Part B: Up to 30 days after EOT (approximately 13 weeks for subjects who completed the 9-week treatment period)

Adverse event reporting additional description

Safety population included all subjects who received any dose of Debio 1143 or placebo or cisplatin or RT.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Part A: Debio 1143 100 mg + CRT

Reporting group description

Subjects were assigned Debio 1143 100 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion, once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Reporting group title

Part A: Debio 1143 200mg + CRT

Reporting group description

Reporting group title

Part A: Debio 1143 300mg + CRT

Reporting group description

Reporting group title

Part B: Debio 1143 200mg + CRT

Reporting group description

Subjects were assigned Debio 1143 200 mg, oral solution, once daily for 14 days in each 21-day cycle for 3 cycles, i.e., on Days 1-14, 22-35 and 43-56 along with concomitant CRT [cisplatin, 100 mg/m^2, 1-hour IV infusion once on Day 2 in a 21-day cycle for 3 cycles i.e., on Days 2, 23 and 44 and standard fraction RT of 2 Gy, daily for 5 days per week, up to 7 weeks].

Reporting group title

Part B: Placebo + CRT

Reporting group description

Serious adverse events	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 5 (60.00%)	2 / 6 (33.33%)	3 / 3 (100.00%)	30 / 48 (62.50%)	28 / 47 (59.57%)
number of deaths (all causes)	2	0	1	21	29
number of deaths resulting from adverse events	0	0	0	1	3
Surgical and medical procedures
Parenteral nutrition
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	4 / 47 (8.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asphyxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nutritional condition abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gastrostomy tube site complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 48 (4.17%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	3 / 47 (6.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Ulcerative keratitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 48 (0.00%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	2 / 48 (4.17%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	2 / 48 (4.17%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	4 / 47 (8.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	3 / 47 (6.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial sepsis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 48 (2.08%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 16	2 / 25
Staphylococcal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 48 (4.17%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
Metabolism and nutrition disorders
Malnutrition
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	3 / 47 (6.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A: Debio 1143 100 mg + CRT	Part A: Debio 1143 200mg + CRT	Part A: Debio 1143 300mg + CRT	Part B: Debio 1143 200mg + CRT	Part B: Placebo + CRT
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	48 / 48 (100.00%)	46 / 47 (97.87%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 48 (6.25%)	4 / 47 (8.51%)
occurrences all number	0	1	0	7	7
Hypotension
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Application site pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Asthenia
subjects affected / exposed	4 / 5 (80.00%)	5 / 6 (83.33%)	1 / 3 (33.33%)	16 / 48 (33.33%)	19 / 47 (40.43%)
occurrences all number	4	6	1	16	20
Chest pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Fatigue
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	9 / 48 (18.75%)	6 / 47 (12.77%)
occurrences all number	1	1	0	10	7
General physical health deterioration
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Hyperthermia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0
Mucosal inflammation
subjects affected / exposed	3 / 5 (60.00%)	4 / 6 (66.67%)	3 / 3 (100.00%)	36 / 48 (75.00%)	31 / 47 (65.96%)
occurrences all number	3	4	4	39	33
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	2	0	0
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	5 / 47 (10.64%)
occurrences all number	0	0	0	3	6
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	9 / 48 (18.75%)	6 / 47 (12.77%)
occurrences all number	2	1	1	11	6
Xerosis
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	4 / 48 (8.33%)	2 / 47 (4.26%)
occurrences all number	0	2	0	4	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 5 (60.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	5 / 48 (10.42%)	6 / 47 (12.77%)
occurrences all number	3	2	2	5	7
Dysphonia
subjects affected / exposed	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	5 / 48 (10.42%)	7 / 47 (14.89%)
occurrences all number	2	1	1	5	7
Dyspnoea
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 48 (2.08%)	4 / 47 (8.51%)
occurrences all number	2	1	0	1	5
Epistaxis
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0
Hiccups
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	1	0	0
Lung disorder
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	7 / 48 (14.58%)	4 / 47 (8.51%)
occurrences all number	0	0	0	7	4
Productive cough
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	1 / 47 (2.13%)
occurrences all number	1	0	0	5	1
Respiratory disorder
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	1	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	7 / 48 (14.58%)	3 / 47 (6.38%)
occurrences all number	0	1	1	7	3
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	0	0	0	3	0
Depressed mood
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Insomnia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	5 / 48 (10.42%)	4 / 47 (8.51%)
occurrences all number	1	0	1	5	4
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	13 / 48 (27.08%)	8 / 47 (17.02%)
occurrences all number	0	2	2	20	11
Amylase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 48 (4.17%)	4 / 47 (8.51%)
occurrences all number	1	2	2	2	4
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	9 / 48 (18.75%)	3 / 47 (6.38%)
occurrences all number	0	1	1	13	5
Blood creatinine increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	5 / 47 (10.64%)
occurrences all number	1	0	0	3	6
Blood urea increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	4 / 48 (8.33%)	5 / 47 (10.64%)
occurrences all number	1	1	0	5	6
Blood potassium decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	3
Ejection fraction decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	7 / 48 (14.58%)	5 / 47 (10.64%)
occurrences all number	1	0	0	10	6
Lipase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	4 / 48 (8.33%)	1 / 47 (2.13%)
occurrences all number	1	2	0	4	1
Protein total decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	3
Troponin I increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Weight decreased
subjects affected / exposed	3 / 5 (60.00%)	6 / 6 (100.00%)	2 / 3 (66.67%)	28 / 48 (58.33%)	21 / 47 (44.68%)
occurrences all number	3	6	2	30	27
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	3 / 47 (6.38%)
occurrences all number	0	0	0	6	4
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	3 / 5 (60.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	25 / 48 (52.08%)	20 / 47 (42.55%)
occurrences all number	3	7	3	25	20
Cardiac disorders
Bundle branch block left
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Tachycardia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Ventricular extrasystoles
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	3 / 47 (6.38%)
occurrences all number	0	0	0	1	3
Dysgeusia
subjects affected / exposed	3 / 5 (60.00%)	6 / 6 (100.00%)	1 / 3 (33.33%)	12 / 48 (25.00%)	15 / 47 (31.91%)
occurrences all number	3	7	1	13	15
Headache
subjects affected / exposed	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	4 / 48 (8.33%)	6 / 47 (12.77%)
occurrences all number	1	2	2	4	6
Neuropathy peripheral
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	1 / 47 (2.13%)
occurrences all number	1	0	0	4	1
Neuralgia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 5 (80.00%)	3 / 6 (50.00%)	2 / 3 (66.67%)	30 / 48 (62.50%)	26 / 47 (55.32%)
occurrences all number	6	3	3	38	37
Antiphospholipid syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Leukopenia
subjects affected / exposed	3 / 5 (60.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	7 / 48 (14.58%)	8 / 47 (17.02%)
occurrences all number	4	0	1	9	11
Lymphopenia
subjects affected / exposed	1 / 5 (20.00%)	2 / 6 (33.33%)	3 / 3 (100.00%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	1	2	5	3	0
Neutropenia
subjects affected / exposed	5 / 5 (100.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	12 / 48 (25.00%)	17 / 47 (36.17%)
occurrences all number	5	3	0	16	24
Thrombocytopenia
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	7 / 48 (14.58%)	7 / 47 (14.89%)
occurrences all number	1	2	0	8	10
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0
Ear pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	0 / 47 (0.00%)
occurrences all number	0	0	0	4	0
Hypoacusis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	4 / 48 (8.33%)	3 / 47 (6.38%)
occurrences all number	0	1	0	4	3
Ototoxicity
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Tinnitus
subjects affected / exposed	3 / 5 (60.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	15 / 48 (31.25%)	10 / 47 (21.28%)
occurrences all number	3	3	1	17	11
Vertigo
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0
Abdominal pain upper
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	1	0	0	4	2
Aptyalism
subjects affected / exposed	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	1	0	0	0
Cheilitis
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0
Constipation
subjects affected / exposed	3 / 5 (60.00%)	2 / 6 (33.33%)	3 / 3 (100.00%)	16 / 48 (33.33%)	16 / 47 (34.04%)
occurrences all number	3	2	3	21	18
Diarrhoea
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	7 / 48 (14.58%)	6 / 47 (12.77%)
occurrences all number	1	1	2	8	6
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	20 / 48 (41.67%)	19 / 47 (40.43%)
occurrences all number	1	3	1	21	20
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	0	0	0	3	2
Dysphagia
subjects affected / exposed	4 / 5 (80.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	36 / 48 (75.00%)	29 / 47 (61.70%)
occurrences all number	5	2	3	38	30
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 48 (2.08%)	3 / 47 (6.38%)
occurrences all number	1	1	0	1	3
Glossitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Glossodynia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Melaena
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	3	0	0	0
Nausea
subjects affected / exposed	1 / 5 (20.00%)	6 / 6 (100.00%)	1 / 3 (33.33%)	20 / 48 (41.67%)	17 / 47 (36.17%)
occurrences all number	3	7	1	30	24
Odynophagia
subjects affected / exposed	3 / 5 (60.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	10 / 48 (20.83%)	10 / 47 (21.28%)
occurrences all number	3	1	0	11	10
Oesophagitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	4 / 48 (8.33%)	4 / 47 (8.51%)
occurrences all number	0	1	0	4	4
Oral pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	7 / 48 (14.58%)	1 / 47 (2.13%)
occurrences all number	1	0	1	7	1
Salivary hypersecretion
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	4 / 48 (8.33%)	5 / 47 (10.64%)
occurrences all number	1	0	1	4	5
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	8 / 48 (16.67%)	9 / 47 (19.15%)
occurrences all number	0	2	0	8	9
Vomiting
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	13 / 48 (27.08%)	11 / 47 (23.40%)
occurrences all number	1	1	2	20	13
Hepatobiliary disorders
Renal failure acute
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 5 (20.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	4 / 48 (8.33%)	7 / 47 (14.89%)
occurrences all number	1	2	1	4	7
Dermatitis
subjects affected / exposed	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	20 / 48 (41.67%)	19 / 47 (40.43%)
occurrences all number	2	0	0	22	20
Dermatitis bullous
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 48 (2.08%)	4 / 47 (8.51%)
occurrences all number	0	0	0	1	4
Hair growth abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Pain of skin
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Pigmentation disorder
subjects affected / exposed	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Rash
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 48 (6.25%)	0 / 47 (0.00%)
occurrences all number	0	0	0	3	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Renal failure
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 48 (4.17%)	5 / 47 (10.64%)
occurrences all number	0	1	2	2	5
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	11 / 48 (22.92%)	4 / 47 (8.51%)
occurrences all number	0	0	0	16	5
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Neck pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	9 / 48 (18.75%)	7 / 47 (14.89%)
occurrences all number	1	0	0	10	8
Trismus
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	5 / 48 (10.42%)	1 / 47 (2.13%)
occurrences all number	0	0	0	5	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	0	1	0	3	1
Bronchopneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Folliculitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Fungal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	6 / 48 (12.50%)	4 / 47 (8.51%)
occurrences all number	0	0	0	6	4
Gingivitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Haemophilus infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Herpes zoster
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Impetigo
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Localised infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0
Mucosal infection
subjects affected / exposed	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0
Oral fungal infection
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	2	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	4 / 48 (8.33%)	5 / 47 (10.64%)
occurrences all number	0	0	0	4	5
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	1	0	0
Skin infection
subjects affected / exposed	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	4	0	0	0	0
Staphylococcal skin infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 5 (20.00%)	3 / 6 (50.00%)	2 / 3 (66.67%)	12 / 48 (25.00%)	12 / 47 (25.53%)
occurrences all number	1	3	2	13	12
Hyperkalaemia
subjects affected / exposed	2 / 5 (40.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	3 / 48 (6.25%)	2 / 47 (4.26%)
occurrences all number	2	3	0	4	3
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	5 / 48 (10.42%)	6 / 47 (12.77%)
occurrences all number	0	0	0	6	7
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	6 / 48 (12.50%)	5 / 47 (10.64%)
occurrences all number	0	3	0	6	7
Hypomagnesaemia
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 48 (6.25%)	8 / 47 (17.02%)
occurrences all number	1	2	1	3	9
Hyponatraemia
subjects affected / exposed	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 48 (2.08%)	5 / 47 (10.64%)
occurrences all number	1	1	4	1	7
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 48 (0.00%)	4 / 47 (8.51%)
occurrences all number	0	1	1	0	5
Hyperglycaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	3	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	2	0	0	0
Malnutrition
subjects affected / exposed	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 48 (0.00%)	4 / 47 (8.51%)
occurrences all number	0	0	0	0	4

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Were there any global substantial amendments to the protocol? Yes

10 Jul 2015

This protocol amendment was aimed at correcting, clarifying and improving the contents and structure of Part B prior to its initiation.

24 Aug 2016

The main change introduced by this amendment was the inclusion of HPV-16-positive subjects.

07 Nov 2018

This amendment for study Part B was issued following the decision to: • Add an extra follow up period (extended follow up) and revise statistical sections including establishing an Internal Steering Committee. • Modify secondary endpoints.

05 Mar 2020

• Extension of the survival follow up period by 2 years until 5 years after CRT initiation for the last participant to start treatment. • Collection of subsequent antineoplastic therapy information: Early stopping rules were added for the survival follow-up in case insufficient OS and subsequent antineoplastic therapy information could be collected.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase I/II randomized study to determine the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of Debio 1143 combined with concurrent Chemo-Radiation Therapy in patients with locally advanced squamous cell carcinoma of the head and neck

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Percentage of Subjects Experiencing Dose-Limiting Toxicities (DLTs)

Primary: Part A: Percentage of Subjects Experiencing Dose-Limiting Toxicities (DLTs)

Primary: Part B: Percentage of Subjects Achieving Locoregional Control (LRC) at 18 Months From the End of Chemo-Radiation Therapy (CRT)

Primary: Part B: Percentage of Subjects Achieving Locoregional Control (LRC) at 18 Months From the End of Chemo-Radiation Therapy (CRT)

Secondary: Part A: Number of Subjects Experiencing at Least One Treatment Emergent Adverse Event (TEAE), Grade 3 or Above TEAE, and Serious Adverse Event (SAE)

Secondary: Part A: Number of Subjects Experiencing at Least One Treatment Emergent Adverse Event (TEAE), Grade 3 or Above TEAE, and Serious Adverse Event (SAE)

Secondary: Part A: Number of Subjects With Treatment Discontinuations and Treatment Modifications due to AEs

Secondary: Part A: Number of Subjects With Treatment Discontinuations and Treatment Modifications due to AEs

Secondary: Part A: Percentage of Subjects With Tumour Response: Best Overall Response

Secondary: Part A: Percentage of Subjects With Tumour Response: Best Overall Response

Secondary: Part A: Maximum Observed Plasma Concentration (Cmax) for Debio 1143 and D-1143-MET1

Secondary: Part A: Maximum Observed Plasma Concentration (Cmax) for Debio 1143 and D-1143-MET1

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to the Last Quantifiable Concentration (AUC0-t) for Debio 1143 and D-1143-MET1

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to the Last Quantifiable Concentration (AUC0-t) for Debio 1143 and D-1143-MET1

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to Infinity (AUC∞) for Debio 1143 and D-1143-MET1

Secondary: Part A: Area Under the Plasma Concentration-time Curve From Administration up to Infinity (AUC∞) for Debio 1143 and D-1143-MET1

Secondary: Part B: Progression-Free Survival (PFS)

Secondary: Part B: Progression-Free Survival (PFS)

Secondary: Part B: Duration of Locoregional Control (LRC)

Secondary: Part B: Duration of Locoregional Control (LRC)

Secondary: Part B: Time to Distant Relapse

Secondary: Part B: Time to Distant Relapse

Secondary: Part B: Overall Survival (OS)

Secondary: Part B: Overall Survival (OS)

Secondary: Part B: Number of Subjects Experiencing at Least One TEAE and Grade 3 or Above TEAE

Secondary: Part B: Number of Subjects Experiencing at Least One TEAE and Grade 3 or Above TEAE

Secondary: Part B: Number of Subjects Experiencing Any Late Toxicity

Secondary: Part B: Number of Subjects Experiencing Any Late Toxicity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase I/II randomized study to determine the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of Debio 1143 combined with concurrent Chemo-Radiation Therapy in patients with locally advanced squamous cell carcinoma of the head and neck