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Clinical Trial Results:
Preoperative window-of-opportunity (WoO) study of Debio 1143 with or without cisplatin (CDDP) in patients with resectable squamous cell carcinoma of the head and neck.

Summary
EudraCT number	2014-004655-31
Trial protocol	FR
Global end of trial date	18 Jul 2018

Results information
Results version number	v1(current)
This version publication date	14 Aug 2019
First version publication date	14 Aug 2019
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

Debio 1143-SCCHN-202

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Debiopharm International S.A.

Sponsor organisation address

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

Public contact

Vice President Clinical Research & Development, Debiopharm International S.A., 41 213210111, info-international@debiopharm.com

Scientific contact

Vice President Clinical Research & Development, Debiopharm International S.A., 41 213210111, info-international@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

18 Jul 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2018

Was the trial ended prematurely?

Main objective of the trial

To investigate the pharmacodynamic (PDy) activity of Debio 1143 alone and Debio 1143 combined with cisplatin (CDDP), in subjects with squamous cell carcinoma of the head and neck (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

Evidence for comparator

Actual start date of recruitment

11 Aug 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 26

Worldwide total number of subjects

EEA total number of subjects

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

The study was conducted in France from 11 August 2015 to 18 Jul 2018.

Screening details

Subjects with newly diagnosed resectable SCCHN who were candidates for primary surgical treatment were administered either Debio 1143 or Debio 1143 in combination with cisplatin or cisplatin alone pre-operatively.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Debio 1143

Arm description

Subjects were administered Debio 1143 once daily for 15 (± 2) days until surgery, and the last dose was administered on the day of surgery.

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

1143

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Debio 1143 was administered at a dose of 200 milligram (mg) per oral (PO) once daily for 15 (± 2) days until surgery. The last dose was to be administered on the day of surgery.

Debio 1143 + Cisplatin

Arm description

Subjects were administered Debio 1143 once daily for 15 (± 2) days until surgery, and the last dose was administered on the day of surgery. Cisplatin was administered once weekly on study Days 1 and 8.

Arm type

Experimental

Investigational medicinal product name

Debio 1143

Investigational medicinal product code

1143

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Debio 1143 was administered at a dose of 200 mg PO once daily for 15 (± 2) days until surgery. The last dose was to be administered on the day of surgery.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 40 milligrams per square metre (mg/m^2) intravenous (IV) infusion once weekly on study Days 1 and 8.

Cisplatin

Arm description

Cisplatin was administered once weekly on study Days 1 and 8.

Arm type

Experimental

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cisplatin was administered at a dose of 40 mg/m^2 IV infusion once weekly on study Days 1 and 8.

Number of subjects in period 1	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Started	13	6	7
Completed	12	6	6
Not completed	1	0	1
Surgery cancelled after Serious Adverse Event	-	-	1
Subject postponed surgery	1	-	-

Baseline characteristics

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Reporting group title

Debio 1143

Reporting group description

Subjects were administered Debio 1143 once daily for 15 (± 2) days until surgery, and the last dose was administered on the day of surgery.

Reporting group title

Debio 1143 + Cisplatin

Reporting group description

Reporting group title

Cisplatin

Reporting group description

Cisplatin was administered once weekly on study Days 1 and 8.

Reporting group values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin	Total
Number of subjects	13	6	7	26
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.23 ( 10.89 )	59.83 ( 7.03 )	57.29 ( 7.16 )	-
Gender categorical
Units: Subjects
Female	3	1	1	5
Male	10	5	6	21

End points

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Reporting group title

Debio 1143

Reporting group description

Subjects were administered Debio 1143 once daily for 15 (± 2) days until surgery, and the last dose was administered on the day of surgery.

Reporting group title

Debio 1143 + Cisplatin

Reporting group description

Reporting group title

Cisplatin

Reporting group description

Cisplatin was administered once weekly on study Days 1 and 8.

Primary: Effect of Debio 1143 Alone and Debio 1143 Combined With CDDP on cIAP-1 Levels in Subjects With Squamous Cell Carcinoma of the Head and Neck (SCCHN)

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End point title

Effect of Debio 1143 Alone and Debio 1143 Combined With CDDP on cIAP-1 Levels in Subjects With Squamous Cell Carcinoma of the Head and Neck (SCCHN) ^[1] ^[2]

End point description

The assessment of the levels of cIAP-1 in tumor biopsies was performed using a validated immunohistochemistry (IHC) assay. The assay was developed using a mouse monoclonal anti-cIAP-1. Per protocol (PP) population was defined as all subjects included in the intent to treat (ITT) population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Primary

End point timeframe

Pre-dose (Day 1) and At time of surgery (Day 15)

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 statistics 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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	12	5
Units: H-score
arithmetic mean (standard deviation)
Pre-dose (Day 1)	73.33 ( 86.69 )	93.80 ( 131.09 )
At time of surgery (Day 15)	25.25 ( 30.69 )	71.40 ( 114.61 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign Weight Over Time

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End point title

Change From Baseline in Vital Sign Weight Over Time

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Debio 1143 + Cisplatin at change at follow-up 1 day post-surgery, 99999 indicates standard deviation, as number of subjects evaluated was 1. For arm Cisplatin at change at follow-up 1 day post-surgery, 99999 indicates arithmetic mean and standard deviation as no subject was evaluated.

End point type

Secondary

End point timeframe

Baseline, Day 8, Day of surgery (Day 15), follow-up 1 day post-surgery and follow-up 4 weeks post-surgery

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: kilogram (kg)
arithmetic mean (standard deviation)
Baseline (n=13,6,7)	69.23 ( 9.14 )	78.83 ( 17.17 )	73.29 ( 16.25 )
Change at Day 8 (n=12,6,6)	0.58 ( 2.61 )	0.17 ( 1.33 )	-1.50 ( 1.52 )
Change on Day of surgery (Day 15) (n=5,5,3)	0.40 ( 0.55 )	0.60 ( 2.07 )	-0.33 ( 2.31 )
Change at follow-up 1 day post-surgery (n=6,1,0)	0.67 ( 1.75 )	-1.00 ( 99999 )	99999 ( 99999 )
Change at follow-up 4weeks post-surgery (n=11,6,7)	-4.00 ( 2.68 )	-3.33 ( 1.21 )	-4.00 ( 3.27 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign Body Surface Area Over Time

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End point title

Change From Baseline in Vital Sign Body Surface Area Over Time

End point description

End point type

Secondary

End point timeframe

Baseline, Day 8, Day of surgery (Day 15), Follow-up 1 day post-surgery and Follow-up 4 weeks post-surgery

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: metre square (m²)
arithmetic mean (standard deviation)
Baseline (n=13,6,7)	1.82 ( 0.14 )	1.95 ( 0.26 )	1.86 ( 0.24 )
Change at day 8 (n=12,6,6)	0.01 ( 0.03 )	0.00 ( 0.02 )	-0.02 ( 0.02 )
Change at Day of surgery (Day 15) (n=5,5,3)	0.01 ( 0.01 )	0.01 ( 0.03 )	-0.01 ( 0.03 )
Change at follow-up 1 day post-surgery (n=6,1,0)	0.01 ( 0.03 )	-0.01 ( 99999 )	99999 ( 99999 )
Change at follow-up 4weeks post-surgery (n=11,6,7)	-0.05 ( 0.03 )	-0.04 ( 0.01 )	-0.05 ( 0.04 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign Heart Rate Over Time

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End point title

Change From Baseline in Vital Sign Heart Rate Over Time

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Baseline, Day 8, Day of surgery (Day 15), Follow-up 1 day post-surgery and Follow-up 4 weeks post-surgery

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: beats/min
arithmetic mean (standard deviation)
Baseline (n=13,6,7)	74.23 ( 12.84 )	69.17 ( 9.37 )	70.71 ( 10.92 )
Change at Day 8 (n=12,6,6)	4.75 ( 13.82 )	-1.00 ( 6.81 )	9.33 ( 10.91 )
Change at Day of surgery (Day 15) (n=8,5,4)	-2.13 ( 9.25 )	0.80 ( 8.76 )	-0.50 ( 12.87 )
Change at follow-up 1 day post-surgery (n=9,5,2)	6.44 ( 23.75 )	19.60 ( 13.01 )	26.00 ( 11.31 )
Change at follow-up 4weeks post-surgery (n=12,6,6)	4.50 ( 18.05 )	21.33 ( 11.89 )	16.33 ( 18.74 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign Systolic Blood Pressure Over Time

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End point title

Change From Baseline in Vital Sign Systolic Blood Pressure Over Time

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Baseline, Day 8, Day of surgery (Day 15), Follow-up 1 day post-surgery and Follow-up 4 weeks post-surgery

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: millimetre of mercury (mmHg)
arithmetic mean (standard deviation)
Baseline (n=13,6,7)	142.31 ( 20.17 )	153.67 ( 15.97 )	130.00 ( 26.45 )
Change at Day 8 (n=12,6,6)	-11.92 ( 17.12 )	-18.00 ( 17.84 )	4.33 ( 22.74 )
Change on Day of surgery (Day 15) (n=8,5,4)	-20.25 ( 18.20 )	-10.60 ( 9.50 )	3.00 ( 29.47 )
Change at follow-up 1 day post-surgery (n=9,5,2)	-15.78 ( 21.79 )	-19.60 ( 16.71 )	-19.00 ( 9.90 )
Change at follow-up 4weeks post-surgery (n=12,6,6)	-17.50 ( 24.22 )	-20.67 ( 21.44 )	-13.33 ( 22.10 )

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign Diastolic Blood Pressure Over Time

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End point title

Change From Baseline in Vital Sign Diastolic Blood Pressure Over Time

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Baseline, Day 8, Day of surgery, Follow-up 1 day post-surgery and Follow-up 4 weeks post-surgery

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: mmHg
arithmetic mean (standard deviation)
Baseline (n=13,6,7)	84.69 ( 11.75 )	82.83 ( 14.46 )	79.57 ( 12.99 )
Change at Day 8 (n=12,6,6)	-3.83 ( 12.84 )	-6.50 ( 15.71 )	-3.67 ( 6.35 )
Change on Day of surgery (Day 15) (n=8,5,4)	-13.50 ( 8.65 )	3.20 ( 20.97 )	-0.50 ( 17.60 )
Change at follow-up 1 day post-surgery (n=9,5,2)	-23.22 ( 14.03 )	-18.60 ( 13.97 )	-23.50 ( 7.78 )
Change at follow-up 4weeks post-surgery (n=12,6,6)	-8.08 ( 9.34 )	-2.83 ( 20.13 )	-1.67 ( 12.55 )

No statistical analyses for this end point

Secondary: Eastern Cooperative Oncology Group performance status (ECOG PS) Over Time

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End point title

Eastern Cooperative Oncology Group performance status (ECOG PS) Over Time

End point description

Per the inclusion criteria, subjects that had ECOG PS of 0-1 were analysed. Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Baseline and Follow-up 4 Weeks Post-Surgery (FUPS-4wks)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects
Baseline-Fully active (n=13,6,7)	9	6	6
Baseline-Light work (n=13,6,7)	4	0	1
FUPS-4wks-Fully active (n=11,5,6)	2	2	4
FUPS-4wks-Light work (n=11,5,6)	8	3	2
FUPS-4wks-Unable to work (n=11,5,6)	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Serious Adverse Events (AEs)

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End point title

Number of Subjects with Serious Adverse Events (AEs)

End point description

A serious adverse event any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. The safety population included subjects who received a dose of any of the study drugs (Debio 1143 and/or Cisplatin).

End point type

Secondary

End point timeframe

Screening up to 43 days

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects	1	0	2

No statistical analyses for this end point

Secondary: Number of Subjects and Severity of AEs Graded According to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4 Criteria

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End point title

Number of Subjects and Severity of AEs Graded According to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4 Criteria

End point description

The NCI CTCAE is a descriptive terminology which can be utilized for adverse event (AE) reporting. A grading (severity) scale is provided for each AE term. The CTCAE displays Grades 1 through 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Screening up to 43 days

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects
Grade 1	11	5	7
Grade 2	8	3	6
Grade 3	2	2	6
Grade 4	0	0	1
Unknown	3	1	1

No statistical analyses for this end point

Secondary: Number of Subjects and Severity of Laboratory Abnormalities Graded According to the NCI-CTCAE v4 Criteria

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End point title

Number of Subjects and Severity of Laboratory Abnormalities Graded According to the NCI-CTCAE v4 Criteria

End point description

Laboratory parameters included haematology (activated partial thromboplastin time prolonged [APTT], fibrinogen decreased, haemoglobin increased, anaemia, neutrophil count decreased, platelet count decreased, leukocytosis and white blood cell decreased), clinical chemistry (increased alkaline phosphatase [ALP], increased alanine aminotransferase [ALT], increased aspartate aminotransferase [AST], increased blood bilirubin and increased creatinine). Data for total grades (1-4) has been reported. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). 99999 indicates that abnormalities were not observed for that arm and specified time point.

End point type

Secondary

End point timeframe

Before surgery (screening) and On-treatment period (Day 1 up to Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects
Before surgery: APTT	99999	99999	99999
Before surgery: Fibrinogen decreased	6	2	3
Before surgery: Hemoglobin increased	99999	99999	99999
Before surgery: Anaemia	6	4	3
Before surgery: Neutrophil count decreased	99999	99999	99999
Before surgery: Platelet count decreased	99999	3	99999
Before surgery: Leukocytosis	99999	99999	99999
Before surgery: White blood cell decreased	99999	99999	99999
On-treatment: APTT	99999	99999	99999
On-treatment: Fibrinogen decreased	6	2	3
On-treatment: Hemoglobin increased	99999	99999	99999
On-treatment: Anaemia	13	6	3
On-treatment: Neutrophil count decreased	99999	99999	99999
On-treatment: Platelet count decreased	99999	4	99999
On-treatment: Leukocytosis	99999	99999	99999
On-treatment: White blood cell decreased	99999	99999	99999
Before surgery: Increased ALP	2	99999	1
Before surgery: Increased ALT	1	3	99999
Before surgery: Increased AST	1	2	99999
Before surgery: Increased blood bilirubin	99999	1	99999
Before surgery: Increased creatinine	11	6	2
On-treatment: Increased ALP	2	99999	1
On-treatment: Increased ALT	1	3	99999
On-treatment: Increased AST	3	3	99999
On-treatment: Increased blood bilirubin	1	2	99999
On-treatment: Increased creatinine	12	6	2

No statistical analyses for this end point

Secondary: Number of Subjects With Severe Post-operative Bleeding

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End point title

Number of Subjects With Severe Post-operative Bleeding

End point description

Severe post-operative bleeding was defined as decrease of haemoglobin (Hb) > 2 gram per decilitre (g/dL) and clinical evidence of blood loss (e.g. melena, hematuria or surgical wound bleeding). Safety population included subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

During 4 weeks post-surgery (up to Day 28 post surgery)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Delayed Wound Healing

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End point title

Number of Subjects With Delayed Wound Healing

End point description

Delayed wound healing was defined as presence of surgical wound or surgical wound healing complications at 3-4 weeks from surgery as per the Surgeon's judgment. Safety population included subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

During 4 weeks post-surgery (up to Day 28 post surgery)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	13	6	7
Units: subjects	2	2	3

No statistical analyses for this end point

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Serum Samples

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End point title

Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Serum Samples

End point description

Serum samples were obtained from subjects at baseline, during and after treatment with Debio 1143 for the detection (by ELISA) of caspase-cleaved cytokeratin (CK) 18 fragment M30 antigen (CK18-M30), which is a marker of epithelial cellular apoptosis. PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Day 1-Pre Dose, Day 1 - 4 Hours Post-Dose, Day of Surgery (Day 15) - Pre-Dose, Day of Surgery (Day 15) - 4 Hours Post-Dose and End of Study - 4 Weeks Post-Dose

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: units per litre (U/L)
arithmetic mean (standard deviation)
CK18-M30: Day 1 - Pre-Dose (n=9,5,6)	225.60 ( 93.63 )	232.78 ( 228.00 )	179.00 ( 66.29 )
CK18-M30: Day 1 - 4 Hours Post-Dose (n=9,5,6)	218.45 ( 73.38 )	224.51 ( 198.89 )	146.16 ( 28.89 )
CK18-M30: Day of Surgery - Pre-Dose (n=8,5,5)	273.4 ( 92.84 )	260.67 ( 180.50 )	173.51 ( 89.05 )
CK18-M30:Day of Surgery-4Hours Post-Dose (n=9,5,6)	270.00 ( 73.56 )	304.17 ( 254.60 )	152.65 ( 32.92 )
CK18-M30:End of Study-4 Weeks Post-Dose (n=9,4,4)	198.37 ( 65.11 )	160.87 ( 90.16 )	148.86 ( 40.94 )

No statistical analyses for this end point

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Tumor Samples

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End point title

Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Tumor Samples

End point description

The effect of treatment on apoptosis was evaluated based on the levels of cleaved caspase-3, given that inhibitor of apoptosis protein suppress apoptosis by blocking caspases. PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Pre dose (Day 1) and at time of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: per millimetre square (/mm²)
arithmetic mean (standard deviation)
Cleaved Caspase-3 Positive Cells: Pre dose (Day 1)	0.67 ( 1.15 )	0.00 ( 0.00 )	0.00 ( 0.00 )
Cleaved Caspase-3Positive Cells:At time of surgery	1.50 ( 1.98 )	0.00 ( 0.00 )	0.00 ( 0.00 )

No statistical analyses for this end point

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Necrosis

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End point title

Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Necrosis

End point description

PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Pre dose (Day 1) and at time of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: percent
arithmetic mean (standard deviation)
Pre dose (Day 1)	0.83 ( 2.89 )	0.00 ( 0.00 )	0.00 ( 0.00 )
At time of surgery (Day 15)	1.67 ( 5.77 )	0.00 ( 0.00 )	0.00 ( 0.00 )

No statistical analyses for this end point

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Proliferation Markers in Tumors

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End point title

Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Proliferation Markers in Tumors

End point description

The expression of the Ki67 protein was used as a proliferation marker. PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Pre dose (Day 1) and At time of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: percent
arithmetic mean (standard deviation)
Pre dose (Day 1)	64.17 ( 23.53 )	91.00 ( 2.24 )	40.83 ( 34.84 )
At time of surgery (Day 15)	70.83 ( 25.12 )	67.00 ( 26.4 )	61.67 ( 27.87 )

No statistical analyses for this end point

Secondary: Measurement of any Early Biological Response to Debio 1143 Alone or Combined With CDDP and CDDP Alone by 18F-FDG PET

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End point title

Measurement of any Early Biological Response to Debio 1143 Alone or Combined With CDDP and CDDP Alone by 18F-FDG PET

End point description

The biological response was assessed by treatment cohort as the standardised uptake value (SUV) percentage change from baseline to Day -1 prior to surgery (S-1). PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

From baseline to Day -1 prior to surgery (Day 14)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	4
Units: percent change
arithmetic mean (standard deviation)	6.47 ( 26.90 )	-8.75 ( 41.19 )	24.29 ( 58.42 )

No statistical analyses for this end point

Secondary: Percent Change From Pre-dose for Cytokine and Chemokine

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End point title

Percent Change From Pre-dose for Cytokine and Chemokine

End point description

The downstream effects of IAP inhibition by Debio 1143 on NF-κB signaling were assessed by measuring level of cytokines and chemokines using multiplex assay, which allows detection of 30 biomarkers. PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Day of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: percent change
arithmetic mean (standard deviation)
Tumor necrosis factor alpha (TNFα) (n= 10, 1, 2)	26.68 ( 21.01 )	14.86 ( 99999 )	1.17 ( 16.84 )
Monocyte chemoattractant protein-1 (n=11, 2, 0)	31.79 ( 17.6 )	53.63 ( 10.67 )	99999 ( 99999 )
CK18-M30 (n=8,5,5)	53.92 ( 94.02 )	37.49 ( 50.96 )	-0.49 ( 26.63 )
Interferon gamma (IFNg) (n=11,2,3)	38.5 ( 118.06 )	0 ( 0 )	-26.01 ( 45.05 )
Eotaxin-1 (n=10,2,0)	1.64 ( 25.19 )	13.96 ( 38.01 )	99999 ( 99999 )
Eotaxin-3 (n=9,2,0)	0 ( 0 )	7.69 ( 10.88 )	99999 ( 99999 )
GMCSF (n=2,0,2)	0 ( 0 )	99999 ( 99999 )	0 ( 0 )
Interleukin (IL) 10 (n=10,4,3)	0 ( 0 )	0 ( 0 )	0 ( 0 )
IL12 IL23p40 (n=11,5,5)	138.47 ( 64.92 )	40.28 ( 95.68 )	-32.61 ( 17.27 )
IL12p70 (n=5,1,2)	0 ( 0 )	0 ( 9999 )	0 ( 0 )
IL13 (n=6,3,0)	0 ( 0 )	0 ( 0 )	99999 ( 99999 )
IL15 (n=9,5,5)	73.16 ( 64.83 )	28.72 ( 14.19 )	1.33 ( 10.19 )
IL16 (n=11,5,5)	26.16 ( 47.46 )	-15.32 ( 28.72 )	35.05 ( 81.44 )
IL17 (n=2,4,5)	0 ( 0 )	29.26 ( 58.53 )	0 ( 0 )
IL1a (n=0,1,0)	99999 ( 99999 )	0 ( 99999 )	99999 ( 99999 )
IL1b (n=0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
IL2 (n=3,1,1)	0 ( 0 )	0 ( 99999 )	0 ( 99999 )
IL4 (n=4,1,1)	0 ( 0 )	0 ( 99999 )	0 ( 99999 )
IL5 (n=2,4,0)	0 ( 0 )	0 ( 0 )	99999 ( 99999 )
IL6 (n=11,5,5)	0 ( 0 )	-14.10 ( 31.53 )	36.86 ( 121.5 )
IL7 (n=11,5,5)	-18.5 ( 38.99 )	-47.57 ( 21.82 )	-30.12 ( 33.45 )
IL8 HA (n=0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
IL8 LA (n=11,2,2)	51.25 ( 118.15 )	-16.33 ( 15.26 )	23.44 ( 19.97 )
Interferon inducible protein10 (IP10) (n=11,2,0)	14.01 ( 36.35 )	27.16 ( 11.80 )	99999 ( 99999 )
Monocyte chemoattractant protein-4 (n=11,2,0)	27.02 ( 43.33 )	29.02 ( 29.16 )	99999 ( 99999 )
Macrophage derived chemokine (MDC) (n=11,2,0)	46.47 ( 34.97 )	7.13 ( 42.13 )	99999 ( 99999 )
Macrophage inflammatory protein 1 alpha (n=3,1,0)	0 ( 0 )	0 ( 99999 )	99999 ( 99999 )
Macrophage inflammatory protein 1 beta (n=11,2,0)	-2.21 ( 16.79 )	1.12 ( 48 )	99999 ( 99999 )
TARC (n=11,2,0)	88.73 ( 85.30 )	50.65 ( 69.25 )	99999 ( 99999 )
TNFβ (n=3,3,1)	0 ( 0 )	0 ( 0 )	0 ( 99999 )
Vascular endothelial growth factor (n=10,5,5)	3.20 ( 32.48 )	-15.53 ( 29.33 )	-10.21 ( 33.74 )
CK18-M65 (n=10,5,5)	234.56 ( 304.57 )	96.23 ( 189.02 )	29.76 ( 70.65 )

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Maximum Plasma Concentration (Cmax) of Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[3]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: nanogram/millilitre (ng/mL)
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=13,6)	1999.84 ( 68.08 )	2039.25 ( 24.43 )
Debio 1143: Day 8 (n=13,3)	2129.74 ( 50.91 )	1743.57 ( 27.26 )
Debio 1143 Metabolite: Day 1 (n=13,6)	979.63 ( 49.07 )	855.65 ( 31.32 )
Debio 1143 Metabolite: Day 8 (n=13,3)	1400.79 ( 43.99 )	878.97 ( 19.94 )

No statistical analyses for this end point

Secondary: Time to Maximum Concentration (Tmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Time to Maximum Concentration (Tmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[4]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1 and Day 8

Notes
[4] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: hour (h)
median (full range (min-max))
Debio 1143: Day 1 (n=13,6)	1.50 (0.38 to 3.10)	1.09 (0.45 to 1.58)
Debio 1143: Day 8 (n=13,3)	1.50 (0.47 to 4.25)	1.75 (1.50 to 3.03)
Debio 1143 Metabolite: Day 1 (n=13,6)	3.02 (1.50 to 23.60)	2.98 (1.50 to 7.67)
Debio 1143 Metabolite: Day 8 (n=13,3)	3.00 (1.58 to 6.00)	6.12 (1.50 to 6.25)

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve (AUC) on the Dosing Interval Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Area under the plasma concentration-time curve (AUC) on the Dosing Interval Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[5]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: hournanogram per millilitre (hng/mL)
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=13,6)	8037.79 ( 57.94 )	8484.93 ( 40.83 )
Debio 1143: Day 8 (n=13,3)	9643.20 ( 44.77 )	7621.50 ( 40.05 )
Debio 1143 Metabolite: Day 1 (n=11,5)	11114.70 ( 47.60 )	8812.51 ( 32.66 )
Debio 1143 Metabolite: Day 8 (n=11,2)	17471.39 ( 53.10 )	11200.00 ( 0.00 )

No statistical analyses for this end point

Secondary: T1/2 Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

T1/2 Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[6]

End point description

Safety population included subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Debio 1143 + Cisplatin at Day 8 for Debio 1143 Metabolite, 99999 indicates standard deviation, as number of subjects evaluated was 0.

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: hour
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=12,6)	6.2 ( 9.9 )	6.11 ( 14.58 )
Debio 1143: Day 8 (n=13,3)	6.82 ( 18.71 )	6.96 ( 6.79 )
Debio 1143 Metabolite: Day 1 (n=7,2)	7.43 ( 22.24 )	6.3 ( 11.58 )
Debio 1143 Metabolite: Day 8 (n=4,0)	6.17 ( 13.4 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Ctrough Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Ctrough Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[7]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 2, Day 8, Day 9, Day of Surgery (Day 15), Follow-up (FU) 1 Day Post-Surgery (Day 16)

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Debio 1143: Day 2 (n=13,6)	51.39 ( 81.17 )	53.44 ( 54.49 )
Debio 1143: Day 8 (n=12,4)	65.03 ( 72.79 )	63.20 ( 9.13 )
Debio 1143: Day 9 (n=13,4)	71.18 ( 61.49 )	63.53 ( 49.25 )
Debio 1143: Day of Surgery (n=12,6)	93.32 ( 71.11 )	56.84 ( 87.95 )
Debio 1143: FU 1 Day Post-Surgery (n=12,6)	88.49 ( 86.08 )	63.04 ( 39.50 )
Debio 1143 Metabolite: Day 2 (n=13,6)	201.89 ( 79.11 )	124.71 ( 37.49 )
Debio 1143 Metabolite: Day 8 (n=12,4)	317.00 ( 106.60 )	257.13 ( 27.74 )
Debio 1143 Metabolite: Day 9 (n=13,4)	301.12 ( 123.64 )	191.73 ( 101.92 )
Debio 1143 Metabolite: Day of Surgery (n=12,6)	331.18 ( 99.44 )	87.04 ( 243.05 )
Debio 1143 Metabolite:FU 1Day Post-Surgery(n=12,6)	332.68 ( 115.35 )	102.61 ( 95.10 )

No statistical analyses for this end point

Secondary: Average Concentration (Cav) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Average Concentration (Cav) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[8]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Debio 1143: Day 8 (n=13,3)	401.49 ( 44.73 )	317.87 ( 40.03 )
Debio 1143 Metabolite: Day 8 (n=11,2)	727.71 ( 53.06 )	467.00 ( 0.30 )

No statistical analyses for this end point

Secondary: Accumulation Ratio Based on Cmax (ARCmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Accumulation Ratio Based on Cmax (ARCmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[9]

End point description

Accumulation ratio based on Cmax is calculated as Cmax(Day 8)/Cmax(Day 1). Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ratio
geometric mean (geometric coefficient of variation)
Debio 1143: Day 8 (n=13,3)	1.07 ( 44.07 )	0.90 ( 28.18 )
Debio 1143 Metabolite: Day 8 (n=13,3)	1.43 ( 56.23 )	1.20 ( 22.63 )

No statistical analyses for this end point

Secondary: Accumulation Ratio Based on AUC (ARAUC ) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Accumulation Ratio Based on AUC (ARAUC ) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[10]

End point description

ARAUCt was calculated as AUCτ(Day 8)/AUCτ(Day 1). Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ratio
geometric mean (geometric coefficient of variation)
Debio 1143: Day 8 (n=13,3)	1.20 ( 37.41 )	1.01 ( 29.81 )
Debio 1143 Metabolite: Day 8 (n=10,2)	1.39 ( 55.40 )	1.26 ( 7.28 )

No statistical analyses for this end point

Secondary: Linearity Index Based on AUC (LIAUC) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Linearity Index Based on AUC (LIAUC) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[11]

End point description

LIAUC, calculated as AUCτ(Day 8)/AUC(Day 1). Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Debio 1143 + Cisplatin, Debio 1143 metabolite category, 99999 indicates geometric mean and geometric CV as no subject was evaluated at the specified time point.

End point type

Secondary

End point timeframe

Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ratio
geometric mean (geometric coefficient of variation)
Debio 1143: Day 8 (n=12,3)	1.15 ( 39.02 )	0.96 ( 27.80 )
Debio 1143 Metabolite: Day 8 (n=5,0)	0.85 ( 48.01 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Accumulation Index (AI) Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

Accumulation Index (AI) Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[12]

End point description

AI calculated as 1/|1-e- λ|. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Debio 1143 + Cisplatin, Debio 1143 metabolite category, 99999 indicates geometric mean and geometric CV, as no subject was evaluated at the specified time point.

End point type

Secondary

End point timeframe

Day 8

Notes
[12] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: ratio
geometric mean (geometric coefficient of variation)
Debio 1143: Day 8 (n=13,3)	1.10 ( 4.25 )	1.10 ( 1.82 )
Debio 1143 Metabolite: Day 8 (n=4,0)	1.07 ( 3.06 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Apparent Total Body Clearance (CL/F) Debio 1143 in Plasma

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End point title

Apparent Total Body Clearance (CL/F) Debio 1143 in Plasma ^[13]

End point description

Apparent total body clearance (oral clearance) to be calculated as dose/AUC∞. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: litre per hour (L/h)
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=12,6)	23.91 ( 61.96 )	22.28 ( 41.39 )
Debio 1143: Day 8 (n=13,3)	20.74 ( 44.64 )	26.22 ( 40.15 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Debio 1143 Alone

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End point title

Apparent Volume of Distribution During the Terminal Phase (V/F) of Debio 1143 Alone ^[14]

End point description

Apparent volume of distribution during the terminal phase to be calculated as (CL/F)/λz. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1 and Day 8

Notes
[14] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: litre(s)
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=12,6)	213.92 ( 58.58 )	196.40 ( 41.63 )
Debio 1143: Day 8 (n=13,3)	204.23 ( 47.82 )	263.49 ( 33.94 )

No statistical analyses for this end point

Secondary: Tumor Concentration Distribution of Debio 1143 Based on an Appropriate Mass Spectrometry Method

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End point title

Tumor Concentration Distribution of Debio 1143 Based on an Appropriate Mass Spectrometry Method ^[15]

End point description

The molecular distribution of Debio 1143 in tumour biopsies was assessed by matrix-assisted laser desorption/ionization (MALDI) imaging. The different histological regions were identified on stained sections adjacent to the ones used for Quantitative Mass Spectrometry Imaging, leading to a specific quantification integrating the biological characterization of the tumour heterogeneity. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day of surgery (Day 15)

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: microgram per gram (mcg/g)
arithmetic mean (standard deviation)
Day of surgery (n=10,5)	11.83 ( 11.03 )	26.50 ( 18.48 )

No statistical analyses for this end point

Secondary: AUClast: Free and Total CDDP in Plasma

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End point title

AUClast: Free and Total CDDP in Plasma ^[16]

End point description

Total and free CDDP were determined in plasma and ultracentrifuged plasma, respectively, using a validated inductively coupled plasma mass spectrometry (ICP/MS) method. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Cisplatin, 99999 indicates geometric mean and geometric CV, as no subject was evaluated at the specified time point.

End point type

Secondary

End point timeframe

Day 1 and Day 8

Notes
[16] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 + Cisplatin and Cisplatin.

End point values	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	6	7
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cisplatin Free: Day 1 (n=3,3)	2870.80 ( 124.57 )	2163.09 ( 21.65 )
Cisplatin Free: Day 8 (n=2,0)	3718.47 ( 17.01 )	99999 ( 99999 )
Cisplatin Total: Day 1 (n=6,5)	41102.10 ( 24.13 )	8902.75 ( 61.38 )
Cisplatin Total: Day 8 (n=3,0)	53968.44 ( 5.99 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: CL/F: Free and Total CDDP in Plasma

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End point title

CL/F: Free and Total CDDP in Plasma ^[17]

End point description

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 + Cisplatin and Cisplatin.

End point values	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	6	7
Units: L/h
geometric mean (geometric coefficient of variation)
Cisplatin Free: Day 1 (n=2,4)	31.81 ( 36.32 )	52.44 ( 51.81 )
Cisplatin Free: Day 8 (n=3,0)	48.22 ( 27.36 )	99999 ( 99999 )
Cisplatin Total: Day 1 (n=4,6)	17.18 ( 27.73 )	22.32 ( 44.74 )
Cisplatin Total: Day 8 (n=5,0)	21.60 ( 2.00 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Clast: Free and Total CDDP in Plasma

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End point title

Clast: Free and Total CDDP in Plasma ^[18]

End point description

Total and free CDDP were determined in plasma and ultracentrifuged plasma, respectively, using a validated inductively coupled plasma mass spectrometry (ICP/MS) method. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Cisplatin at Day 8, 99999 indicates geometric mean and geometric CV, as no subject was evaluated at the specified time point.

End point type

Secondary

End point timeframe

Day 1 and Day 8

Notes
[18] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 + Cisplatin and Cisplatin.

End point values	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	6	7
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cisplatin Free: Day 1 (n=3,3)	48.30 ( 54.01 )	55.39 ( 18.09 )
Cisplatin Free: Day 8 (n=2,0)	50.31 ( 21.81 )	99999 ( 99999 )
Cisplatin Total: Day 1 (n=6,5)	1881.87 ( 35.88 )	1989.84 ( 20.10 )
Cisplatin Total: Day 8 (n=3,0)	2071.62 ( 8.59 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Css: Free and Total CDDP in Plasma

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End point title

Css: Free and Total CDDP in Plasma ^[19]

End point description

Total and free CDDP were determined in plasma and ultracentrifuged plasma, respectively, using a validated inductively coupled plasma mass spectrometry (ICP/MS) method. Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP). For arm Cisplatin at Day 8, 99999 indicates geometric mean and geometric CV, as no subject was evaluated at the specified time point.

End point type

Secondary

End point timeframe

Day 1 and Day 8

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: The endpoint was planned to be reported for the reporting arms Debio 1143 + Cisplatin and Cisplatin.

End point values	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	6	7
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cisplatin Free: Day 1 (n=3,4)	339.99 ( 20106.07 )	1206.91 ( 39.20 )
Cisplatin Free: Day 8 (n=3,0)	1647.45 ( 40.35 )	99999 ( 99999 )
Cisplatin Total: Day 1 (n=6,7)	385.37 ( 53779.14 )	1155.60 ( 2410.79 )
Cisplatin Total: Day 8 (n=5,0)	3647.98 ( 11.79 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Visual Predictive Check of Relationships Between Selected Pharmacokinetic (PK) Parameters and Pharmacodynamic (PDy) and Pharmacogenetics (PGx) Markers

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End point title

Visual Predictive Check of Relationships Between Selected Pharmacokinetic (PK) Parameters and Pharmacodynamic (PDy) and Pharmacogenetics (PGx) Markers ^[20]

End point description

End point type

Secondary

End point timeframe

Day of surgery (Day 15)

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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	0 ^[21]	0 ^[22]
Units: units
arithmetic mean (standard deviation)	( )	( )

Notes
[21] - Data collected was too premature to make a conclusion on this endpoint – hence no data shown.
[22] - Data collected was too premature to make a conclusion on this endpoint – hence no data shown.

No statistical analyses for this end point

Secondary: Association of Predictive Markers With a Pdy Activity of Debio 1143

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End point title

Association of Predictive Markers With a Pdy Activity of Debio 1143 ^[23]

End point description

End point type

Secondary

End point timeframe

Baseline, Day of surgery (Day 15)

Notes
[23] - 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: The endpoint was planned to be reported for the reporting arm Debio 1143.

End point values	Debio 1143
Number of subjects analysed	0 ^[24]
Units: units
arithmetic mean (standard deviation)	( )

Notes
[24] - Data collected was too premature to make a conclusion on this endpoint – hence no data shown.

No statistical analyses for this end point

Secondary: Genetic Variations in Drug Metabolizing Enzyme and Transporter (DMET) Genes Associated With Differences in the PK Disposition of Debio 1143

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End point title

Genetic Variations in Drug Metabolizing Enzyme and Transporter (DMET) Genes Associated With Differences in the PK Disposition of Debio 1143 ^[25]

End point description

End point type

Secondary

End point timeframe

Day of surgery (Day 15)

Notes
[25] - 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: The endpoint was planned to be reported for the reporting arm Debio 1143.

End point values	Debio 1143
Number of subjects analysed	0 ^[26]
Units: units
arithmetic mean (standard deviation)	( )

Notes
[26] - Data was not summarised as no association signal was identified.

No statistical analyses for this end point

Secondary: Exploration of Relationships Between 18F-FDG PET Imaging Results and PK/PDy Markers if Deemed Appropriate

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End point title

Exploration of Relationships Between 18F-FDG PET Imaging Results and PK/PDy Markers if Deemed Appropriate

End point description

End point type

Secondary

End point timeframe

Baseline, Day of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	0 ^[27]	0 ^[28]	0 ^[29]
Units: units
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[27] - Data was not summarised as no clear trend was observed.
[28] - Data was not summarised as no clear trend was observed.
[29] - Data was not summarised as no clear trend was observed.

No statistical analyses for this end point

Secondary: Effect of CDDP Alone on cIAP-1 Levels in Subjects With SCCHN

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End point title

Effect of CDDP Alone on cIAP-1 Levels in Subjects With SCCHN ^[30]

End point description

The assessment of the levels of cIAP-1 in tumor biopsies was performed using a validated IHC assay. The assay was developed using a mouse monoclonal anti-cIAP-1. PP population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

Pre-dose (Day 1) and At time of surgery (Day 15)

Notes
[30] - 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: The endpoint was planned to be reported for the reporting arm Cisplatin.

End point values	Cisplatin
Number of subjects analysed	6
Units: H-Score
arithmetic mean (standard deviation)
Pre-dose (Day 1)	100.83 ( 108.74 )
At time of surgery (Day 15)	106.67 ( 116.22 )

No statistical analyses for this end point

Secondary: Percent Change From Pre-dose for Programmed Cell Death Protein 1 (PD1), Programmed Death-Ligand 1 (PDL-1), Cluster of Differentiation (CD) 3, CD4 and CD8

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End point title

Percent Change From Pre-dose for Programmed Cell Death Protein 1 (PD1), Programmed Death-Ligand 1 (PDL-1), Cluster of Differentiation (CD) 3, CD4 and CD8

End point description

PP population population was defined as all subjects included in ITT population, but excluding those who did not receive the study drugs, did not undergo a pre-treatment and post-treatment PDy assessment, received non-permitted concomitant treatments, violated clinically relevant inclusion/non-inclusion criteria, did not receive at least 75% of the planned Debio 1143 dose, did not receive at least 50% of the planned CDDP dose or did not receive Debio 1143 the day before surgery and on the day of surgery.

End point type

Secondary

End point timeframe

At time of surgery (Day 15)

End point values	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Number of subjects analysed	12	5	6
Units: percent change
arithmetic mean (standard deviation)
PD1 (n=7,5,5)	435.71 ( 546.74 )	121.33 ( 223.66 )	4024.00 ( 8875.63 )
CD3 (n=11,5,6)	3.90 ( 30.99 )	127.00 ( 266.26 )	70.37 ( 158.80 )
CD4 (n=11,5,6)	7.79 ( 29.26 )	100.48 ( 227.31 )	80.65 ( 152.11 )
CD8 (n=11,5,6)	203.99 ( 564.58 )	23.33 ( 95.45 )	210.42 ( 369.83 )
PDL-1 (n=8,5,6)	137.5 ( 159.8 )	380 ( 334.66 )	183.33 ( 278.69 )

No statistical analyses for this end point

Secondary: AUC From Time 0 Extrapolated to Infinity Debio 1143 and Metabolite D 1143-MET1 in Plasma

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End point title

AUC From Time 0 Extrapolated to Infinity Debio 1143 and Metabolite D 1143-MET1 in Plasma ^[31]

End point description

Safety population was defined as subjects who received a dose of any of the study drugs (Debio 1143 and/or CDDP).

End point type

Secondary

End point timeframe

Day 1

Notes
[31] - 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: The endpoint was planned to be reported for the reporting arms Debio 1143 and Debio 1143 + Cisplatin.

End point values	Debio 1143	Debio 1143 + Cisplatin
Number of subjects analysed	13	6
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Debio 1143: Day 1 (n=12,6)	8362.60 ( 61.88 )	8978.54 ( 41.32 )
Debio 1143 Metabolite: Day 1 (n=4,2)	13927.38 ( 37.91 )	12299.59 ( 1.15 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Screening up to 43 days

Adverse event reporting additional description

The safety population included subjects who received a dose of any of the study drugs (Debio 1143 and/or Cisplatin).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Debio 1143

Reporting group description

Subjects were administered Debio 1143 once daily for 15 (± 2) days until surgery, and the last dose was administered on the day of surgery.

Reporting group title

Debio 1143 + Cisplatin

Reporting group description

Reporting group title

Cisplatin

Reporting group description

Cisplatin was administered once weekly on study Days 1 and 8.

Serious adverse events	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	2 / 7 (28.57%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Laryngeal repair
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Debio 1143	Debio 1143 + Cisplatin	Cisplatin
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 13 (92.31%)	6 / 6 (100.00%)	7 / 7 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Dry gangrene
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Hypertension
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Thrombophlebitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 13 (23.08%)	2 / 6 (33.33%)	2 / 7 (28.57%)
occurrences all number	3	2	2
Pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)
occurrences all number	0	0	2
Pyrexia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	0	2
Chills
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Face oedema
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
First bite syndrome
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Hyperthermia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Impaired healing
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Stenosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Bronchial obstruction
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Hypoxia
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 13 (7.69%)	2 / 6 (33.33%)	0 / 7 (0.00%)
occurrences all number	1	2	0
Insomnia
subjects affected / exposed	3 / 13 (23.08%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	3	0	0
Agitation
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Confusional state
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Investigations
Weight decreased
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	0	1	2
Lipase increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	2	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Aspiration tracheal
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Blood creatinine decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Crystal urine
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Limb injury
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Procedural pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Seroma
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Skin flap necrosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Tracheostomy malfunction
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Vasoplegia syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Wound complication
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Tachycardia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	1	0
Dysarthria
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Hypoaesthesia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Neuralgia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Paraesthesia
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
VIIth nerve paralysis
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 13 (30.77%)	1 / 6 (16.67%)	2 / 7 (28.57%)
occurrences all number	5	2	4
Thrombocytopenia
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 13 (7.69%)	3 / 6 (50.00%)	1 / 7 (14.29%)
occurrences all number	1	3	1
Nausea
subjects affected / exposed	2 / 13 (15.38%)	2 / 6 (33.33%)	1 / 7 (14.29%)
occurrences all number	2	2	1
Diarrhoea
subjects affected / exposed	2 / 13 (15.38%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	3	0	2
Dyspepsia
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Leukoplakia oral
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Oral mucosal discolouration
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Oral pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Salivary hypersecretion
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Stomatitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Stomatitis necrotising
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Tooth discolouration
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Toothache
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Vomiting
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	2 / 13 (15.38%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0
Acne
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Pain of skin
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Pruritus
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Rash
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Skin necrosis
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Decreased nasolabial fold
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Fistula
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Neck pain
subjects affected / exposed	0 / 13 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0
Pain in extremity
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Abscess neck
subjects affected / exposed	2 / 13 (15.38%)	0 / 6 (0.00%)	2 / 7 (28.57%)
occurrences all number	2	0	2
Bronchitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	1
Fungal infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Fungal skin infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Postoperative wound infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 13 (7.69%)	1 / 6 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	1	0
Abnormal loss of weight
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0
Hyperkalaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 6 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Apr 2016

• The interim analysis was conducted on the first 8 subjects in the Debio 1143 monotherapy cohort (Step 1) instead of the planned 12 subjects. • Screening period was extended from 14 to 28 days. • Human immunodeficiency virus (HIV)-positive subjects were excluded due to newly published in vitro data suggesting that Smac mimetics may have the ability to reverse HIV-1 latency by activating NF-κB. • Subjects with squamous cell carcinoma of the nasopharynx, nasal cavity, and paranasal sinuses were allowed into the study. • Previously excluded subjects with prior malignancies were allowed into the study provided there was no demonstrated evidence of the recurrence of the disease. • Pancreatic enzyme testing (amylase and lipase) was added following 3 cases of asymptomatic and reversible amylase and lipase increases in subjects receiving Debio 1143 combined with CDDP and radiotherapy in study 2013-000044-25.

04 Apr 2017

• Treatment allocation in Step 2 was modified. Instead of all 12 subjects in Step 2 receiving Debio 1143 in combination with CDDP, the subjects were to be split into two subcohorts of 6 subjects. One cohort of 6 subjects (Step 2a) would receive Debio 1143 in combination with CDDP, and the second cohort of 6 subjects (Step 2b) would receive CDDP alone. The rationale for this change was to better discriminate between the effect due to CDDP alone vs Debio 1143 in combination with CDDP. As a result of these changes, the primary and secondary objectives as well as the corresponding endpoints were updated to include the CDDP monotherapy cohort. This was considered a substantial amendment to the protocol. • Other changes included removing blood sampling for flow cytometry and saliva sampling in Step 2 based on unreliable results from these tests at Step 1 interim analysis. In addition a more sensitive analytical method was implemented for CDDP sample analysis.

19 Jul 2017

• The CDDP monotherapy cohort was removed from the primary objective and primary endpoint. The assessment of cIAP in the CDDP monotherapy cohort was added as a secondary objective and endpoint. • Guidelines for the management of febrile neutropenia/neutropenia were added.

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: Preoperative window-of-opportunity (WoO) study of Debio 1143 with or without cisplatin (CDDP) in patients with resectable 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: Effect of Debio 1143 Alone and Debio 1143 Combined With CDDP on cIAP-1 Levels in Subjects With Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Primary: Effect of Debio 1143 Alone and Debio 1143 Combined With CDDP on cIAP-1 Levels in Subjects With Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Secondary: Change From Baseline in Vital Sign Weight Over Time

Secondary: Change From Baseline in Vital Sign Weight Over Time

Secondary: Change From Baseline in Vital Sign Body Surface Area Over Time

Secondary: Change From Baseline in Vital Sign Body Surface Area Over Time

Secondary: Change From Baseline in Vital Sign Heart Rate Over Time

Secondary: Change From Baseline in Vital Sign Heart Rate Over Time

Secondary: Change From Baseline in Vital Sign Systolic Blood Pressure Over Time

Secondary: Change From Baseline in Vital Sign Systolic Blood Pressure Over Time

Secondary: Change From Baseline in Vital Sign Diastolic Blood Pressure Over Time

Secondary: Change From Baseline in Vital Sign Diastolic Blood Pressure Over Time

Secondary: Eastern Cooperative Oncology Group performance status (ECOG PS) Over Time

Secondary: Eastern Cooperative Oncology Group performance status (ECOG PS) Over Time

Secondary: Number of Subjects with Serious Adverse Events (AEs)

Secondary: Number of Subjects with Serious Adverse Events (AEs)

Secondary: Number of Subjects and Severity of AEs Graded According to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4 Criteria

Secondary: Number of Subjects and Severity of AEs Graded According to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4 Criteria

Secondary: Number of Subjects and Severity of Laboratory Abnormalities Graded According to the NCI-CTCAE v4 Criteria

Secondary: Number of Subjects and Severity of Laboratory Abnormalities Graded According to the NCI-CTCAE v4 Criteria

Secondary: Number of Subjects With Severe Post-operative Bleeding

Secondary: Number of Subjects With Severe Post-operative Bleeding

Secondary: Number of Subjects With Delayed Wound Healing

Secondary: Number of Subjects With Delayed Wound Healing

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Serum Samples

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Serum Samples

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Tumor Samples

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Apoptosis Using Tumor Samples

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Necrosis

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Necrosis

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Proliferation Markers in Tumors

Secondary: Effect of Debio 1143 Alone or Combined with CDDP and CDDP Alone on Proliferation Markers in Tumors

Secondary: Measurement of any Early Biological Response to Debio 1143 Alone or Combined With CDDP and CDDP Alone by 18F-FDG PET

Secondary: Measurement of any Early Biological Response to Debio 1143 Alone or Combined With CDDP and CDDP Alone by 18F-FDG PET

Secondary: Percent Change From Pre-dose for Cytokine and Chemokine

Secondary: Percent Change From Pre-dose for Cytokine and Chemokine

Secondary: Maximum Plasma Concentration (Cmax) of Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Maximum Plasma Concentration (Cmax) of Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Time to Maximum Concentration (Tmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Time to Maximum Concentration (Tmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Area under the plasma concentration-time curve (AUC) on the Dosing Interval Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Area under the plasma concentration-time curve (AUC) on the Dosing Interval Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: T1/2 Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: T1/2 Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Ctrough Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Ctrough Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Average Concentration (Cav) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Average Concentration (Cav) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Ratio Based on Cmax (ARCmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Ratio Based on Cmax (ARCmax) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Ratio Based on AUC (ARAUC ) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Ratio Based on AUC (ARAUC ) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Linearity Index Based on AUC (LIAUC) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Linearity Index Based on AUC (LIAUC) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Index (AI) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Accumulation Index (AI) Debio 1143 and Metabolite D 1143-MET1 in Plasma

Secondary: Apparent Total Body Clearance (CL/F) Debio 1143 in Plasma

Secondary: Apparent Total Body Clearance (CL/F) Debio 1143 in Plasma

Secondary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Debio 1143 Alone

Secondary: Apparent Volume of Distribution During the Terminal Phase (V/F) of Debio 1143 Alone

Secondary: Tumor Concentration Distribution of Debio 1143 Based on an Appropriate Mass Spectrometry Method

Secondary: Tumor Concentration Distribution of Debio 1143 Based on an Appropriate Mass Spectrometry Method

Secondary: AUClast: Free and Total CDDP in Plasma

Secondary: AUClast: Free and Total CDDP in Plasma

Secondary: CL/F: Free and Total CDDP in Plasma

Secondary: CL/F: Free and Total CDDP in Plasma

Secondary: Clast: Free and Total CDDP in Plasma

Secondary: Clast: Free and Total CDDP in Plasma

Secondary: Css: Free and Total CDDP in Plasma

Secondary: Css: Free and Total CDDP in Plasma

Clinical Trial Results:
Preoperative window-of-opportunity (WoO) study of Debio 1143 with or without cisplatin (CDDP) in patients with resectable squamous cell carcinoma of the head and neck.