A Dose-optimization, Exploratory Phase Ib/II Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143, When Given in Combination With the Anti-PD-1 Antibody Nivolumab in Patients With Specific Solid Tumors Who Have Progressed During or Immediately After Anti-PD-1/PD-L1 Treatment
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Debiopharm International SA

Official Title: 
A Dose-optimization, Exploratory Phase Ib/II Study to Assess Safety and 
Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) 
Mimetic Debio 1143, When Given in Combination with the Anti-PD-1 Antibody 
Nivolumab in Patients With Specific Solid Tumors Who Have Progressed 
During or Immediately After Anti-PD-1/PD-L1 Treatment 
NCT Number: 
NCT04122625 
Document Date: 
Protocol Version 4: 07 April 2020 

  
 
 
 
STUDY PROTOCOL 
 
 
SMARTPLUS-106: Debio 1143 a SMAC Mimetic in Combination with Nivolumab in 
Patients Failing Prior PD-1/PD-L1 Treatment: A Basket Trial  
A dose-optimization, exploratory phase Ib/II study to assess safety and efficacy of the Second 
Mitochondrial-derived Activator of Caspases (SMAC) mimetic Debio 1143, when given in 
combination with the anti-PD-1 antibody nivolumab in patients with specific solid tumors who 
have progressed during or immediately after anti-PD-1/PD-L1 treatment 
 
Investigational Medicinal Product (IMP): Debio 1143 
Investigational Medicinal Product (IMP): Nivolumab 
Study Number: Debio 1143-106 
EudraCT Number: 2018-003546-16 
US IND Number: 105074 
 
 
SPONSOR: 
Debiopharm International SA 
Forum "après-demain" 
Chemin Messidor 5-7 
P.O. Box 5911 
 
CH-1002 Lausanne  
 
Switzerland  
 
 
 
Final version No.4, 03 April 2020 incorporating Amendment No. 3 
 
The information in this study protocol is confidential and is provided to potential Investigators 
and their team and to the Institutional Review Board(s) (IRB) / Independent Ethics Committee(s) 
(IEC) reviewing the protocol. No information can be provided to a third party without the written 
agreement of Debiopharm International SA, except medical personnel directly concerned by the 
trial and the patient and their family. 
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TABLE OF CONTENTS 
1. 
INTRODUCTION 
27 
2. 
PHARMACEUTICAL AND BACKGROUND INFORMATION 
27 
2.1. 
Nivolumab ........................................................................................................... 27 
2.2. 
Debio 1143.......................................................................................................... 28 
2.2.1. 
Chemical structure, formula, and molecular weight ............................................ 28 
2.2.2. 
International non-proprietary name, brand name, and code name ..................... 28 
2.2.3. 
Mechanisms of action ........................................................................................ 28 
2.3. 
Brief summary of non-clinical and clinical data .................................................... 28 
3. 
RATIONALE AND RISK BENEFIT ASSESSMENT 
30 
4. 
STUDY OBJECTIVES 
31 
4.1. 
Primary objectives ............................................................................................... 31 
4.1.1. 
Part A ................................................................................................................ 31 
4.1.2. 
Part B ................................................................................................................ 31 
4.2. 
Secondary objectives .......................................................................................... 31 
4.2.1. 
Part A ................................................................................................................ 31 
4.2.2. 
Part B ................................................................................................................ 31 
4.3. 
Exploratory objectives ......................................................................................... 31 
5. 
STUDY DESIGN AND TREATMENT 
32 
5.1. 
Study design ....................................................................................................... 32 
5.1.1. 
Part A ................................................................................................................ 32 
5.1.2. 
Part B ................................................................................................................ 33 
5.2. 
DLT period and definition of DLTs ....................................................................... 34 
5.3. 
Study treatments ................................................................................................. 34 
5.4. 
Dose modifications .............................................................................................. 36 
6. 
STUDY POPULATION 
39 
6.1. 
Inclusion criteria .................................................................................................. 39 
6.2. 
Exclusion criteria ................................................................................................. 40 
6.3. 
Patient replacement ............................................................................................ 42 
7. 
CLINICAL SUPPLIES 
42 
7.1. 
Investigational medicinal products ....................................................................... 42 
7.1.1. 
Debio 1143 ........................................................................................................ 42 
7.1.2. 
Nivolumab ......................................................................................................... 42 
7.2. 
Packaging and storage of IMPs ........................................................................... 42 
7.2.1. 
Packaging ......................................................................................................... 42 
7.2.2. 
Labeling ............................................................................................................. 42 
7.2.3. 
Storage .............................................................................................................. 43 
7.3. 
Dispensing and accountability of IMPs ................................................................ 43 
7.4. 
Patient numbering ............................................................................................... 43 
7.4.1. 
Screening number ............................................................................................. 43 
7.5. 
Blinding and unblinding methods ......................................................................... 43 
7.6. 
Method of administration and compliance ........................................................... 44 
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7.6.1. 
Debio 1143 ........................................................................................................ 44 
7.6.2. 
Nivolumab ......................................................................................................... 44 
7.7. 
Concomitant therapy ........................................................................................... 55 
7.7.1. 
Permitted medications ....................................................................................... 55 
7.7.2. 
Prohibited medications ...................................................................................... 55 
7.7.3. 
Contraceptive measures .................................................................................... 56 
8. 
STUDY ENDPOINTS, ASSESSMENTS, AND PROCEDURES 
57 
8.1. 
Endpoints ............................................................................................................ 57 
8.1.1. 
Primary endpoints ............................................................................................. 57 
8.1.2. 
Secondary endpoints ......................................................................................... 57 
8.1.3. 
Exploratory endpoints ........................................................................................ 58 
8.2. 
Study assessments ............................................................................................. 58 
8.2.1. 
Efficacy .............................................................................................................. 58 
8.2.2. 
Safety ................................................................................................................ 60 
8.2.3. 
Pharmacokinetics .............................................................................................. 61 
8.2.4. 
Pharmacodynamics and predictive biomarkers .................................................. 66 
8.2.5. 
Pharmacogenomics and pharmacogenetics ...................................................... 66 
8.3. 
Study procedures ................................................................................................ 68 
8.3.1. 
Study plan ......................................................................................................... 68 
8.3.2. 
Study discontinuation ........................................................................................ 72 
8.4. 
Study duration and EOS...................................................................................... 74 
9. 
ADVERSE EVENTS 
74 
9.1. 
Definitions and assessment criteria ..................................................................... 75 
9.1.1. 
Adverse event ................................................................................................... 75 
9.1.2. 
Serious adverse event ....................................................................................... 75 
9.1.3. 
Unexpected or expected adverse events ........................................................... 75 
9.1.4. 
Severity of adverse events ................................................................................ 75 
9.1.5. 
Relatedness to IMPs ......................................................................................... 76 
9.1.6. 
Adverse events of special interest ..................................................................... 76 
9.2. 
Reporting of serious adverse events to the Sponsor ........................................... 77 
9.2.1. 
Reporting during the study ................................................................................. 77 
9.2.2. 
Reporting post-study ......................................................................................... 77 
9.3. 
Follow-up of serious adverse events ................................................................... 77 
9.4. 
Procedure for SAE communication ..................................................................... 78 
9.5. 
Pregnancies ........................................................................................................ 78 
10. 
MONITORING AND STUDY COMMITTEES 
78 
10.1. 
Monitoring ........................................................................................................... 78 
10.2. 
Study committees................................................................................................ 78 
10.2.1. 
Data Safety Monitoring Committee .................................................................... 78 
11. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
79 
11.1. 
Sample size ........................................................................................................ 79 
11.2. 
Data management and handling ......................................................................... 79 
11.2.1. 
Data capture, verification and validation ............................................................ 79 
11.2.2. 
Missing data handling for statistical analysis...................................................... 80 
11.3. 
Handling of values below (or above) a threshold ................................................. 80 
11.4. 
Handling of unscheduled assessments or retests................................................ 80 
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11.4.1. 
Derived parameters and endpoints .................................................................... 80 
11.5. 
Selection of patients for statistical analysis ......................................................... 82 
11.5.1. 
RP2D population (part A only) ........................................................................... 82 
11.5.2. 
Safety population ............................................................................................... 82 
11.5.3. 
ITT population ................................................................................................... 82 
11.5.4. 
Efficacy population ............................................................................................ 82 
11.6. 
Statistical analysis ............................................................................................... 83 
11.6.1. 
Part A ................................................................................................................ 83 
11.6.2. 
Part B ................................................................................................................ 83 
11.6.3. 
Interim analyses ................................................................................................ 84 
11.6.4. 
Final analysis ..................................................................................................... 84 
12. 
SPONSOR AND INVESTIGATOR OBLIGATIONS 
88 
12.1. 
Good Clinical Practice and Declaration of Helsinki .............................................. 88 
12.2. 
Institutional Review Board / Independent Ethics Committee ................................ 89 
12.3. 
Informed consent ................................................................................................ 89 
12.4. 
Patient confidentiality .......................................................................................... 89 
12.5. 
Data reporting and electronic case report forms .................................................. 89 
12.6. 
Retention of data ................................................................................................. 90 
12.7. 
Deviations from the protocol/protocol amendments ............................................. 90 
12.8. 
IMP accountability ............................................................................................... 90 
12.9. 
Study monitoring ................................................................................................. 90 
12.10. 
Sponsor audits .................................................................................................... 91 
12.11. 
Regulatory agency inspections ............................................................................ 91 
12.12. 
Publications ......................................................................................................... 91 
12.13. 
Insurance policy .................................................................................................. 91 
12.14. 
Premature study termination ............................................................................... 91 
13. 
REFERENCES 
92 
14. 
APPENDICES 
95 
14.1. 
Appendix A: World Medical Association Declaration of Helsinki .......................... 95 
14.2. 
Appendix B: Prohibited medications and special warnings .................................. 98 
14.3. 
Appendix C: Response to treatment criteria ...................................................... 103 
 
TABLE OF TABLES 
 
Table 1-1 
Schedule of assessments ..................................................................................... 20 
Table 5-1 
Days of treatment for each treatment cycle ........................................................... 35 
Table 5-2 
Study treatment starting doses .............................................................................. 36 
Table 5-3 
Re-treatment criteria ............................................................................................. 37 
Table 7-1 
Treatment modification for symptoms of infusion-related reactions associated with 
nivolumab ......................................................................................................................... 45 
Table 7-2 
Management of immune-related AEs .................................................................... 46 
Table 8-1 
Sampling days and times for PK on Cycle 1 .......................................................... 63 
Table 8-2 
Sampling days and times for PK (for Cycle 3 exclusively, irrespective of nivolumab 
schedule switch) ............................................................................................................... 64 
Table 8-3 
Sampling day and times (for Cycle 6 and EOT exclusively, irrespective of 
nivolumab switch of schedule) .......................................................................................... 65 
Table 8-4 
Sampling days and times for PDy and biomarkers ................................................ 67 
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Table 8-5 
Windows of tolerance for PK, PDy and biomarker samples ................................... 67 
Table 8-6 
Schedule of assessments ..................................................................................... 69 
Table 11-1  
Metrics and corresponding values ..................................................................... 86 
Table 11-2 
Futility Early stopping boundaries ...................................................................... 86 
Table 11-3 
Boundaries for declaring efficacy ....................................................................... 86 
 
 
 
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STUDY SYNOPSIS 
STUDY TITLE  
SMARTPLUS-106: Debio 1143 a SMAC Mimetic In Combination With Nivolumab In 
Patients Failing Prior PD-1/PD-L1 Treatment: A Basket Trial 
A dose-optimization, exploratory phase Ib/II study to assess safety and efficacy of the Second 
Mitochondrial-derived Activator of Caspases (SMAC) mimetic Debio 1143, when given in 
combination with the anti-PD-1 antibody nivolumab in patients with specific solid tumors who 
have progressed during or immediately after anti-PD-1/PD-L1 treatment 
STUDY NUMBER 
Debio 1143-106  
EUDRACT 
NUMBER 
2018-003546-16 
US IND NUMBER 
105074 
STUDY PHASE/ 
INDICATION 
Phase Ib/II / Basket trial in selected solid tumors 
PARTICIPATING 
COUNTRIES AND 
NUMBER OF SITES  
Part A- Up to six active sites in France and Spain  
Part B- In addition to Part A sites, up to 10 sites in the US. 
(Full list to be provided separately) 
STUDY DESIGN 
This study consists of two sequential parts:  
1. Part A: a dose-optimization phase Ib 
2. Part B: an exploratory phase II basket trial 
 
Part A has an open-label, multicenter and dose-optimization design applying the classical 
3+3 method, aiming at optimizing the Debio 1143 dose in combination with standard doses 
of nivolumab (OPDIVO®) in order to define a safe recommended phase II dose (RP2D) and 
to assess its safety and feasibility in pretreated patients with selected advanced/unresectable 
solid tumors, including: small cell lung cancer (SCLC); squamous cell carcinoma of the head 
and neck (SCCHN); known microsatellite instability-high (MSI-H), mismatch repair 
deficiency (MMRd) or other known DNA damage repair (DDR) abnormalities, including 
homologous recombination deficiency (HRD) in gastrointestinal (GI) cancers; known DNA 
MMRd/MSI-H, breast cancer (BRCA)-1/2 hereditary or somatic/sporadic mutations, or other 
DDR abnormalities including HRD in platinum-resistant ovarian, endometrial, primary 
peritoneal or cervical cancers. Patients must have received at least one prior systemic line of 
standard treatment and must have progressed or relapsed during or immediately after a prior 
anti-programmed cell death-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1)-based 
treatment, given either as a single agent or in combination with standard/approved 
chemotherapy, tyrosine kinase inhibitors (TKIs) or other monoclonal antibodies (mAbs) that 
are not known to modulate/inhibit immune checkpoints. Patients with prior cytotoxic T-
lymphocyte antigen 4 (CTLA-4) or lymphocyte activation gene-3 (LAG-3) combinations 
with PD-1/PD-L1 are excluded; any other prior combinations with checkpoint inhibitors 
(CPI) should be discussed and agreed by the Sponsor before patient inclusion. 
Eligible patients will enter the study in cohorts of three evaluable patients.  
The starting dose of Debio 1143 will be 150 mg daily, administered orally for 10 consecutive 
days every 2 weeks (i.e., Days 1-10 and Days 15-24 of each 28-day cycle [q4w]). The dose 
will be optimized according to the observed dose limiting toxicities (DLTs), patient treatment 
compliance, safety/tolerability and pharmacokinetics (PK) data, if applicable. The DLT 
period is defined as Cycle 1 (i.e., lasting 4 weeks or longer in case of dosing delays). 
Treatment-related toxicities fulfilling DLT criteria but occurring after Cycle 1 (i.e., delayed 
DLTs) may also be considered for RP2D definition after discussion and agreement between 
the Investigators and the Sponsor. 
Nivolumab will be administered at 240 mg flat dose over at least 30 minutes as an intravenous 
(IV) infusion on Days 1 and 15 of a 28-day cycle. From Cycle 3, patients may be switched 
to nivolumab at a dose of 480 mg IV over at least 60 minutes on Day 1 q4w, exclusively upon 
Investigator request with the Sponsor agreement.  
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(unconfirmed) rate (ORR) will be used. In each cohort, if no unconfirmed response is observed 
according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or Gynecologic 
Cancer Intergroup (GCIG) criteria (Cohort 4) once the initial 8 evaluable patients have been 
assessed at least twice after baseline or have discontinued their treatment earlier, futility will 
be concluded and the recruitment will be stopped in that cohort. If at least one response 
(unconfirmed) is documented in the initial 8 evaluable patients, recruitment shall continue up 
to 11 evaluable patients. At least two unconfirmed responses must then be observed in these 11 
evaluable patients to continue the recruitment up to 15 evaluable patients in that cohort.  
A homogeneity test will be conducted in any non-futile cohorts showing a confirmed response 
rate of at least 15%. If homogeneous response rates are seen across the cohorts, efficacy data 
will be pooled, and an overall efficacy analysis will be conducted in addition to the analyses by 
cohort. For the final analysis, first proof of efficacy will be claimed in a given cohort if at least 
4 objective responses (confirmed) are reported in the 15 evaluable patients. 
In the case of insufficient accrual in any cohort (e.g., less than 2 patients in 6 months) despite 
concrete measures aiming at increasing the recruitment, enrolment may be stopped in that 
cohort.  
A Data Safety Monitoring Committee (DSMC), composed at least of all actively involved 
investigators (or their designees), the Sponsor Medical Director and the Contract Research 
Organization (CRO) medical monitor as voting members, will meet regularly to overview the 
clinical safety of the patients and laboratory data and the conduct of the study during both study 
parts A and B. Ad hoc members may be invited upon needed.  
During Part A, calls will be scheduled monthly or according to patient recruitment as necessary. 
A charter will be provided as a separate document. 
During Part B the DSMC will meet approximately every three months, and more frequently if 
needed in the event of rapid recruitment. A charter will be provided separately. 
STUDY 
OBJECTIVES 
Primary objectives 
Dose-optimization study (Part A):  
To determine the RP2D taking into account DLT/s in Cycle 1, overall safety/tolerability and 
PK, by optimizing doses of Debio 1143 when combined with the standard dose of nivolumab, 
as well as treatment compliance in patients with advanced solid malignancies who failed prior 
systemic standard treatments. 
Basket trial (Part B):  
To evaluate the preliminary anti-tumor activity of Debio 1143 at the RP2D in combination with 
nivolumab at the standard dose, overall and in each patient cohort.  
Secondary objectives 
Part A:  
1. To assess the PK disposition of Debio 1143 (and its metabolite Debio 1143-MET1) 
and nivolumab when administered in combination. 
2. To assess the anti-tumor activity of Debio 1143 in combination with nivolumab in 
patients with advanced solid malignancies. 
Part B:  
1. To assess the safety and tolerability of the RP2D of Debio 1143 when given in 
combination with nivolumab in patients with advanced solid malignancies.  
2. To assess the PK disposition of Debio 1143 (including its metabolite Debio 1143-
MET1) and nivolumab when administered in combination. 
Exploratory objectives 
 
To explore potential predictive and pharmacodynamic (PDy) biomarkers of 
Debio 1143 and nivolumab when administered in combination, in blood and tumor 
tissue
 
 
 
 
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 
To explore genetic variations in drug metabolism enzyme and transporter (DMET) 
genes associated with differences in the PK disposition of Debio 1143 in 
combination with nivolumab. 
 
To explore the exposure/response relationship for efficacy and safety (including 
PK/PDy correlations, if applicable) of Debio 1143 in combination with nivolumab  
 
To explore correlations between response, clinical parameters, immune correlates, 
and putative biomarkers, 
 
 
To explore the relationship between Debio 1143 plasma concentrations and QTcF 
ENDPOINTS  
Primary: 
Part A: 
 
RP2D of Debio 1143 when combined with the standard dose of nivolumab, in patients 
with advanced solid malignancies who received prior systemic standard treatment and 
failed a prior PD-1/PD-L1-containing treatment, as per DLT occurrence in less than 
one-third of evaluable treated patients at the RP2D dose level.  
Part B:   
 
Confirmed ORR as per RECIST v1.1 and/or GCIG criteria (in Cohort 4, if applicable). 
 
Secondary (for both study parts unless otherwise specified): 
 
Incidence and severity of TEAEs and clinical laboratory abnormalities, according to 
NCI-CTCAE v5.0  
 
Changes in vital signs: systolic/diastolic blood pressure, heart rate (both after at least 
5 minutes of supine rest), temperature, and weight; electrocardiograms (ECG) and 
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 
 
Incidence of premature treatment discontinuations and treatment modifications due to 
TEAEs and laboratory abnormalities (i.e., treatment compliance).  
 
Confirmed (Part A) and unconfirmed (Parts A and B) ORR using standard RECIST 
v1.1 and/or GCIG criteria (Cohort 4, if applicable).  
 
Disease control rate (DCR), defined as any response, partial response (PR) or complete 
response (CR), + stable disease (SD) 
 
Time-related endpoints as median time to response, median duration of response 
(DOR), median progression-free survival (PFS), PFS rate at 6,12 and 18 months, 
median overall survival (OS), OS rate at 12 months and 18 months (if data allow) 
 
PK parameters of Debio 1143 and Debio 1143-MET1, as defined in the available 
population PK disposition model and, if appropriate, post-hoc estimates of areas 
under the curve (AUCs), Cmax, and Cmin; serum concentration versus time profiles of 
nivolumab and, if deemed appropriate, relevant nivolumab PK parameters derived 
from a population PK model. 
Exploratory: 
 
Potential predictive and PDy biomarkers of Debio 1143 combined with nivolumab in 
blood and tumor tissue 
 
 
 
 
Best overall response (BOR) evaluation as per iRECIST criteria 2017 guideline for 
immunotherapeutics 
 
Correlations between PK disposition of Debio 1143 combined with nivolumab and 
clinical response and/or any tumor metrics 
 
Correlations between PK disposition of Debio 1143 combined with nivolumab and 
safety profile, and PDy if applicable 
 
Correlations between Debio 1143 and Debio 1143-MET1 plasma concentrations 
and changes from baseline QTcF. 
 
Correlations between response, clinical parameters, immune correlates and putative 
biomarkers, 
 
 
Genetic variations in DMET genes associated with differences in the PK disposition 
of Debio 1143 in combination with nivolumab 
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STUDY 
POPULATION 
Patients with selected advanced/unresectable or metastatic solid tumors, for whom standard 
therapy has failed, including progression to prior treatments with anti PD-1/PD-L1 given as 
single agent or in combination with standard/approved chemotherapy, TKIs or other targeted 
agents, RT, hormonal therapy or any other non-CPI mAbs, but excluding other antibody or drug 
specifically targeting T-cell co-stimulation or immune checkpoints pathways (i.e., CTLA-4). 
Any other potential CPI combinations previously administered to the candidate should be 
discussed and agreed by the Sponsor before patient inclusion. 
The same indications will be eligible in both study Part A and B. In Part B, separate cohorts are 
defined as follows. 
Part A: 
 
Between 3 and 12 patients evaluable for DLT planned.  
 
Patients will be evaluable for DLT if they received at least 70% of Debio 1143 and 
one planned nivolumab dose during Cycle 1 and were evaluated for DLT or if the 
patient discontinued treatment earlier due to any toxicity that could be considered a 
DLT. 
 
Non-evaluable patients will be replaced, as appropriate. 
 
Part B:  
Cohort 1: SCLC (including extrapulmonary small-cell carcinomas or large cell 
neuroendocrine lung carcinoma, as per WHO Classification of Lung Tumors of  2015)1 
Cohort 2: SCCHN (nasopharyngeal carcinomas are excluded) 
Cohort 3: GI cancers (including esophageal, gastric, colorectal or pancreatobiliary) with 
known MSI-H/MMRd or other DDRs abnormalities, including HRD.  
Cohort 4: platinum-resistant EOC, endometrial cancer, PPC or cervical cancer, with known 
MSI-H/MMRd, hereditary/somatic mutations of the BRCA1 and BRCA2 genes or other 
DNA DDR abnormalities (incl. HRD).  
 
Between 32 (if all cohorts are futile) and 60 evaluable patients (if none of the 4 cohorts 
is futile). 
 
Patients will be evaluable for efficacy if the two conditions below are met: 
a. 
Measurable disease at baseline as per RECIST v1.1 or GCIG criteria (Cohort 
4), 
b. At least one efficacy assessment done, either computed tomography (CT) or 
magnetic resonance imaging (MRI) for RECIST evaluable patients; or CA-
125 dosage performed after baseline, if applicable or treatment 
discontinuation occurred before the efficacy assessment is done due to 
treatment failure, defined as any of the following: death, unacceptable 
toxicity, clinical deterioration and/or symptoms worsening. 
 
Non-evaluable patients will be replaced. 
 
INCLUSION 
CRITERIA 
The same tumor types are eligible in Part A and B. 
 
Patients must fulfill all the following criteria (in both Parts A and B, unless specified otherwise): 
 
1. Willing and able to sign a written informed consent form;  
2. Male or female ≥18 years of age. 
3. Histologically and/or cytologically confirmed advanced/ unresectable or metastatic 
solid tumor, for one of the following indications. 
a. 
SCLC 
b. SCCHN (nasopharyngeal carcinomas are excluded) 
c. 
GI cancers, including esophageal, gastric, colorectal or pancreatobiliary with 
known MSI-H/MMRd or any other known DDRs abnormalities, including 
HRD  
d. Platinum-resistant* EOC, endometrial cancer, PPC or cervical cancer, with 
known MSI-H/ MMRd, hereditary/somatic mutations of the BRCA1 and 
BRCA2 genes or other known DNA DDRs abnormalities (incl. HRD)  
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* Platinum-resistant is defined as relapse or progressive disease (PD) 
occurring within 1 to 6 months (180 days) after a platinum-containing 
chemotherapy.  
4. Have received at least one prior line of standard systemic chemotherapy in the 
advanced/unresectable cancer setting (standard adjuvant/neoadjuvant treatment is 
acceptable if relapse occurred within six months of treatment end) and have no 
established standard therapeutic alternatives 
5. Have progressed or relapsed during or after a prior anti-programmed cell death-1 (PD-
1)/ programmed cell death-ligand 1 (PD-L1)-based treatment, given either as a single 
agent or in combination with standard/approved chemotherapy, tyrosine kinase 
inhibitors (TKIs), radiotherapy (RT) or other monoclonal antibodies (mAbs) that are 
not known to modulate/inhibit immune checkpoints (CPIs). 
6. Minimum washout periods since prior therapy until treatment start (C1D1) (in cases 
of more than one prior treatment type, whichever has the longest minimum period 
applies):  
a. 
3 weeks for chemotherapy (6 weeks, specifically for nitrosoureas or 
mitomycin C containing regimens)  
b. 4 weeks for any prior mAbs or live vaccines; for investigational mAbs 4 
weeks or at least the duration of one treatment cycle whichever is longest  
c. 
3 weeks for prior RT (1 week in case of localized antalgic/hemostatic 
hypofractionated RT flash)  
d. 2 weeks for TKIs, hormonal therapy, other anti-cancer treatment not 
previously specified or investigational agents 
e. 
4 weeks for any major surgery  
f. 
Immunosuppressive medication: within 2 weeks, with the exception of 
intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological/replacement doses, which should never exceed 10 mg/d 
prednisone, or an equivalent corticosteroid 
7. Measurable disease (Part B only) according to RECIST v1.1 and/or GCIG criteria in 
Cohort #4 (if applicable) and documented PD during or after prior PD-1/PD-L1 based 
therapy 
8. ECOG Performance Status = 0 or 1  
9. Adequate hematologic, renal and hepatic function: 
a. 
absolute neutrophil count (ANC) ≥ 1.5 x109/L,  
b. platelets ≥ 100 x109/L,  
c. 
hemoglobin ≥ 9.0 g/dL,  
d. AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases are present)   
e. 
total bilirubin ≤ 1.5 x ULN,  
f. 
serum creatinine ≤ 1.5 x ULN, 
g. serum albumin ≥ 30 g/L 
10. Available archived tumor samples for biomarker analysis obtained after prior PD-
1/PD-L1 treatment failure or, if no archived tumor sample is available, patient must 
be suitable and willing to undergo a percutaneous or endoscopic biopsy without 
unacceptable major risks before starting study treatment 
11. Participants with known central nervous system (CNS) and/or meningeal involvement 
will be eligible if they are clinically asymptomatic, have completed primary CNS 
therapy more than 4 weeks before treatment start (such as whole brain RT, stereotactic 
radiosurgery, or complete surgical resection), and have remained off steroids 
(including tapering doses) for at least 2 weeks 
12. Women of child-bearing potential (WOCBP): 
a. 
Negative serum pregnancy test at screening; 
b. Agreement to use highly effective contraception methods from study entry 
and for up to 5 months after the last day of study treatment 
c. 
Agreement from her male partner to use contraception methods 
13. Male patients with WOCBP partners must agree to use highly effective contraception 
methods from study entry and for up to 5 months after the last day of study treatment 
 
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EXCLUSION 
CRITERIA 
Patients must NOT fulfill any of the following criteria (in both Parts A and B, unless specified 
otherwise): 
 
1. Thoracic or head and neck radiation >30 Gy within the 6 weeks prior to C1D1 
2. Have received, in total, more than 3 (i.e. Cohorts 1&2) or 4 (i.e. Cohorts 3&4) lines 
of prior systemic treatments (including adjuvant or neoadjuvant regimens if relapse 
within six months prior to C1D1) 
3. Active moderate alcohol consumption, at screening, more than 100/140 grams 
(3.5/4.9 ounces) of alcohol per week for female/ male patients, respectively 
4. Liver cirrhosis Child-Pugh score B or C 
5. Prior treatment with an anti-CTLA-4 or anti-LAG3 in combination with PD-1/ PD-
L1 CPI, unless discussed and agreed with the Sponsor 
6. Prior treatment with SMAC mimetics 
7. Prior PD-1/PD-L1 discontinuation due to severe immune-related toxicity, not 
resolved upon adequate steroids/immunosuppressive treatment 
8. Requirement of concomitant treatment with any prohibited medication (See 
Appendix B: Prohibited medications and special warnings) 
9. Ongoing toxicity from prior administration of any other investigational drug and/or 
anti-cancer treatment of > Grade 1 NCI-CTCAE v5.0 before treatment start (except 
for grade 2 alopecia, stable sensory neuropathy, vitiligo or any endocrinopathy 
adequately managed by replacement hormonal therapy)  
10. Patients with known history of: 
a. 
Uncontrolled or symptomatic angina or myocardial infarction, within the 
last 12 months prior to C1D1 
b. Elevated (>ULN) troponins (T or I) or creatine phosphokinase (CPK) > 
1.5xULN during screening 
c. 
Symptomatic intestinal sub-occlusion 
d. Infection, active or latent by human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) and hepatitis C virus (HCV) 
e. 
Ongoing arrhythmias requiring treatment, including asymptomatic QTc 
interval as corrected by Fridericia (F) >480 msec  
f. 
In patients previously treated with anthracycline-containing chemotherapy 
or thoracic RT, non-adequate cardiac function with left ventricular ejection 
fraction (LVEF) <50%, measured by an echocardiogram (ECHO) or a 
multigated acquisition (MUGA) as per institutional standards 
g. Active rheumatoid arthritis, active inflammatory bowel disease (IBD), 
primary sclerosing cholangitis, autoimmune hepatitis, systemic lupus 
erythematous (SLE), multiple sclerosis or any other ongoing autoimmune 
disease requiring systemic treatment (excluding vitiligo, mild cutaneous 
psoriasis and asymptomatic autoimmune endocrinopathy well controlled 
under hormonal replacement therapy) 
h. Evidence of active, non–infectious pneumonitis or a history of interstitial 
lung disease 
i. 
Active ongoing infection requiring systemic antibiotic therapy, including 
active tuberculosis  
11. Evidence or clinical suspicion of active bleeding or requirement of red blood cell 
(RBC) transfusions within 2 weeks prior to C1D1 
12. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Debio 1143 or nivolumab or their constituents 
13. History of another non-metastatic, low grade malignancy other than the primary 
tumor within the last 1 year prior to C1D1, except: completely resected non-
melanoma skin cancer, second SCCHN tumors, completely resected minimally 
invasive bladder cancer, low grade prostate cancer, if Prostate-specific antigen (PSA) 
≤ 10 ng/mL; non-metastatic localized low grade renal cell carcinoma (RCC) or any 
previous (non-synchronous) malignancy if related to germ-line mutations linked to 
either MSI-High (lynch syndrome) or BRCA-1/2 hereditary cancer syndromes, for 
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patients included either in cohort 3 or 4. For these indications there are no time 
restrictions with regard to their occurrence prior to C1D1.  
14. Pregnant or lactating females 
15. Unable to swallow or retain oral medications 
16. Known contraindication to contrast-enhanced MRI and CT 
17. Patient unwilling or unable to comply with study visits/assessments 
 
DLT PERIOD AND 
DEFINITION OF 
DLTS 
The DLT period is defined as Cycle 1*.  
DLT is defined as any of the following treatment-emergent adverse events (TEAEs) which 
are possibly, probably or definitely related to the combination treatment and occurring in 
Cycle 1 (1 cycle=4 weeks): 
 
Any Grade 4 or 5 hematologic toxicity, clinical or laboratory non-hematologic 
toxicity 
 
Febrile neutropenia any grade, Grade 3 thrombocytopenia if associated with bleeding 
or requiring platelet transfusion 
 
Grade 2 or higher cardiac or neurologic toxicities, pneumonitis that does not resolve 
within 3 days after starting steroids at adequate doses or that was recurrent upon 
steroid tapering or withdrawal, myasthenia gravis, myositis, polymyositis, Guillain-
Barre syndrome (excluding peripheral purely-sensory neuropathies) 
 
Grade 2 or higher alanine transaminase (ALT)/ aspartate transaminase (AST) 
increase with a concurrent increase of total bilirubin ≥2 x upper limit of normal 
(ULN) and concurrent with alkaline phosphatase (ALP) ≤2 x ULN (Hy’s law), in the 
absence of objective causes of biliary obstruction due to obvious disease-related 
causes 
 
Any other Grade 3 non-hematologic, treatment-related clinical toxicity lasting 3 or 
more days despite optimal supportive care, or requiring admission for appropriate 
medical management; hypersensitivity and/or infusion-related reactions are excluded 
if not reoccurring after appropriate pre-medication and/or prolonging infusion time 
 
Grade 3 non-hematologic laboratory value (excluding lipase, amylase and/or 
autoimmune endocrinopathies manageable by replacement therapies) if: 
a. 
Symptomatic and 
b. Medical intervention was promptly required to treat the patient, or 
c. 
The abnormality led to hospitalization or 
d. The abnormality did not resolve to at least Grade 1 within 2 weeks 
(including the steroid tapering period) despite adequate medical 
intervention/treatment  
 
A delay of >2 weeks due to drug-related toxicity in initiating Cycle 2   
 
Unable to complete at least 70% of the scheduled treatment, i.e., more than six 
Debio 1143 skipped doses in Cycle 1 due to treatment-related toxicity 
 
Required dose reduction in Cycle 1 or on Cycle 2 Day 1 or requirement for treatment 
withdrawal due to treatment-related toxicity (even if not meeting other DLT criteria) 
 
* Any toxicity fulfilling one or more of these criteria but occurring from C2D1, may be 
defined as delayed DLTs after discussion and agreement between Principal Investigators 
(PIs), DSMC and the Sponsor, and may be considered for RP2D definition, if appropriate. 
INVESTIGATIONAL 
MEDICINAL 
PRODUCTS, DOSE 
AND MODE OF 
ADMINISTRATION 
Investigational products:  
 
Debio 1143 capsules (75 and 100 mg), as bottles of 10 capsules each, oral route.  
 
Nivolumab (OPDIVO®) 10 mg/mL concentrate for solution for infusion, intravenous 
route (IV). 
Oral Debio 1143 will be administered at a starting dose of 150 mg/d on Days 1-10 and Days 
15-24 every four weeks (q4w). One dose increment of 50 mg (i.e. to 200 mg/d) is planned for 
the subsequent dose level. No dose escalation beyond 200 mg/d is foreseen in this study. In 
individual cases of severe toxicity or DLT, the Debio 1143 dose will be reduced by a maximum 
of up to two reductions of 50 mg each, and to a minimum dose of 100 mg/d.  
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Debio 1143 will be administered on site on D1 and D15, immediately before nivolumab. 
Remaining daily doses are to be taken by the patient at home following relevant medical 
instructions, except on days where PK samples are planned, during the first cycle, and the third 
cycle. Administration compliance will be recorded in a patient diary which will be supplied as 
a separate document.  
Nivolumab will be administered, as per current prescribing information, at a dose of 240 mg, 
flat dose by IV infusion over at least 30 minutes on Days 1 and 15, q4w (i.e., 2 infusions per 
cycle). From Cycle 3 on, patients may be switched to nivolumab infusion at a dose of 480 mg 
over at least 60 minutes on Day 1 exclusively q4w (i.e., 1 infusion per cycle), upon the 
Investigator’s request and Sponsor approval. Neither lower nor higher doses of nivolumab will 
be explored; dose reduction or increase will not be allowed.  
Infusion of nivolumab will be stopped in case of Grade ≥2 hypersensitivity, inflammatory 
response, or infusion-related reactions. Infusions may be resumed after Grade ≤2 events upon 
resolution of the events within less than 4 hours and after medical assessment and agreement 
by a qualified Investigator. Infusion duration will not be shorter than 120 minutes after 
resumption in all subsequent infusions. Treatment will be withdrawn definitively after the 
occurrence of any Grade ≥3 infusion-related reactions, hypersensitivity or cytokine-release 
syndrome. Appropriate standard measures must be in place for the medical management of the 
patients under these circumstances. 
Formal premedication is not required. However, premedication might be used after C1D1 
administration, if needed on an individual patient basis, per clinical judgment and local 
institutional guidelines, as appropriate.  
TREATMENT 
DURATION 
Participants are planned to be treated with Debio 1143 and nivolumab for up to 52 weeks (13 
cycles), until any of the following events occurs: symptomatic PD, asymptomatic but confirmed 
PD (as per iRECIST), unacceptable toxicity per Investigator judgment and despite up to two 
dose adjustments, patient withdrawal, or treatment delay greater than 4 and 8 weeks (+1 week 
tolerance) for Debio 1143 and nivolumab, respectively.  
Permission to prolong the study treatment for one additional year can be exceptionally granted 
by the Sponsor, if patients are deriving continuous clinical benefit from the study treatment. 
Medical justification for extending the treatment and the assessment of the risk/benefit balance 
must be provided by the Study Investigator and will be discussed with the Sponsor. The 
decision to further extend study treatment will be re-evaluated on a yearly basis for each patient. 
Re-treatment criteria are listed in Table 2.  
From Cycle 2, if a patient does not meet the requirements for treatment continuation on Day 1 
of any cycle, both study drugs will be withheld until recovery or for a maximum of 4 and 8 
weeks (+1 week tolerance window) for Debio 1143 and nivolumab, respectively. After this 
delay-period, the patient should withdraw from treatment. 
If a patient does not meet the requirements for treatment continuation on any days other than 
D1 (D2-10 or D15-24), treatment will be immediately interrupted and the corresponding Debio 
1143 dose (and nivolumab if on D15) will be omitted. Patients should be re-assessed (ideally 
every 48-72 hours, if clinically indicated) and treatment will only be resumed after all re-
treatment criteria are met. 
All patients who withdraw from treatment for any reason will be followed for safety up to 
5 months (± 15 days) after the last nivolumab infusion, complete resolution or stabilization of 
any ongoing toxicity, unless the patient starts a new treatment, end-of-life-care or withdraws 
consent. 
If for any reason, treatment with nivolumab is temporarily withheld, Debio 1143 may be 
continued; however, at any time, and regardless of the reason, if nivolumab is permanently 
discontinued then Debio 1143 must also be withdrawn. If for any reason Debio 1143 is withheld 
temporarily, nivolumab will also be withheld until treatment may be resumed. Patients will not 
receive any further nivolumab infusions during the study until Debio 1143 treatment is 
resumed.    
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After PD or start of any new cancer treatment, follow-up for overall survival (OS) will be 
collected, by telephone, email or mail every 4 months (± 1 month) until the end of the Main 
study period.  
There will be up to two visits planned for screening and at least two treatment visits per cycle 
on D1 and 15 up to Cycle 3, then at least one treatment visit from Cycle 4 onwards if 
applicable, plus one EOT ± follow-up visit, as applicable. The total number of onsite visits 
per patient will depend on the total number of cycles delivered which is based on disease 
progression status, clinical deterioration, start of new cancer treatments or end-of-life care or 
death whichever occurs first.  
STUDY VISITS & 
ASSESSMENTS 
Cf. Figure ‘Study plan’ and Table ‘schedule of assessments’  
STUDY PERIOD 
First patient included (FPI): ~ Q1-2019 
Dose optimization part: ~ 3 months 
FPI Basket trial part: ~ Q2-2019 
 
 
 
 
 
Assessment of the primary clinical endpoint for futility: ~ 6-9 months after FPI 
Complete accrual in non-futile indications: ~ 3-9 months (according to results)  
Accrual period: ~ from 9 to 18 months (depending on futility assessments) 
 End of the Main study period: 18 months after LPI or 60 days after last patient last visit 
(LPLV), whichever occurs first   
Extended study period: Only for patients treated beyond 13 cycles. Starts after the Main study 
period and lasts until LPLV. 
End of study (EOS): End of Main study period or End of Extended study period, whichever 
occurs last. 
Final analysis (Final CSR): within 1 year of end of the Main study period. Data collected 
during the Extended study period will be summarized in an addendum to the Final CSR, after 
the End of Extended study period.   
 
STATISTICAL 
METHODS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample size 
Part A:  The sample size will be determined by the number of patients included per dose level 
and the observed toxicities. Given that (i) a maximum number of two dose levels will be 
explored, (ii) a classical 3+3 design will be used and (iii) at least 6 evaluable patients need to 
be treated at the RP2D before the phase II part starts formally, between 3-12 evaluable patients 
will be included.  
Part B: Up to 15 evaluable patients will be included in each of the 4 cohorts. In case of no 
early stopping due to futility and no patient replacement, the total sample size will be 60 
patients. 
 
Randomization  
Not applicable 
 
Statistical analysis 
Part A: There will be no formal interim analysis during dose-optimization, only a review of data 
when dose increase, repeat or reduction is to be decided at DSMC meetings. The statistical 
analysis of Part A will be mostly descriptive unless otherwise specified.  
Part B: The efficacy of Debio 1143 in combination with nivolumab will be tested in each cohort 
by using the Bayesian posterior probability with early stopping rules for futility. The primary 
efficacy endpoint will be the confirmed ORR based on RECIST v1.1 and/or GCIG (Cohort 4), 
if applicable. However, for the futility stopping rules the unconfirmed ORR will be used. The 
cut-off for the futility analyses is defined as the time when the last ongoing patient from the first 
8/11 evaluable patients has performed at least 2 post-baseline tumor assessments or prematurely 
discontinued. The number of patients included in the interim analyses and the futility boundaries 
were defined assuming an unconfirmed ORR of 17%, a futility response rate of 5%, a maximum 
sample size of 15 patients by cohort and a probability confidence threshold for futility of 20%. 
The futility stopping boundaries are defined as follows: 0 response out of 8 evaluable patients 
for the first interim analysis and ≤1 response out of 11 evaluable patients for the second interim 
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analysis. Consequently, if no unconfirmed response is documented as per RECIST v1.1 and/or 
GCIG (Cohort 4, if applicable) after the 8th patient is assessed, futility will then be concluded, 
and recruitment will be stopped in the corresponding cohort. If at least one unconfirmed 
response is documented in the first 8 patients, recruitment shall continue up to 11 patients when 
a second futility analysis will be conducted. If at least two unconfirmed responses are 
documented in the first 11 evaluable patients, recruitment will continue up to 15 evaluable 
patients; otherwise the recruitment will be stopped. For the final efficacy assessment in each 
cohort, first proof of efficacy will be claimed if at least 4 confirmed responses are reported in 
the 15 evaluable patients. This efficacy boundary was derived assuming a confirmed ORR of 
15% and a probability confidence threshold of efficacy of 80%. 
No formal interim analysis will be performed during the futility monitoring. Only the number 
of patients with unconfirmed responses as per RECIST v1.1 or GCIG criteria will be checked 
vs. the futility boundaries in each cohort independently.  
The final analysis including all the study endpoints will be performed at the end of the Main 
study period. A homogeneity test will be conducted in the non-futile cohorts showing a 
confirmed response rate of at least 15%. 
 
In case of homogeneous response rates across the cohorts, efficacy data will be pooled and an 
overall efficacy analysis will be conducted in addition to the analyses by cohort. Otherwise, 
efficacy will only be reported by cohort. All other endpoints such as demographics, baseline 
characteristics, safety, PK, PDy etc. will be presented overall and for each cohort. In case of 
promising efficacy results, further confirmatory trials will be then envisaged. 
 
Efficacy analysis 
Efficacy analysis will be conducted in the efficacy and ITT populations (as defined in section 
11.5.4). The main efficacy analysis will be conducted in the efficacy population. 
ORR, immune-related BOR, and DCR will be presented using contingency tables. Time-to-
response, DOR, PFS and OS medians and rates will be determined using the Kaplan-Meier 
method.  
 
Safety analysis 
Safety analysis will be conducted in the Safety population (as defined section 11.5.2). 
TEAEs including those related to study drugs, TEAEs by severity (according to the NCI-
CTCAE v5.0 criteria), TEAEs leading to treatment discontinuation and serious adverse events 
(SAEs) will be summarized by system organ class (SOC) and preferred term (PT) overall and 
by dose (Part A) and by cohort (Part B). 
Data of safety laboratory parameters, vital signs, ECG and ECOG-PS will be presented using 
descriptive statistics. Shift tables and scatter plots will be provided.  
 
PK analysis 
Plasma/serum concentrations and PK parameters will be presented individually and by 
descriptive statistics. Graphic displays of plasma concentration vs. time curves will be presented 
individually by patient and as arithmetic and geometric means. Pharmacokinetic parameters will 
be presented by patient and summarized by dose (Part A) and cohort (Part B) and overall as 
descriptive statistics. They will also be derived by population PK data.  
The relationship between PK disposition and clinical response, PDy, safety and genetic 
variations in DMET genes will be analyzed by regression methods or association analyses. 
These relationships will also be evaluated in a dedicated Exposure/Response by population 
analysis approach where data from several clinical studies with Debio 1143 will be pooled. Such 
evaluation will be described in a separate report. 
Pharmacodynamics analysis 
Pharmacodynamics will be presented at baseline and at any scheduled visit with the 
corresponding fold changes (log2) from baseline by using descriptive statistics. The maximum 
increase while on-treatment will be similarly presented, along with its fold change from 
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baseline. 
Graphics displaying PDy parameters absolute values and fold changes from baseline will be 
presented as individual curve and mean (±standard deviation) curve vs. time.  
Exploratory analyses will be conducted to investigate the relationship between PDy biomarkers, 
efficacy and safety parameters by using regression methods. 
 
Pharmacogenetic factors/predictive biomarker analysis 
Pharmacogenetic factors and predictive biomarkers assessments will be exploratory. The 
correlation between efficacy, pharmacogenetic factors and predictive biomarkers will be 
analyzed by regression methods. 
 
 
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*  Examinations should be performed in the following order as applicable: physical examination, vital signs, ECG, safety blood/urine samples, followed by blood sampling for PK/PDy according to specific 
instructions, and other examinations: Note: ECGs always have to be taken before PK/PDy sampling. 
 
Assessments should be performed on schedule, but occasional changes may be allowed. If the study schedule is shifted, both assessments and dosing must be shifted to ensure the collection of data is 
completed prior to dosing. Windows:  Laboratory assessments and clinical examinations: Screening period: -4 days (i.e., day -32); EOT visit: ±5 days; follow up visits ±1week, in case of holidays, vacations; 
other administrative reasons: ± 3 days in all cycles. Window for CT/MRI assessment = ± 1 week 
#  
Assessments for concomitant medications, pregnancy test and AEs will be performed only at the first two FU visits, if applicable. CT scan or MRI assessments will be performed until confirmed iRECIST 
PD, symptomatic PD or any new anticancer treatment or end-of-life hospice care is started or until EOS whichever occurs first.  
µ  
Height only collected at screening. 
1  
Digital triplicate 12-lead ECGs will be recorded after 10 minutes of supine rest at the following 3 time points: pre-, 0.5-2h Debio 1143 post-dose (before starting the nivolumab infusion or after nivolumab 
perfusion was removed)  and 4-6 h post-dose ;There should be at least 1 minute between each ECG and all 3 ECGs should be completed within 10 minutes or less. ECG readings must be performed before 
PK/PDy sampling. ECG reading will be done centrally and also locally for screening purposes. 
2  
Pre-dose (as per section 8.2.2.5) only required if screening test were performed > 7 days prior to C1D1 or if inclusion/exclusion criteria were not met during screening:  
2a  HIV, HCV and HBV serology testing and CPK and Troponins (I or T whichever is applicable): Only at screening, to be repeated if clinically indicated only. 
2b  FSH/LH and total testosterone (in male) or estrogens (in female patients), free-cortisol (at morning) and ACTH: Only at screening and to be repeated if clinically indicated.  
2c  Hemoglobin, hematocrit, platelets and complete blood cell count and differential counts, creatinine, sodium, potassium, calcium, total bilirubin (if >ULN, then also measure direct bilirubin), ALP, 
AST, ALT,  amylase, lipase, LDH, total protein, albumin, CRP.  
2d 
Part A patients (only): Total bilirubin (if >ULN, then direct bilirubin should also be measured), ALP, AST, ALT, and creatinine. 
2e  
TSH, FT3 and FT4: At Day 1 and Day 15 in Cycle 1 and every Day 1 of each subsequent cycle. 
2f  CA-125 to be performed at screening within 4 weeks of C1D1, exclusively in applicable patients included in Cohort 4, and to be repeated before start of each new cycle if abnormally elevated 
before treatment start, unless PD, any new anticancer treatment or end-of-life hospice care is started before. 
3  
In women of childbearing potential only: blood test at screening (only required if screening test were performed > 7 days prior to C1D1), then urine dipstick test alone would be sufficient, at the beginning 
of each treatment cycle while on study up to 5 months after EOT.  
4  
Every 8 weeks (±1 week) from first on-treatment scan until Cycle 10, then from Cycle 13, every 12 weeks (± 1 week) until confirmed iRECIST PD, symptomatic PD or any new anticancer treatment or end-
of-life hospice care is started or until the end of the Main study period, whichever occurs first. For patients who continue study treatment in the Extended study period, tumor response assessments will be 
performed at the frequency of local institutional care practice until EOT. All patients will have CT or MRI at the time of disease progression, if none previously available. CT or MRI done before screening, 
as part of patient’s standard of care and not older than 8 weeks (+1 week tolerance) before C1D1 can be used instead of repeating a new assessment at screening even if done before ICF signature with 
patient specific agreement, if deemed clinically appropriate by the Investigator. 
 
A contrast enhanced brain CT or MRI is mandatorily at baseline only in SCLC cohort, subsequent brain scans to be done if clinically indicated. 
5  
Up to 3 tumor tissue samples will be collected:  
1) An archived biopsy at diagnosis (before prior PD-1/PD-L1 therapy) = optional;  
2) An archived biopsy if collected after prior PD1/PD-L1 or, if not available a fresh biopsy collected at screening will be mandatory;  
3) A fresh biopsy collected at end of Cycle 2 (day 28=Day 1 of the following cycle) = optional 
6  
Timepoints as specified in Table 8-1, Table 8-2 and Table 8-3 and windows of tolerance as specified in Table 8-5.  
6a  
Patients included in Part A only. 
6b  
Debio 1143 PK, nivolumab PK, and nivolumab ADA sample at C6D1 only. In addition, for patients discontinuing the study at the end of the Main study period, the last nivolumab ADA will be 
collected at EOT, and for patients entering the Extended study period, the last nivolumab ADA will be collected at C13D1 instead of at EOT. 
7  
Timepoints as specified in Table 8-4 and windows of tolerance as specified in Table 8-5.   
7a Only at Cycle 6: PGx ctDNA. 
8  
Debio 1143 will be taken orally on D1-10 and D15-24 on an empty stomach (patients will fast for 2 h before dosing and for at least 1 h after dosing) at approximately the same time each day. Water is 
permitted freely. A missed dose can be taken as soon as the patient remembers but no later than 6 h after the planned dose. If >6 h have elapsed, the missed dose should be skipped and the next dose taken 
according to the regular dosing schedule. A double dose should not be taken to make up for a missed dose. Debio1143 will be  given in the hospital (before nivolumab infusion whenever is applicable) 
during: Cycle 1 on Days 1,3 (only Part A), 8, 15, 17 (only Part A), 22; Cycle 2 on Days 1 and 15; Cycle 3 on Days 1, 3 (only Part A) , 15, and 17 (only Part A); and on Days 1 ± 15  of all subsequent cycles. 
The rest of the days will be taken at home following relevant medical instructions. A patient’s diary to record treatment compliance will be provided as a separate document and it will be reconciled with 
the returning capsules by the study nurse. 
9  
Nivolumab will be administered, as per current prescribing information, at a dose of 240 mg, flat dose by IV infusion over at least 30 minutes on Days 1 and 15, every 4 weeks (i.e., 2 infusions in each 
cycle). 
9a  From Cycle 3 on, the switch to an administration of 480 mg of nivolumab only on Day 1 of each 28-day cycle is allowed based on the Investigator’s judgment and Sponsor’s agreement. 
± Dispensing of nivolumab will depend on the nivolumab schedule administered from Cycle 3 onwards.   
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10  
Continuous AE monitoring, with Investigator’s assessment and documentation at scheduled study visits up to EOT visit and second follow up visit, if applicable. The SAE reporting period is up to 5 months 
after the last nivolumab administration. Patients continuing in follow-up (FU) after EOT, in the first and/or second FU visits will have final AEs update of any ongoing toxicity at this time, if applicable, 
unless start of new anticancer treatment or end-of-life-care, in which case visit should be scheduled ideally before. 
 11     For Part B, visits on Cycle 1 and Cycle 3 on Days 3 and 17 will not be performed 
12    Including information on current and previous tobacco and alcohol use/consumption 
13    Only applicable for patients treated beyond Cycle 13
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LIST OF ABBREVIATIONS 
ACC 
American College of Cardiology  
ACTH 
adrenocorticotropic hormone  
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AHA 
American Heart Association 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase 
AMV 
assisted mechanical ventilation 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical  
AUC 
area under the curve 
BAL 
Bronchoalveolar lavage 
BOR 
best overall response 
BP 
blood pressure 
bpm 
beats per minute 
BRCA 
breast cancer  
C 
cycle 
CA-125 
carbohydrate antigen 125 
CAS 
Chemical Abstract Service  
CBCDA 
Carboplatin  
CD4+ / CD8+ 
cluster of differentiation 4/8 
CI 
confidence interval 
CNS 
central nervous system 
CPI 
checkpoint inhibitors 
CPK 
creatine phosphokinase  
CR 
complete response 
CRA 
clinical research associate 
CRO 
contract research organization 
CRP 
C-reactive protein 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte antigen-4 
CV 
coefficient of variation 
CYP  
cytochrome P450  
D 
day 
DCR 
disease control rate 
DDR 
DNA damage repair 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DLT 
dose limiting toxicity 
DMET 
drug metabolism enzymes and transporters 
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DOR 
duration of response 
DPI 
DSMC 
Debiopharm International SA 
data safety monitoring committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECL 
electrochemiluminescence 
ECOG-PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOC 
epithelial ovarian cancer 
EOS 
end of study 
EOT 
end of treatment 
ESC 
European Society of Cardiology 
FPI 
first patient included 
FSH 
follicle-stimulating hormone 
FT3 
free tri-iodothyronine 
FT4 
free thyroxine  
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyl transferase 
GH 
growth hormone 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
HBV 
hepatitis B virus  
HCV 
hepatitis C virus 
HIV  
human immunodeficiency virus  
HRD 
homologous recombination deficiency 
IAP 
inhibitor of apoptosis  
IBD 
inflammatory bowel disease  
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor 1  
IgG4 
immunoglobulin G4 
IL-8 
interleukin 8 
IMP 
investigational medicinal product 
INN 
International Non-proprietary Name 
IRB 
Institutional Review Board 
ITT 
intention-to-treat  
IUD 
intrauterine device  
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IVIG 
intravenous immunoglobulins 
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LAG-3 
lymphocyte activation gene-3  
LDH 
lactate dehydrogenase  
LH 
luteinizing hormone 
LOQ 
limit of quantification  
LPI 
last patient-in 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody  
MCP-1 
monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRd 
mismatch repair deficiency  
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high  
MTD 
maximum tolerated dose  
MUGA 
multigated acquisition 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events  
NFκB 
nuclear factor κB  
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-ligand 1  
Pdy 
pharmacodynamic  
PFS 
progression-free survival 
PGx 
pharmacogenomics 
PGt 
pharmacogenetics 
PI 
principal Investigator 
PK 
pharmacokinetics 
PPC 
primary peritoneal cancer 
PR 
partial response 
PRL 
PSA 
prolactin 
Prostate-specific antigen 
PT 
preferred term 
qxw 
every x weeks 
QTcF 
QTc interval as corrected by Fridericia 
RBC 
red blood cells 
RCC 
renal cell carcinoma  
RECIST 
Response Evaluation Criteria in Solid Tumors  
RP2D 
recommended phase II dose 
RT 
radiotherapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer  
SD 
stable disease 
SLE 
systemic lupus erythematosus 
SMAC 
second mitochondrial activator of caspase 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TIL 
tumor –infiltrating lymphocyte 
TKI 
tyrosine kinase inhibitor  
TNFa 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone  
TTP 
time to progression 
TXL 
paclitaxel 
ULN 
upper limit of normal 
USAN 
U.S. Adopted Name 
WHO 
World Health Organization 
WOCBP 
woman of child-bearing potential 
 
DEFINITION 
IMP 
“A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, or when used for an unauthorized indication, or 
when used to gain further information about the authorized form.” 
According to the above definition, the Debiopharm International (DPI) active substance being tested as 
well as associate or comparator drugs used during the study are to be considered as IMPs. 
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1. INTRODUCTION 
Immune checkpoint inhibition has resulted in impressive response rates and long-term disease control in 
some cancers and patients.(1, 2) The tumor-derived neo-antigen repertoire plays a key role for immune T-
cell reactivity and sensitivity to immune checkpoint inhibition with anti-cytotoxic T-lymphocyte antigen-4 
(CTLA-4) and anti-programmed cell death 1/-ligand 1 (PD-1/PD-L1) therapies.(3) Patients whose tumors 
have a high mutation burden (>10 somatic mutations/Mb) and neo-antigen load, such as those with 
melanoma and lung cancer, have been shown to benefit most from immune checkpoint inhibition.(4-6) 
Despite the fact that improved progression-free survival (PFS) and overall survival (OS) have been reported 
with immune checkpoint blockade in several advanced malignancies, only 10-30% of patients respond to 
treatment and most patients ultimately develop resistance to therapy. Therefore, strategies to expand the 
extent and quality of response to immune checkpoint inhibition are required to optimize cancer 
immunotherapy.(7) Combination of immune checkpoint inhibitors (CPI) with compounds that foster anti-
tumor immunity and also promote programmed cell death (apoptosis) in tumor cells may have great 
therapeutic potential to achieve this goal.(8) 
2. PHARMACEUTICAL AND BACKGROUND INFORMATION  
2.1. 
Nivolumab 
Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody, which binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2. When PD-L1 that is found on tumor cells binds 
to PD-1 that is found on immune system cells, the PD-1 signaling pathway is activated, inhibiting an 
immune response. By blocking this interaction, nivolumab allows the immune system to recognize and 
attack tumor cells. In two pivotal phase I trials in advanced solid tumors, nivolumab showed significant 
clinical anti-tumor activity and was relatively well tolerated at 10 mg/kg once every 2 weeks (q2w) as 
monotherapy or in combination with other agents (non-CPIs).(9, 10) This led to several randomized phase 
III trials of nivolumab monotherapy in advanced cancers including melanoma, non-small cell lung cancer 
(NSCLC), renal cell carcinoma (RCC), classical Hodgkin lymphoma, squamous cell carcinoma of the head 
and neck (SCCHN) and others.(11) In the pooled dataset of all patients enrolled in these phase III trials and 
receiving nivolumab 3-10 mg/kg q2w as monotherapy across tumor types (n = 2,578) with minimum 
follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥ 10%) were fatigue (30%), 
rash (17%), pruritus (13%), diarrhea (13%), and nausea (12%). The majority of adverse reactions were mild 
to moderate (Grade 1 or 2). With a minimum of 24 months follow-up in NSCLC, no new safety signals 
were identified.(12, 13)  
Efficacy of nivolumab monotherapy was assessed in a recent meta-analysis that included 27 worldwide 
clinical trials (n=5,551). The pooled objective response rate (ORR), the 6-month PFS and the 1-year OS 
rates were 26% (95% confidence interval (CI) 21–31), 40% (95% CI 34–46) and 52% (95% CI: 43–62), 
respectively.(14) In Europe, nivolumab (OPDIVO®) as monotherapy or in combination with ipilimumab 
is currently indicated for the treatment of advanced melanoma, NSCLC, RCC, classical Hodgkin's 
lymphoma, SCCHN and urothelial carcinoma.  Due to antibody-specific kinetics, a flat dose was derived 
from the 3 mg/kg q2w dose by multiplying for an average 80 kg weight, thus based on the current 
prescribing information, a nivolumab infusion at either 240 mg (flat dose) q2w or 480 mg every four weeks 
(q4w) (starting from Cycle 3) was identified as the recommended phase II dose (RP2D). The two treatment 
schedules are currently being used in daily oncology practice given the extended terminal half-life of IgG4 
antibodies such as nivolumab and the relative lack of potential interactions.(12) It is anticipated that 
switching the nivolumab schedule as of Cycle 3, from D1, 15 q4w to D1 q4w with the higher dose, if the 
treating investigator considers this appropriate, is not expected to raise any concerns in regards to efficacy 
or safety, while simplifying treatment administration and hospital visits and contributing to alleviate 
patient’s time constraints and treatment burden to a significant extent.  
 
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shown to enhance anti-PD-1 mediated tumor growth inhibition by increasing the percentage of activated 
CD4 and CD8 T-cells in the tumor.(24)  
A first-in-man study in 31 patients with advanced cancers evaluated short course Debio 1143 monotherapy 
(5-900 mg), given orally once daily on days 1-5 (q2w or q3w). Debio 1143 was well tolerated up to the 
maximum dose of 900 mg, with pharmacodynamic (PDy) effects noted at daily doses >80 mg.(25) 
Pharmacokinetics (PK) studies demonstrated a mean half-life on Day 1 of 5.2 - 7.1 h, regardless of the dose. 
The maximum tolerated dose (MTD) was not reached. Common treatment-related adverse events (AE) that 
occurred with a frequency of >10% included fatigue (26%), nausea (23%), and vomiting (13%).(25) While 
gastrointestinal (42%) and skin/subcutaneous (29%) AEs were common, most drug-related AEs were mild 
to moderate in severity and the frequency and grade of AEs were not dose-dependent. Of the 8 patients 
(26%) with serious adverse events (SAE), none was considered related to Debio 1143. Four patients (13%) 
discontinued treatment with Debio 1143 due to AEs (alanine transaminase [ALT] increase, cranial nerve 
disorder, abdominal pain, dyspnea), with only ALT elevation deemed related to treatment.  
In combination with carboplatin (CBCDA) and paclitaxel (TXL), short-course Debio 1143 at a dose of 
200 mg once daily (Days 1-5, q3w) has been determined to be safe and is the RP2D in combination with 
chemotherapy.(26) Particularly promising results were observed in heavily pre-treated ovarian cancer 
patients treated with Debio 1143 in combination with CBCDA and TXL, in which 6 patients out of 18 had 
confirmed partial response (PR) (33.3%). Extended daily administration of Debio 1143 (Days 1-14, q3w) 
of 200 to 400 mg daily dosing has also been reported.(15) The extended schedule was found to have good 
tolerability and a toxicity profile similar to the short-course regimen, with cellular IAP-1 degradation in 
surrogate tissue noted at all doses evaluated.(15) The MTD was not reached up to 400 mg/d and only one 
isolated dose limiting toxicity (DLT) of asymptomatic reversible transaminase elevation was observed at 
200 mg/d, but not at higher doses.  
Extended daily dosing of Debio 1143 is currently being evaluated in combination with concurrent chemo-
radiation in patients with locally advanced SCCHN.(27) Debio 1143 at the dose of 200 mg/d on Days 1-14 
every 21 days has been determined to be safe and is the selected RP2D in combination with concurrent 
chemo-radiation.(28) Preliminary findings showed that 10/14 (71.4%) patients had complete response (CR) 
and 3 (21.4%) additional patients had PR. Double-blind, placebo-controlled, randomized phase II trials  
(Debio 1143-201B and Debio 1143-203) are ongoing to better address the exact contribution of Debio 1143 
to the efficacy and safety of these regimens.  
In addition, a phase Ib/II study (Debio 1143-NSCLC-105) of Debio 1143 in combination with avelumab 
(anti-PD-L1) is ongoing in NSCLC patients naïve to CPI. As of 21st of November 2018, 16 patients were 
included and treated with Debio 1143 doses ranging from 100 mg daily up to 250 mg daily on Days 1-10 
and Days 15-24 q4w with the standard avelumab dose (10 mg/kg on Days 1 and 15 q4w)(29).The MTD 
was not reached and the RP2D has been defined as 200 mg QD. The study used an adaptive modified 
continual reassessment method design.  Preliminary results showed treatment was well tolerated without 
any major issues identified so far except for some expected mild grade avelumab infusion-related reactions, 
which have been well described in the literature. One NSCLC patient, treated at 150 mg/d Debio 1143 had 
an ongoing confirmed RECIST v1.1 PR at Cycle 6+ as of the cutoff and 5 stable disease (SD) were 
observed, providing early evidence of clinical activity. Other clinical studies evaluating other CPI 
combinations are planned to assess the immunomodulatory properties of IAP inhibition.(30) 
In summary, as of July 2018 nearly 300 patients have been included in Debio 1143 studies, receiving 
treatment as single agent in the first-in-human study, or most cases as part of a combination containing 
either chemotherapy, chemoradiation or immunotherapy. Debio 1143 was given at a daily dose ranging 
from 400-900 mg/d as single agent without the MTD being reached. Debio 1143 at 200 mg/d can be safely 
given in combination with carboplatin/paclitaxel, cisplatin, daunorubicin/cytarabine or with concomitant 
chemo-radiotherapy with cisplatin. In terms of combining Debio 1143 with an anti-PD-L1, preliminary 
clinical data from the ongoing Debio 1143-NSCLC-105 study, suggest that 150 mg/d is non-toxic and 200 
mg/d Debio 1143 combined with standard avelumab is tolerable. PDy evidence of target occupancy and 
IAP degradation in blood is available from patients treated at doses as low as 120 mg/d. 
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3. RATIONALE AND RISK BENEFIT ASSESSMENT 
Evasion from apoptosis and immune-surveillance have been recognized as two key hallmarks of cancer. A 
dual combination approach that overcomes both of these barriers has been shown in preclinical models to 
effectively eradicate tumors. Small-molecule IAP antagonists, known as SMAC mimetics render cancer 
cells susceptible to cell death and stimulate effector immune cells, resulting in increased anti-tumor 
immunity.(16) The SMAC mimetic Debio 1143 is expected to expand and enhance patients’ response to 
immune CPIs. 
Immune checkpoint inhibition – in particular monoclonal antibodies targeting PD-1/PD-L1 – is changing 
the treatment paradigm for many cancer types. Pembrolizumab, a PD-1 antagonist is the first drug approved 
in oncology which is indicated for the treatment of tumors with particular molecular features, such as 
microsatellite instability-high (MSI-H) or mismatch repair deficiency (MMRd), which cause errors in DNA 
replication resulting in a high mutation load and likely enhanced neoantigen presentation to immune cells 
irrespective of their primary tumor origin or location. Nevertheless, only a limited subset of patients 
responds to single-agent blockade. Combination therapies are often a means of increasing response rates. 
Furthermore, benefit associated with CPI treatment in patients with malignant melanoma and other tumors 
was suggested when patients were continuously treated even beyond initial tumor progression.(31, 32) The 
immunogenic properties of the IAP antagonists provide a good rationale for combining Debio 1143 with 
immune CPIs such as nivolumab. 
In a phase III trial enrolling 423 NSCLC patients with a PD-L1 expression level of 5% or more, nivolumab, 
as first-line therapy, was well tolerated with 18.0% of patients experiencing grade 3/4 treatment-related 
toxicity. Among the 75 patients with follow up >13 weeks, median PFS was 4.2 months and the ORR was 
26.1% (CR: 2%, PR: 24%), with 38% of patients achieving stable disease (33). 
In clinical trials, Debio 1143 monotherapy was well tolerated up to a maximum of 900 mg without reaching 
the MTD with a schedule of Days 1-5 q2w or q3w. The extended dosing schedule of Debio 1143 (Days 1-
14 q3w) also showed good tolerability, with a toxicity profile similar to the short-course regimen, and the 
MTD not reached with doses up to 400 mg/d. PDy effects were seen with daily doses >80 mg/d. Treatment-
related AEs (TEAEs) with a frequency of >10% included fatigue (26%), nausea (23%), and vomiting (13%). 
Gastrointestinal (42%) and skin/subcutaneous (29%) AEs were common, but most drug-related AEs were 
mild to moderate in severity and the frequency and grade of AEs were not dose-dependent. More recently, 
results of a window-of-opportunity trial in patients with SCCHN showed an increased level of tumor-
infiltrating lymphocytes (TILs), especially CD8+ T-cells; as well as increased expression of PD-L1 and 
PD-1 in tumors resected 14-days post-treatment with Debio 1143. 
 
  
The combination of immune CPI with compounds that foster anti-tumor immunity and promote 
programmed cell death (apoptosis) in tumor cells has strong therapeutic potential and based on their good 
tolerability, the benefit risk balance is positive.  
A combination of Debio 1143 and avelumab, a CPI targeting PD-L1, is currently being tested in patients 
with solid tumors and NSCLC, using the same schedule as that proposed in this study, Days 1-10 and Days 
15-24 q4w. Results available from 16 patients treated up to 21st of  November 2018 in the Debio 1143 dose 
range explored (100-250 mg/d) plus the standard avelumab dose showed an acceptable safety profile 
without any unexpected toxicities. The MTD was not reached and the RP2D had been defined at 200 mg/d 
D1-10 and D15-24 combined with avelumab i.v. at 10 mg/kg on D1 and 15, both q4w (29). Preliminary 
PK/PDy data from this and other studies (i.e., Debio 1143-101/AT-406-C2S-001 and Debio 1143-202 
Window-of-Opportunity), show target engagement, adequate tumor distribution and concentrations and 
potential immunomodulatory properties with the 200 mg/d Debio 1143 dose (some already apparent at 80-
100 mg). It also has an acceptable safety profile both as single agent and when combined with a variety of 
other treatments (concomitant chemo-radiotherapy, carboplatin and paclitaxel, cisplatin weekly, etc). Based 
on the known safety profile of CPIs and SMAC mimetics, and particularly Debio 1143 when given orally 
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at 200 mg/d, the risk-benefit ratio for patients treated with the combination as proposed in this study is 
favorable. See Section 5.3 for the Debio 1143 administration schedule rationale.  
Regarding the risk of drug-drug interactions (DDIs), Debio 1143 is transported by P-glycoprotein (P-gp). 
Accordingly, strong P-gp inhibitors and inducers are prohibited. In addition, in vitro Debio 1143 
significantly inhibits CYP 3A4/5 and P-gp and has the potential to induce and downregulate CYP 3A4/5, 
2Cs, 2B6, and to downregulate 1A2. The clinical relevance of these phenomena is unknown.  
Accordingly, narrow therapeutic range or sensitive CYP 3A substrates are prohibited. Also, narrow 
therapeutic range or sensitive substrates of P-gp, CYP 2Cs, 2B6 or 1A2 should be closely monitored. 
4. STUDY OBJECTIVES 
4.1. 
Primary objectives 
4.1.1. 
Part A 
The primary objective of the dose-optimization part of the study is to determine the RP2D taking into 
account DLT/s in Cycle 1, overall safety/tolerability and PK, by optimizing doses of Debio 1143 when 
combined with the standard dose of nivolumab, as well as treatment compliance in patients with advanced 
solid malignancies who failed prior systemic standard treatments. 
4.1.2. 
Part B 
The primary objective of the basket trial is to evaluate the preliminary anti-tumor activity of Debio 1143 at 
the RP2D in combination with nivolumab at the standard dose, overall and in each patient cohort. 
4.2. 
Secondary objectives 
4.2.1. 
Part A 
For the dose-optimization part, secondary objectives are to assess the: 
1. PK disposition of Debio 1143 (including its metabolite Debio 1143-MET1) and nivolumab when 
administered in combination. 
2. Anti-tumor activity of Debio 1143 in combination with nivolumab in patients with advanced solid 
malignancies.  
 
4.2.2. 
Part B 
For the basket trial, secondary objectives are to assess the: 
1. Safety and tolerability of the RP2D of Debio 1143 when given in combination with nivolumab in 
patients with advanced solid malignancies.  
2. PK disposition of Debio 1143 (and its metabolite Debio 1143-MET1) and nivolumab when 
administered in combination. 
 
4.3. 
Exploratory objectives 
1. To explore potential predictive and PDy biomarkers of Debio 1143 and nivolumab when 
administered in combination, in blood and tumor tissue, 
 
 
  
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2. To explore genetic variations in drug metabolism enzyme and transporter (DMET) genes associated 
with differences in the PK disposition of Debio 1143 in combination with nivolumab 
3. To explore the exposure/response relationship for efficacy and safety (including PK/PDy 
correlations, if applicable) of Debio 1143 in combination with nivolumab 
4. To explore correlations between response, clinical parameters, immune correlates, and putative 
biomarkers, 
 
5. To explore the relationship between Debio 1143 plasma concentrations and QTcF 
5. STUDY DESIGN AND TREATMENT 
5.1. 
Study design 
This study will be conducted in  two sequential parts, i.e., a dose-optimization phase Ib (Part A) and an 
exploratory phase II basket (multiple parallel cohorts) trial (Part B), to evaluate Debio 1143 in combination 
with the standard dose of nivolumab in patients with advanced/unresectable solid malignancies who have 
progressed during or immediately after anti-PD1/PD-L1 treatment. 
A Data Safety Monitoring Committee (DSMC) will overview study conduct during both parts A and B. A 
full charter will be provided as a separate document.  
5.1.1. 
Part A 
Part A has an open-label, multicenter dose-optimization design applying the classical 3+3 method, aiming 
at optimizing the Debio 1143 dose in combination with standard doses of nivolumab (OPDIVO®) to 
determine the RP2D taking into account safety/tolerability and PK, as well as the treatment compliance in 
pretreated patients with advanced solid malignancies including: small cell lung cancer (SCLC); SCCHN; 
MSI-H, MMRd or other DNA damage repair (DDR) abnormalities, including homologous recombination 
deficiency (HRD) in gastrointestinal (GI) cancers; known DNA MMRd/MSI-H, breast cancer (BRCA)-1/2 
hereditary or somatic/ sporadic mutations, or other DDR abnormalities including HRD in platinum-resistant 
ovarian, endometrial, primary peritoneal or cervical cancers. Patients must have received at least, one prior 
systemic line of standard treatment and must have progressed or relapsed during or immediately after a 
prior anti-programmed cell death-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) based-treatment, 
given either as a single agent or in combination with standard/approved chemotherapy, tyrosine kinase 
inhibitors (TKIs) or other monoclonal antibodies (mAbs) that are not known to modulate/inhibit immune 
checkpoints. Patients with prior cytotoxic T-lymphocyte antigen 4 (CTLA-4) or lymphocyte activation 
gene-3 (LAG-3) combinations with PD-1/PD-L1 are excluded; any other prior combinations with 
checkpoint inhibitors (CPI) should be discussed and agreed by the Sponsor before patient inclusion.  
Eligible patients will enter Part A of the study in cohorts of three evaluable patients. The starting dose of 
Debio 1143 will be 150 mg, daily, administered orally for 10 consecutive days every 2 weeks (i.e., Days 1-
10 and Days 15-24 inclusively of each 28-day cycle [q4w]). The dose will be optimized according to the 
observed DLTs, patient treatment compliance, safety/tolerability and PK data, if applicable.  
The DLT period is defined as Cycle 1 (i.e. lasting 4 weeks or longer in case of dosing delays). Treatment-
related toxicities fulfilling DLT criteria but occurring after Cycle 1 (i.e., delayed DLTs) may also be 
considered for RP2D definition after discussion and agreement between the Investigators, DSMC and the 
Sponsor.  
Nivolumab will be administered at 240 mg (flat dose) over at least 30 minutes as an IV infusion on Days 1 
and 15 of a 28-day cycle. From Cycle 3, patients may be switched to nivolumab at a dose of 480 mg IV 
over at least 60 minutes on Day 1 q4w, exclusively upon Investigator request with the Sponsor agreement. 
The maximum explored Debio 1143 dose will be 200 mg/d. Neither Debio 1143 dose escalation beyond 
this threshold nor any nivolumab dose increases are foreseen in this study. In individual cases of severe 
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toxicity, the Debio 1143 dose may be reduced by a maximum of two decrements of 50 mg/d or up to a 
minimum dose of 100 mg/d.  
According to the 3+3 dose-optimization design, if none of the three patients at the starting dose cohort 
experiences a DLT, three more patients will be treated at the next dose level. However, if one of the first 3 
patients experiences a DLT during Cycle 1, 3 more patients will be treated at the same dose level. If ≤ 1 
out of 6 evaluable patients experience a DLT during the first cycle, at the starting dose level, dose escalation 
will then proceed to the second dose level. If ≥ 2 DLTs are observed during the first cycle among the 3 or 
6 evaluable patients treated with the initial dose level, recruitment will then be stopped temporarily or 
definitively until the reasons for this finding have been clarified. If the dose is increased to the second dose 
level, 3 to 6 evaluable patients will be included and the 3+3 design rules will be applied again. If ≤ 1 out of 
6 evaluable patients experience a DLT during the first cycle at the second dose level, this dose will be 
considered the optimal dose level. If ≥ 2 out of 3 or 6 evaluable patients experience a DLT during the first 
cycle at the second dose level, the initial dose level will then be declared the optimal dose, given that < 
33% of evaluable patients have experienced a DLT during the first cycle and there are at least 6 evaluable 
patients treated at this dose level. Patients within a cohort may all start treatment simultaneously.  
At least 6 evaluable patients should be treated at the RP2D before Part B of the study may start. Once the 
RP2D is defined, any patient still receiving treatment can be switched to the RP2D, if deemed appropriate 
by the Investigator and agreed by the sponsor. 
 
5.1.2. 
Part B 
Part B is a multicenter, open-label, basket trial using Debio 1143 in combination with nivolumab at the 
RP2D as previously defined in Part A, in patients with advanced/unresectable solid tumors. Eligible patients 
will be simultaneously included into four cohorts according to tumor type:  
 
Cohort 1: SCLC (including extrapulmonary small-cell carcinomas or large cell neuroendocrine 
lung carcinoma, as per WHO Classification of Lung Tumors of 2015 (34) 
 
Cohort 2: SCCHN (nasopharyngeal carcinomas are excluded) 
 
Cohort 3: GI cancers, including esophageal, gastric, colorectal or pancreatobiliary tumors, with 
known MSI-H/ MMRd or other known DDRs abnormalities (incl. HRD).  
 
Cohort 4: platinum-resistant EOC), endometrial cancer, PPC and cervical cancer, with known 
MSI-H/ MMRd, hereditary/somatic mutations of the BRCA1 and BRCA2 genes or other known 
DNA DDRs abnormalities (incl. HRD).  
The primary objective of Part B is to assess whether the combination of Debio 1143 with nivolumab is 
active overall and in each cohort. Early futility stopping rules based on ORR (unconfirmed) will be used. 
In each cohort, if no unconfirmed response is observed according to Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1) or Gynecologic Cancer Intergroup (GCIG) criteria (Cohort 4, if applicable) once 
the initial 8 evaluable patients have been assessed at least twice after baseline or have discontinued their 
treatment earlier, futility will be concluded and recruitment will be stopped in that cohort. If at least one 
response (unconfirmed) is documented in the initial 8 evaluable patients, recruitment shall continue up to 
11 evaluable patients. At least two unconfirmed responses must then be observed in these 11 evaluable 
patients to continue the recruitment up to 15 evaluable patients in that cohort.  
A homogeneity test will be conducted in any non-futile cohorts showing a confirmed response rate of at 
least 15%. If homogeneous response rates are seen across the cohorts, efficacy data will be pooled and an 
overall efficacy analysis will be conducted in addition to the analyses by cohort. For the final efficacy 
assessment, first proof of efficacy will be claimed in a given cohort if at least 4 confirmed objective 
responses are reported in the 15 evaluable patients. 
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In the case of insufficient accrual in any cohort (e.g. less than 2 patients in 6 months) despite concrete 
measures aiming at increasing the recruitment, enrolment may be stopped in that cohort. 
During part B the DSMC will meet approximately every 3 months, and more frequently if needed in the 
event of rapid recruitment. A charter will be provided separately. 
5.2. 
DLT period and definition of DLTs  
The DLT period is defined as Cycle 1*. 
DLT is defined as any of the following treatment-emergent adverse events (TEAEs) which are possibly, 
probably or definitely related to the combination treatment and occurring in Cycle 1 (1 cycle=4 weeks): 
 
 
Any Grade 4 or 5 hematologic toxicity, clinical or laboratory non-hematologic toxicity 
 
Febrile neutropenia any grade, Grade 3 thrombocytopenia if associated with bleeding or requiring 
platelet transfusion 
 
Grade 2 or higher cardiac or neurologic toxicities, pneumonitis that does not resolve within 3 days 
after starting steroids at adequate doses or that was recurrent upon steroid tapering or withdrawal, 
myasthenia gravis, myositis, polymyositis, Guillain-Barre syndrome (excluding peripheral purely-
sensory neuropathies) 
 
Grade 2 or higher alanine transaminase (ALT)/ aspartate transaminase (AST) increase with a 
concurrent increase of total bilirubin ≥2 x upper limit of normal (ULN) and concurrent with alkaline 
phosphatase (ALP) ≤2 x ULN (Hy’s law), in the absence of objective causes of biliary obstruction 
due to obvious disease-related causes 
 
Any other Grade 3 non-hematologic, treatment-related clinical toxicity lasting 3 or more days 
despite optimal supportive care, or requiring admission for appropriate medical management; 
hypersensitivity and/or infusion-related reactions are excluded if not reoccurring after appropriate 
pre-medication and/or prolonging infusion time 
 
Grade 3 non-hematologic laboratory value (excluding lipase, amylase and/or autoimmune 
endocrinopathies manageable by replacement therapies) if: 
a. Symptomatic and 
b. Medical intervention was promptly required to treat the patient, or 
c. The abnormality led to hospitalization or 
d. The abnormality did not resolve to at least Grade 1 within 2 weeks (including the steroid 
tapering period) despite adequate medical intervention/treatment  
 
A delay of >2 weeks due to drug-related toxicity in initiating Cycle 2   
 
Unable to complete at least 70% of the scheduled treatment, i.e. more than six Debio 1143 skipped 
doses in Cycle 1 due to treatment-related toxicity 
 
Required dose reduction in Cycle 1 or on Cycle 2 Day 1 or requirement for treatment withdrawal 
due to treatment-related toxicity (even if not meeting other DLT criteria) 
*Any toxicity fulfilling one or more of these criteria but occurring from C2D1, may be defined as delayed 
DLTs after discussion and agreement between principal Investigators (PIs) and the Sponsor, and may be 
considered for RP2D definition, if appropriate. 
5.3. 
Study treatments 
Debio 1143: rationale for dose regimen  
Since Debio 1143 is a chemosensitizer, radiosensitizer and immunosensitizer, its schedule of administration 
in clinical trials is adapted to the standard treatment used in the combination. 
A 10-day on / 4-days off schedule given every 2 weeks (i.e., repeated twice in a 4-week cycle) of Debio 
1143 was selected to optimize the activity of the combination with standard nivolumab. This schedule is 
being tested in an ongoing Debio 1143-NSCLC-105 study in combination with avelumab (NCT03270176). 
The 4-day wash-out period allows recovery from potential Debio 1143-related toxicity and gives a lower 
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tolerance). During this period, patients may continue to receive Debio 1143 as per protocol, if appropriate. 
Patients requiring more than 8 weeks (±1 week) of nivolumab interruption and those who permanently 
discontinue nivolumab for any reason, will discontinue Debio 1143 permanently and will be withdrawn 
from the study. The nivolumab dose will not be adjusted under any circumstances. 
Patients experiencing any treatment-related grade 4 toxicity (clinically or laboratory, excluding grade 4 
amylases and/or lipase and/or non-febrile neutropenia) will withdraw from treatment definitively without 
further reduction (see section 8.3.2.1 for details).  
Patients experiencing any other treatment-related toxicity fulfilling applicable DLT criteria (as shown 
below) at any time during the study must stop treatment and may only resume treatment after adequate 
recovery to re-treatment criteria.  
Treatment must be re-started with a Debio 1143 dose reduction. Individual patients may have up to two 
dose adjustments of 50 mg/d (each one) up to a minimum dose of 100 mg/d Debio 1143 (i.e. 1st dose 
reduction 150 mg/d, 2nd dose reduction 100 mg/day). Patients still requiring a dose adjustment with a dose 
of 100 mg/d will be withdrawn from the study. Once adjusted, Debio 1143 dose will not be re-escalated 
under any circumstances.  
Up to 2 dose reductions must be implemented in the event of any of the following:  
 
Any Debio 1143-related Grade 4 hematologic toxicity 
 
Debio 1143-related febrile neutropenia any grade, or Grade 3 thrombocytopenia if associated with 
bleeding or requiring platelet transfusion 
 
Debio 1143-related grade 2 or higher alanine transaminase (ALT)/ aspartate transaminase (AST) 
increase with a concurrent increase of total bilirubin ≥2 x upper limit of normal (ULN) and 
concurrent with alkaline phosphatase (ALP) ≤2 x ULN (Hy’s law), in the absence of objective 
causes of biliary obstruction due to obvious disease-related causes 
 
Any Grade 3, treatment-related, non-hematologic clinical toxicity lasting 3 or more days despite 
optimal supportive care, or requiring admission for appropriate medical management; 
hypersensitivity and/or infusion-related reactions are excluded if not reoccurring after appropriate 
pre-medication and/or prolonging infusion time 
 
Grade 3 non-hematologic laboratory value (excluding lipase, amylase and/or autoimmune 
endocrinopathies manageable by replacement therapies) 
 
A delay of >2 weeks due to drug-related toxicity in initiating subsequent cycles, or a second delay 
lasting >24 h but <2 weeks   
 
Unable to complete at least 70% of the scheduled treatment, i.e. more than six Debio 1143 skipped 
doses during any cycle due to treatment-related toxicity or more than 2 treatment interruptions >24 
h but <6 days 
If for any reason Debio 1143 is withheld temporarily, nivolumab will also be withheld until treatment may 
be resumed. Patients discontinuing Debio 1143 definitively for any reason will also discontinue nivolumab 
study treatment. 
Patients requiring no more than 1 treatment interruption per cycle and for not more than 3 consecutive days, 
may resume treatment without dose adjustments. Patients requiring one interruption greater than 3 days, or 
more than one interruption during any given cycle, may resume treatment only after full recovery and 
adjustment of Debio 1143 dose upon the Sponsor’s agreement (if applicable). 
Patients interrupting treatment or delaying the start of a new cycle due to any Grade 3 treatment-related 
toxicity will resume treatment after Debio 1143 adjustment (except Grade 3 neutropenia, 
thrombocytopenia, non-optimally treated fatigue, diarrhea, or nausea). Patients experiencing any Grade 4 
treatment-related toxicity will immediately stop treatment without any possible therapy resumption. 
Omitted Debio 1143 doses will not be re-administered under any circumstances. Every new cycle D1 will 
start with the Debio 1143 dose. In case of any cycle delays (Day 1 delayed greater than 72 hours), all 
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subsequent doses will be administered according to the new planning, if feasible (i.e. Day 1-10 followed 
by Day 11-14 pause).  
6. STUDY POPULATION 
All patients included in the study must have selected advanced/unresectable or metastatic solid tumors, and 
must have received at least one prior systemic line of standard treatment and have progressed or relapsed 
during or immediately after a prior anti-PD-1/PD-L1-based treatment, given either as a single agent or in 
combination with standard/approved chemotherapy, TKIs or other mAbs that are not known to 
modulate/inhibit immune checkpoints. Patients with prior CTLA-4 or LAG-3 combinations with PD-1/PD-
L1 are excluded; any other prior CPI combinations should be discussed and agreed by the Sponsor before 
patient inclusion. 
In Part A: 
 
Between 3 and 12 evaluable patients are planned.  
 
Non-evaluable patients will be replaced, as appropriate. 
In Part B:  
 
Cohort 1: SCLC (including extrapulmonary small-cell carcinomas or large cell neuroendocrine 
lung carcinoma, as per WHO Classification of Lung Tumors of 2015 (34) 
 
Cohort 2: SCCHN (nasopharyngeal carcinomas are excluded) 
 
Cohort 3: GI cancers (including esophageal, gastric, colorectal or pancreatobiliary) with known 
MSI-H/MMRd or other DDR abnormalities, including HRD.  
 
Cohort 4: platinum-resistant EOC, endometrial cancer, PPC or cervical cancer, with known MSI-
H/ MMRd, hereditary/somatic mutations of the BRCA1 and BRCA2 genes or other DNA DDR 
abnormalities (incl. HRD).  
 
Between 32 evaluable patients (if all cohorts are futile) and 60 evaluable patients (if none of the 4 
cohorts is futile) (see section 11.1 for details on sample size). 
 
Non-evaluable patients will be replaced. 
6.1. 
Inclusion criteria 
The same tumor types are eligible in Part A and B. 
 
All patients must fulfil all the following criteria (both Parts A and B, unless specified otherwise): 
1. Willing and able to sign a written informed consent form;  
2. Male or female ≥18 years of age. 
3. Histologically and/or cytologically confirmed advanced/ unresectable or metastatic solid tumor for 
one the following indications: 
a. 
SCLC 
b. SCCHN (except nasopharyngeal carcinoma) 
c. 
GI cancers, including esophageal, gastric, colorectal or pancreatobiliary with known MSI-H/MMRd 
or any other known DDRs abnormalities, including HRD  
d. Platinum-resistant* EOC, endometrial cancer, PPC or cervical cancer, with known MSI-H/ MMRd, 
hereditary/somatic mutations of the BRCA1 and BRCA2 genes or other known DNA DDRs 
abnormalities (incl. HRD)  
* Platinum-resistant is defined as relapse or progressive disease (PD) occurring within 1 to 6 months 
(180 days) after a platinum-containing chemotherapy.  
4. Have received at least one prior line of standard systemic chemotherapy in the 
advanced/unresectable cancer setting (standard adjuvant/neoadjuvant treatment is acceptable if 
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relapse occurred within six months of treatment end) and have no established standard therapeutic 
alternatives. 
5. Have progressed or relapsed during or after a prior anti-programmed cell death-1 (PD-1)/ 
programmed cell death-ligand 1 (PD-L1)-based treatment, given either as a single agent or in 
combination with standard/approved chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy 
(RT) or other monoclonal antibodies (mAbs) that are not known to modulate/inhibit immune 
checkpoints (CPIs) 
6. Minimum washout periods since prior therapy until treatment start (C1D1) (in cases of more than 
one prior treatment type, whichever has the longest minimum period applies):  
a. 3 weeks for chemotherapy (6 weeks, specifically for nitrosoureas or mitomycin C 
containing regimens);  
b. 4 weeks for any prior mAbs or live vaccines; for any investigational mAbs 4 weeks or at 
least the duration of one treatment cycle whichever is longest    
c. 3 weeks for prior RT (1 week in case of localized antalgic/hemostatic hypofractionated RT 
flash)  
d. 2 weeks for TKIs, hormonal therapy, other anti-cancer treatment not previously specified 
or investigational agents  
e. 4 weeks for any major surgery 
f. Immunosuppressive medication: within 2 weeks, with the exception of intranasal and 
inhaled corticosteroids or systemic corticosteroids at physiological/replacement doses, 
which should never exceed 10 mg/d prednisone, or an equivalent corticosteroid 
7. Measurable disease (Part B only) according to RECIST v1.1 or GCIG criteria in Cohort #4 (if 
applicable) and documented PD during or after prior PD-1/PD-L1 based therapy 
8. ECOG Performance Status = 0 or 1  
9. Adequate hematologic renal and hepatic function: 
a. absolute neutrophil count (ANC) ≥ 1.5 x109/L,  
b. platelets ≥ 100 x109/L,  
c. hemoglobin ≥ 9.0 g/dL,  
d. AST and ALT ≤ 3 x ULN (≤ 5x ULN if liver metastases are present), 
e. total bilirubin ≤ 1.5 x ULN,  
f. serum creatinine ≤ 1.5 x ULN, 
g. serum albumin ≥ 30 g/L 
10. Available archived tumor samples for biomarker analysis obtained after prior PD-1/PD-L1 
treatment failure or, if no archived tumor sample is available, patient must be suitable and willing 
to undergo a percutaneous or endoscopic biopsy without unacceptable major risks before starting 
study treatment. 
11. Participants with known central nervous system (CNS) and/or meningeal involvement will be 
eligible if they are clinically asymptomatic, have completed primary CNS therapy more than 4 
weeks before treatment start (such as whole brain RT, stereotactic radiosurgery, or complete 
surgical resection), and have remained off steroids (including tapering doses) for at least 2 weeks 
12. Women of child-bearing potential (WOCBP): 
a. Negative serum pregnancy test at screening; 
b. Agreement to use highly effective contraception methods from study entry and for up to 5 
months after the last day of study treatment 
c. Agreement from her male partner to use contraception methods 
13. Male patients with WOCBP partners must agree to use highly effective contraception methods from 
study entry and for up to 5 months after the last day of study treatment 
6.2. 
Exclusion criteria 
Any of the following would render a patient ineligible for inclusion (in both Parts A and B, unless specified 
otherwise): 
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1. Thoracic or head and neck radiation >30 Gy within the 6 weeks prior to C1D1; 
2. Have received, in total, more than 3 (i.e. Cohorts 1&2) or 4 (i.e. Cohorts 3&4) lines of prior systemic 
treatments (including adjuvant or neoadjuvant regimens if relapse within six months prior to C1D1); 
3. Active moderate alcohol consumption, at screening, more than 100/140 grams (3.5/4.9 ounces) of 
alcohol per week for female and male patients, respectively 
4. Liver cirrhosis Child-Pugh score B or C 
5. Prior treatment with an anti-CTLA-4 or anti-LAG3 in combination with PD-1/ PD-L1 CPI, unless 
discussed and agreed with the Sponsor 
6. Prior treatment with SMAC mimetics 
7. Prior PD-1/PD-L1 discontinuation due to severe immune-related toxicity, not resolved upon adequate 
steroids/immunosuppressive treatment 
8. Requirement of concomitant treatment with any prohibited medication (See Appendix B: Prohibited 
medications and special warnings) 
9. Ongoing toxicity from prior administration of any other investigational drug and/or anti-cancer 
treatment of > Grade 1 NCI-CTCAE v5.0 before treatment start (except for grade 2 alopecia, stable 
sensory neuropathy, vitiligo or any endocrinopathy adequately managed by replacement hormonal 
therapy) 
10. Patients with known history of: 
a. Uncontrolled or symptomatic angina or myocardial infarction, within the last 12 months prior 
to C1D1  
b. Elevated (>ULN) troponins (T or I) or creatine phosphokinase (CPK) > 1.5xULN during 
screening 
c. Symptomatic intestinal sub-occlusion 
d. Infection, active or latent by human immunodeficiency virus (HIV), hepatitis B virus (HBV) 
and hepatitis C virus (HCV) 
e. Ongoing arrhythmias requiring treatment, including asymptomatic QTc interval as corrected 
by Fridericia (F) >480 msec 
f. In patients previously treated with anthracycline-containing chemotherapy or thoracic RT, non-
adequate cardiac function with left ventricular ejection fraction (LVEF) <50%, measured by an 
echocardiogram (ECHO) or a multigated acquisition (MUGA) as per institutional standards 
g. Active rheumatoid arthritis, active inflammatory bowel disease (IBD), primary sclerosing 
cholangitis, autoimmune hepatitis, systemic lupus erythematous (SLE), multiple sclerosis or 
any other ongoing autoimmune disease requiring systemic treatment (excluding vitiligo, mild 
cutaneous psoriasis and asymptomatic autoimmune endocrinopathy well controlled under 
hormonal replacement therapy) 
h. Evidence of active, non–infectious pneumonitis or a history of interstitial lung disease 
i. 
Active ongoing infection requiring systemic antibiotic therapy, including active tuberculosis 
11. Evidence or clinical suspicion of active bleeding or requirement of red blood cell (RBC) transfusions 
within 2 weeks prior to C1D1  
12. History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
Debio 1143 or nivolumab or their constituents 
13. History of another non-metastatic, low grade malignancy other than the primary tumor within the last 
1 year prior to C1D1, except: completely resected non-melanoma skin cancer, second SCCHN tumors, 
completely resected minimally invasive bladder cancer, completely resected ≤ pT1N0 invasive breast 
cancer, low grade prostate cancer if PSA ≤ 10 ng/mL, non-metastatic localized low grade RCC or any 
previous (non-synchronous) malignancy if related to germ-line mutations linked to either MSI-High- 
(lynch syndrome) or BRCA-1/2 hereditary cancer syndromes, for patients included either in cohort 3 
or 4. For these indications there are no time restrictions with regards to occurrence prior to C1D1.   
14. Pregnant or lactating females 
15. Unable to swallow or retain oral medications  
16. Known contraindication to contrast-enhanced MRI and CT 
17. Patient unwilling or unable to comply with study visits/assessments 
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6.3. 
Patient replacement 
Part A 
Patients will be evaluable for DLT, if they received at least 70% of Debio 1143 (i.e., a maximum of 6 missed 
Debio 1143 doses) and at least one nivolumab dose as planned in Cycle 1 and were evaluated for DLT or if 
the patient discontinued treatment early due to any toxicity that could be considered a DLT. 
Non-evaluable patients will be replaced, as appropriate (see section 11.5.1).  
Part B 
Patients will be evaluable for efficacy if the following two conditions are met: 
o Measurable disease at baseline as per RECIST v1.1 and/or GCIG criteria (Cohort 4, if applicable), 
o At least one efficacy assessment, either computed tomography (CT) or magnetic resonance imaging 
(MRI) for RECIST evaluable patients, or CA-125 dosage performed after baseline, if applicable, 
or treatment discontinuation occurred before the efficacy assessment was done due to treatment 
failure, defined as any of the following: death, unacceptable toxicity, clinical deterioration and/or 
symptoms worsening. 
Non-evaluable patients will be replaced. 
7. CLINICAL SUPPLIES 
7.1. 
Investigational medicinal products  
7.1.1. 
Debio 1143  
Debio 1143 will be provided by the Sponsor as size 1 hard gelatin capsules (75 mg yellow, 100 mg white 
opaque) containing API powder along with starch as excipient, for oral administration.  
7.1.2. 
Nivolumab  
Commercially available nivolumab (Opdivo®) will be provided by the Sponsor.  
7.2. 
Packaging and storage of IMPs 
Packaging and labeling will be in accordance with applicable local regulatory requirements and applicable 
Good Manufacturing Practice (GMP) guidelines. 
7.2.1. 
Packaging 
Debio 1143 hard gelatin capsules will be packed in opaque high density polyethylene bottles with a sealed 
child-resistant closure. Each bottle will contain 10 capsules of either 75 mg yellow capsules or 100 mg 
white capsules.  
Nivolumab (Opdivo®) commercial presentations, 1 x 4 mL vials, 1 x 10 mL vials and/or 1 x 24 mL vials.   
7.2.2. 
Labeling 
Debio 1143 bottles containing 75 mg capsules will have a yellow label, those with 100 mg capsules will 
have a white one. Commercial pack Nivolumab (Opdivo®) will be overlabelled to dispense study related 
information as appropriate per local regulations, storage conditions and expiry date in local languages. 
Label text will comply with local health authority requirements in each participating country.  
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7.2.3. 
Storage 
Debio 1143 capsules should be stored at a controlled temperature of 15-25°C, protected from direct heat 
and contact with water. It will be shipped and dispensed at ambient temperature. Do not freeze. 
Nivolumab must be shipped and stored at 2-8°C until use. Do not freeze. 
7.3. 
Dispensing and accountability of IMPs 
The IMPs and certificates of analysis will be provided to the Investigators by and under the responsibility 
of the Sponsor, who will also ensure release of the IMPs as per current GMP guidelines. Any documentation 
required by local health authorities for import of the IMPs will be appropriately submitted. 
The Investigator/pharmacist at each study site will inventory and acknowledge receipt of all IMP shipments. 
The IMPs accompanied by analytical reports when appropriate, must be kept in a locked area with access 
restricted to designated study personnel, and must be stored in accordance with the manufacturer's 
instructions.  
The Investigator/pharmacist at each study site will keep accurate records of the IMP (and other study-related 
drugs) dispensed. These records will specify dates and amounts dispensed, to and by whom (drug 
dispensing list), and report any IMPs accidentally or deliberately destroyed. 
Each dispensing of study drug will be documented by recording the patient’s number, and date dispensed 
on the Drug Accountability Form in the electronic case report form (eCRF)/electronic data capture (EDC) 
system. 
At study closure, unused IMPs will be counted and returned to the Sponsor or destroyed with their written 
permission. Any discrepancies between the IMPs returned and the expected balance must be justified. 
Unused IMPs must not be discarded or used for any purpose other than the present study. Throughout the 
study, the Sponsor’s monitor/representative will collect the drug accountability forms along with any 
unused IMPs in the original packaging. 
  
7.4. 
Patient numbering 
7.4.1. 
Screening number 
During the screening period (between Day –28 to –1), each potential study patient will be identified by a 
unique screening number which is displayed when the patient is first recorded in the eCRF via the internet-
based application. The screening number allows the patient’s data to be entered into the eCRF and 
subsequently ensures an expedited process when s/he is ready to start the study. 
The Screening # consists of a unique 6-digit identifier. The first 3 digits represent the number of the study 
center and digits 4-5-6 identify the screening order of the subject at the center (starting at 001). Screening 
#106001, for example, identifies the first subject (001) screened at study center 106. The second subject 
screened at the same study center will be given Screening # 106002, etc. 
If a screened patient fulfils all eligibility criteria and none of the exclusion criteria, the Investigator or 
designated study coordinator will request enrollment of the patient via the eCRF on study Day 1. Enrollment 
should not be requested before the patient is fully eligible and ready to start treatment. 
7.5. 
Blinding and unblinding methods 
Not applicable, as this is an open-label study. 
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7.6. 
Method of administration and compliance 
7.6.1. 
Debio 1143 
Debio 1143 capsules are ready to use and will be taken orally once daily for 10 consecutive days every 
2 weeks of a 28-day cycle (Days 1 to 10 and Days 15 to 24 q4w).  
Patients should fast 2 hours before dosing and should fast at least 1hour post-dose. Water is permitted freely. 
Beyond the onsite visits, study medication will be self-administered by patients at home and should be 
taken at approximately the same time each day. If a dose is forgotten, the patient may take the dose later in 
the day but no later than 6 h after normal intake time. If the delay exceeds 6 h, the patient must wait until 
the next scheduled administration. A double dose should not be taken to make up for a missed dose. 
If a patient vomits after study medication intake, the patient should not take another dose, but wait until the 
next scheduled dose. If vomiting persists, the patient should contact the Investigator. Relevant medical 
instructions should be given to the patient, specifically to not replace any missing doses and to not extend 
treatment beyond Days 10 or 24, during each cycle for any reason. In addition, the patient should be 
instructed to record any occurrences of vomiting in the diary card. 
Patients’ compliance will be verified on Day 1 of each cycle and on days when PK sampling is scheduled 
during Cycles 1 and 3, if applicable. Compliance will be measured by direct visual supervision at dosing 
by the Investigator or his/her designee when administered at the hospital, or by means of a diary card to be 
filled out after each dose when taken at home (the number of capsules, date and time of dosing will be 
recorded). The diary card will be checked by the Investigator or his/her designee at each study visit. Any 
change in the daily dosing of Debio 1143, must be appropriately reflected in the patient’s diary by the 
Investigator or his/her designee, such as dose reduction, dose omissions, and treatment resumption, as 
applicable.  
7.6.2. 
Nivolumab 
7.6.2.1. 
Pre-infusion procedures 
Nivolumab will be administered at 240 mg (flat dose) as an IV infusion, over at least 30 min, on D1 and 
D15 q4w (1 cycle=4 weeks and two infusions) or 480 mg over at least 60 min, on D1 q4w (1 cycle=4 weeks 
and one infusion) from Cycle 3. 
For instructions on preparation of nivolumab infusion, please refer to locally approved labelling.  
A preparation manual will describe in detail the infusion bags and medical devices to be used for the 
preparation of the dilution and subsequent administration.  
Formal premedication is not required. However, premedication might be used after C1D1 administration, 
if needed, on an individual patient basis, per clinical judgment and local institutional guidelines, as 
appropriate.  
7.6.2.2. 
Peri- and post-infusion procedures 
For the infusion, patients must be observed according to standard applicable institutional guidelines, if 
applicable, or for approximately 90 minutes post-infusion, in an area with resuscitation equipment and 
emergency agents. At all times during nivolumab treatment, immediate emergency treatment of an infusion-
related reaction or a severe hypersensitivity reaction according to institutional standards must be assured.  
Infusion of nivolumab will be stopped in case of Grade ≥2 hypersensitivity, inflammatory response, or 
infusion-related reactions. Infusions may be resumed after Grade ≤2 events upon resolution of the events 
within less than 4 hours and after medical assessment and agreement by a qualified Investigator. Infusion 
duration will not be shorter than 120 minutes after resumption in all subsequent infusions.  
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7.7. 
Concomitant therapy 
Administration of concomitant medications/therapies to the patient during the study period must be reported 
on the concomitant medications page of the eCRF. A medication or therapy is defined as concomitant when 
administered between the date of signature of informed consent and end of study (EOS). Information to be 
reported on the eCRF includes: i) international non-proprietary name and trade name, ii) dosage information 
(dose, unit, frequency, route), iii) dates of administration, and iv) reasons for use.  
7.7.1. 
Permitted medications 
Permitted medications are: 
 
Supportive therapies to treat any emergent serious condition notably including medications against 
pain, nausea, vomiting, and diarrhea (per the Investigator’s decision). 
 
Granulocyte colony-stimulating factor (G-CSF) and erythropoietic agents (per the Investigator’s 
decision). 
 
Transfusions and blood-derived products as per local institutional guidelines. 
 
Bisphosphonates or denosumab as per local institutional guidelines in patients with symptomatic 
bone metastases, or malignant hypercalcemia or with increased risk of bone fractures. 
 
Steroids or anti-histaminic drugs according to local institutional standard protocols or guidelines (if 
any) for allergic reactions Grade ≥2 or prophylactically after C1D1.  
 
Patients requiring prolonged systemic steroids administration for any emerging medical cause at 
doses in excess of physiological replacement doses or more than prednisone 10 mg/d, should 
discontinue study treatment according to risk/benefit evaluation.  
 
Levetiracetam and pregabalin (per the Investigator’s decision).  
 
Treatment of pain should be done according to severity and recommended drugs. Study-specific 
guidelines will be available. 
 
Any other medication for the well-being of the patient except those mentioned as prohibited 
medications at the Investigator’s discretion.  
 
The use of oral contraceptives should be carefully evaluated during study treatment as well as the 
use of other drugs reported to cause liver injury. 
7.7.2. 
Prohibited medications 
Attention should be paid to treatment that could influence the intended effects or mask side effects of study 
treatment. Use of drugs reported to cause liver injury should be carefully evaluated. 
Concomitant use (until the EOT visit) of the following drugs and treatment modalities is prohibited (see 
Appendix B: Prohibited medications for the full list), except if they are indicated to treat any TEAEs related 
to study treatment ([i.e. anti-TNF-α therapy]). In this case, administration of these drugs is allowed and 
must be documented after interrupting Debio 1143 treatment.  
 
Strong P-gp inhibitors or inducers (see Appendix B: Prohibited medications) 
 
Anti-TNF-α therapy (e.g, adalimumab [Humera®], etanercept [Enbrel®], infliximab [Remicade®], 
etc.)  
 
Other investigational agents other than mAbs within a 2-week period prior to initial dosing or while 
receiving Debio 1143 
 
Systemic corticosteroids, exceeding 10 mg/d of prednisolone or equivalent or physiological 
replacement doses of hydrocortisone.  Note:  topical corticosteroids for any indication, megestrol, or 
inhaled corticosteroids for reactive airway disease are permitted. 
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 
Alcohol dependency defined as drinking greater than 100/140g (3.5/4.9 ounces) of alcohol per week 
for female/male patients, respectively   
 
Grapefruit juice or grapefruit-containing products and St John’s Wort containing products 
 
Narrow therapeutic range or sensitive CYP 3A substrates or other drugs on the prohibited medication 
list (see Appendix B: Prohibited medications). 
 
Restrictions also apply for P-gp substrates during Debio 1143 on-treatment periods (see Appendix B: 
Prohibited medications). In addition, narrow therapeutic range or sensitive CYP 2Cs (2C8, 2C9, 2C19), 
2B6 or 1A2 substrates should be closely monitored. A list of drugs that are sensitive substrates of CYPs is 
available from website resources such as: Flockhart DA. Drug Interactions: Cytochrome P450 Drug 
Interaction 
Table. 
Indiana 
University 
School 
of 
Medicine 
(2007); 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
Finally, considering that the potential of Debio 1143 to prolong the QTc interval has not yet been fully 
characterized, caution should be exercised when using Debio 1143 with drugs having a known risk of QTc 
prolongation (refer to product label or Arizona CERT database at website: http://www.crediblemeds.org). 
Monitoring of patients’ electrolyte levels is strongly recommended. 
7.7.3. 
Contraceptive measures 
Based on its mechanism of action and data from animal studies, it is known that nivolumab can cause fetal 
harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab 
to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion 
and premature infant death. Human IgG4 is known to cross the placental barrier.  Nivolumab therefore has 
the potential to be transmitted from the mother to the developing fetus, with greater effects during the 
second and third trimesters of pregnancy. Nivolumab is not recommended during pregnancy and in women 
of childbearing potential (WOCBP) not using effective contraception.(12) 
Animal reproductive studies have not been conducted with Debio 1143. Therefore, it is not known if 
Debio 1143 or its metabolites are excreted in milk or can cross the placenta. Thus, pregnant or nursing 
women should not receive Debio 1143. Women of childbearing potential and their partners who are 
included in a clinical trial of Debio 1143 must take adequate contraceptive measures. 
WOCBP patients and male patients, whose partners are WOCBP, enrolled in this clinical trial must take 
adequate contraceptive measures through defined periods during and after study treatment as specified 
below. 
WOCBP patients and male patients whose partners are WOCBP must: 
 
Agree to use one highly effective method of contraception as described below. Contraception will 
be required from study entry up to 5 months after the last day of study treatment, or 
 
Agree to practice complete sexual abstinence, when this is in line with the preferred and usual 
lifestyle of the patient (note: periodic abstinence [e.g., calendar, ovulation, symptothermal post-
ovulation methods] and withdrawal are not acceptable methods of contraception) from study entry 
up to 5 months after the last day of study treatment. 
Highly effective methods of birth control include: 
 
Intrauterine device (IUD).  
 
Intrauterine hormone-releasing system (IUS).  
 
Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal)*. 
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 
Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, 
implantable)*. 
 
Bilateral tubal ligation. 
 
Vasectomized partner. 
 
Double barrier methods (not highly effective, but acceptable) 
*Note: If hormonal contraception is chosen, the use of a barrier method (preferably male condom) is 
mandatory due to potential risk of CYP 3A4/5 induction by Debio 1143 that may reduce hormonal 
contraception efficacy. 
 
WOCBP are non-surgically sterile women whose date of last menstruation is within 12 months before the 
date of the screening visit.  
 
8. STUDY ENDPOINTS, ASSESSMENTS, AND PROCEDURES 
8.1. 
Endpoints 
8.1.1. 
Primary endpoints  
8.1.1.1. 
Part A 
The primary endpoint of part A is the RP2D of Debio 1143 when combined with the standard dose of 
nivolumab, in patients with advanced solid malignancies who received prior systemic standard treatment 
and failed a prior PD-1/PD-L1-containing treatment, as per DLT occurrence in less than one-third of 
evaluable treated patients at the RP2D dose level. 
8.1.1.2. 
Part B 
The primary endpoint of part B is the confirmed ORR as per RECIST v1.1 and/or GCIG criteria (Cohort 4, 
if applicable). 
8.1.2. 
Secondary endpoints 
Secondary endpoints for both study parts (unless otherwise specified) are:  
 
Incidence and severity of TEAEs and clinical laboratory abnormalities, according to NCI-CTCAE 
version 5.0 criteria  
 
Changes in vital signs: systolic/diastolic blood pressure, heart rate (both after at least 5 minutes of 
supine rest), temperature, and weight; ECG and ECOG-PS 
 
Incidence of premature treatment discontinuations and treatment modifications due to AEs and 
laboratory abnormalities (i.e., treatment compliance) 
 
Tumor response determined according to RECIST v1.1 and/or GCIG criteria (Cohort 4, if 
applicable):  
o 
Confirmed (Part A) and unconfirmed (Parts A and B) ORR    
o Disease control rate (DCR), defined as any response, partial or complete (PR or CR) + 
stable disease (SD) 
o Time-related endpoints as median time to response, median DOR, median PFS, PFS rate 
at 6, 12 and 18 months, median OS, OS rate at 12 months and 18 months (if data allow) 
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 
PK parameters of Debio 1143 and Debio 1143-MET1 as defined in the available population PK 
model (36) and, if appropriate, post-hoc estimates of areas under the curve (AUCs), Cmax, and Cmin; 
serum concentration versus time profiles of nivolumab and, if deemed appropriate, relevant 
nivolumab PK parameters derived from a population PK model. (37) 
8.1.3. 
Exploratory endpoints 
Exploratory endpoints are:  
 
Potential predictive and PDy biomarkers of Debio 1143 combined with nivolumab, in blood and 
tumor tissue 
 
 
 
 
Best overall response (BOR) evaluation using the novel iRECIST 2017 guideline for 
immunotherapeutics  
 
Correlations between PK disposition of Debio 1143 combined with nivolumab and clinical response 
and/or any tumor metrics 
 
Correlations between PK disposition of Debio 1143 combined with nivolumab and safety profile, 
and PDy if applicable 
 
Correlations between Debio 1143 and Debio 1143-MET1 plasma concentrations and changes from 
baseline QTcF. 
 
Correlations between response, clinical parameters, immune correlates and putative biomarkers, 
 
 
Genetic variations in DMET genes associated with differences in the PK disposition of Debio 1143 
in combination with nivolumab. 
8.2. 
Study assessments 
8.2.1. 
Efficacy  
Tumors will be assessed according to either RECIST version 1.1 guidelines by CT scan or MRI imaging of 
the target/non target lesions (38), and/or GCIG criteria using the serum marker CA-125 for Cohort 4, if 
applicable.(39) 
CT scan and MRI will be performed at screening, then every 8 weeks (± 1-week tolerance window) during 
the first 10 cycles, then every 12 weeks (± 1 week) from Cycle 13 until symptomatic PD or confirmed 
iRECIST PD or start of any new cancer treatment or end-of-life care or  end of the Main study period, 
whichever occurs first. For patients who exceptionally continue study treatment after completion of 13 
cycles, tumor response assessments will continue at 12-week intervals (± 1 week window) until the end of 
the Main study period, and thereafter at the frequency of local institutional care practice until PD, start of 
any new anticancer therapy, death or EOT.  
Imaging will be performed as per site standard but whenever possible using contrast agent at screening and 
during treatment 
CA-125 dosages will be performed at screening exclusively in patients included in Cohort 4. In case of 
abnormally elevated levels before treatment start, these dosages will be repeated on Day 1 of each 
subsequent cycle. 
In case of response, efficacy assessments will be repeated 4 weeks later after first documentation (+ 1-week 
tolerance window). All patients will have an efficacy assessment (CT scan/MRI or serum CA-125 dosage) 
at the time of disease progression and/or treatment discontinuation, whichever occurs first.  
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As an exploratory analysis, tumor response will also be assessed using the iRECIST criteria (novel modified 
RECIST v1.1 guideline for immunotherapeutics).(40) These exploratory analyses will be described in the 
SAP. 
Patients with asymptomatic, but radiologically observed unconfirmed PD as per iRECIST, may continue 
the study treatment, upon both the Investigator’s request and the Sponsor’s agreement, until PD is 
confirmed as per iRECIST or symptoms occurs or Investigator/patient decision to withdraw treatment, 
whichever occurs first. 
8.2.1.1. 
Measurability of tumor lesions 
Patients must have at least one measurable tumor lesion, according to the RECIST version 1.1 criteria (38) 
and/or GCIG criteria (Cohort 4), if applicable.(39) 
As per RECIST v1.1 guidelines, measurable tumor lesions must be measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded except for measurable lymph nodes) with 
a minimum size of: 
 
10 mm by CT scan (slice thickness ≤5 mm) 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non measurable) 
 
20 mm by chest X-ray 
 
Malignant lymph nodes: ≥15 mm in short axis when assessed by CT scan (slice thickness ≤5 mm). 
Only the short axis is measured. 
As per GCIG criteria (Cohort 4, if applicable), patients can be evaluated according to CA-125 only if they 
have a pretreatment sample that is at least twice the upper limit of the reference range and within 2 weeks 
before starting the treatment. 
8.2.1.2. 
Methods of tumor assessment 
The choice of the imaging method for tumor assessment is taken by the site, based on local feasibility and 
clinical adequacy. However, the same method of assessment and the same technique must be used 
throughout the trial for any given patient. Extent of disease evaluation by institutional guidelines per 
RECIST includes CT scan with IV contrast of the thorax, abdomen, and pelvis as well as other anatomical 
areas as appropriate (i.e., CNS imaging for symptomatic SCLC patients, if appropriate). Of note, all known 
or suspected disease-involved areas assessed at screening should be at least, included in all subsequent 
assessments. MRI may be used to assess sites of disease not adequately imaged by CT or in patients known 
to have an allergy to iodine-containing contrast or moderate to severe renal impairment (calculated 
creatinine clearance <50 ml/min-1). 
For Cohort 4 exclusively, extent of disease evaluation by the GCIG criteria includes a monthly dosage of 
the serum tumor marker CA-125, if applicable, in patients without RECIST measurable disease in ovarian 
cancer, fallopian cancer, PPC, and/or endometrial cancer with elevated CA-125. 
8.2.1.3. 
Tumor response criteria  
For the evaluation of target lesions by the RECIST v1.1 criteria, following definitions will be applied (38): 
 
CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short 
axis to <10 mm. CR must be confirmed by repeat assessments performed no less than 28 days after 
the criteria for response are first met to qualify as CR. 
 
PR: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline 
sum diameter. PR must be confirmed by repeat assessments performed no less than 28 days after 
the criteria for response are first met to qualify as PR. 
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 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered 
progression. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for disease progression, taking as reference the smallest sum diameter while on study. 
As per the GCIG criteria (Cohort 4, if applicable), a CA-125 response is defined as at least a 50% reduction 
in CA-125 levels from a pretreatment sample for patients whose CA-125 level was greater than twice the 
upper limit of the reference range when they started treatment.  
Progressive disease definitions are provided in Appendix C: Response to treatment criteria.  
8.2.2. 
Safety  
Safety assessments will include vital sign measurements, physical examination findings, clinical laboratory 
results, ECOG-PS, ECGs, AE monitoring, and concomitant medications. The schedule of assessments is 
presented in Table 8-6.   
8.2.2.1. 
Adverse events and concomitant medications 
AEs will be monitored and recorded throughout the study, from the time the informed consent form (ICF) 
is signed until up to 5 months after last nivolumab administration provided no new anti-cancer or end-of-
life care was started earlier. Ideally an EOT visit should be planned immediately before whenever is 
feasible. 
AEs will be graded according to NCI-CTCAE version 5.0 (see section 9). 
Concomitant medications and procedures, including blood transfusions, will be recorded from signing 
informed consent through EOS. Alternative cancer therapies will also be recorded during OS follow-up. 
8.2.2.2. 
Physical examination, ECOG score, and vital signs 
A complete physical examination will be performed at screening, on Days 1 and 15 of the first three cycles, 
and then on Day 1 of remaining cycles and at EOT. The ECOG-PS will always be measured along with 
vital signs comprising systolic/diastolic blood pressure, heart rate (both after at least 5 minutes of supine 
rest), temperature, and weight at screening, on Days 1, 8, 15, and 22 of Cycle 1, and on Days 1 and 15 of 
other cycles and at EOT. Height will be recorded only at screening. On dosing days, all assessments should 
be performed predose. 
8.2.2.4. 
12-lead ECG  
High-quality, digital triplicate 12-lead ECGs will be recorded after 10 minutes of supine rest at screening.  
High-quality, digital triplicate 12-lead ECGs will be recorded after 10 minutes of supine rest on Day 1 of 
Cycle 1 and Cycle 3  and on Days 8, 15 and 22 of Cycle 1 at the following 3 time points: pre-, 0.5-2h Debio 
1143 post-dose (before starting the nivolumab infusion or after nivolumab perfusion was removed) and 4-
6 h post-dose. ECG readings must be performed prior to PK/PDy sampling. There should be at least 1 
minute between each ECG and all 3 ECGs should be completed within 10 minutes. Reading will be done 
centrally by a dedicated team. For eligibility purposes, the screening reading will be done also locally by 
the investigator or a cardiologist will be consulted if clinically indicated. 
8.2.2.5. 
Safety laboratory  
Safety laboratory measurements are scheduled at screening, C1D1 pre-treatment (only required if screening 
test were performed > 7 days prior to C1D1 or if inclusion/exclusion criteria were not met during screening), 
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on Days 3 (Part A only), 8, 15, 17 (Part A only), and 22 of Cycle 1, on Days 1 and 15 of Cycle 2 and 3, on 
Days 1 of any other subsequent cycle and at EOT. On dosing days, samples will always be collected predose 
and results reviewed prior to nivolumab infusion, if applicable. All measurements will be performed locally. 
On Days 3 and 17 of Cycle 1 for patients included in Part A only, serum will be collected and measured for 
total bilirubin (if >ULN: direct bilirubin should also be measured), alkaline phosphatase (ALP), AST, ALT 
and creatinine.  
For all other visits mentioned above, blood/serum will be measured for the following panels: 
 
Hematology: Hemoglobin, hematocrit, complete blood count (incl. differential) and platelets  
 
Chemistry: Creatinine, sodium, potassium, calcium, total bilirubin (if >ULN: direct bilirubin 
should also be measured), ALP, AST, ALT, amylase, lipase, lactate dehydrogenase (LDH), total 
protein, albumin and C-reactive protein (CRP) 
In addition, the following laboratory measurements will be collected:  
 
 
on Days 1 and 15 of Cycle 1 and Days 1 of each subsequent cycle:  
TSH, free triiodothyronine (FT3), free thyroxine (FT4),  
 
At screening, the following will also be measured: HIV, HBV, and HCV serology, CPK and 
troponins, FSH/LH and total testosterone (in males) or estrogens (in pre-menopausal female 
patients, meaning those whose last menstruation occurred within 12 months of screening date), 
free-cortisol (at morning) and ACTH. These dosages could be repeated if clinically indicated.  
For applicable patients included in Cohort 4, CA-125 dosages will be performed at screening within 4 
weeks of C1D1 and will be repeated on Day 1 of each subsequent cycle, if abnormally elevated levels are 
obtained before treatment start. Patients are evaluable as per GCIG criteria only if they have a pretreatment 
sample that is at least twice the upper limit of the reference range and within 2 weeks before starting the 
treatment. 
8.2.2.6. 
Pregnancy test  
For WOCPBP, a serum test measuring β-HCG will be performed at screening. A predose urine pregnancy 
test at the beginning of each cycle (at C1D1 only required if screening test were performed > 7 days prior 
to C1D1) will be performed as well while on treatment and up to 5 months after of the last study dose, if 
patients is ongoing follow up. 
8.2.3. 
Pharmacokinetics 
PK samples will be collected as described below for determination of Debio 1143 and Debio 1143-MET1 
plasma concentration, and of nivolumab serum concentrations. In addition, samples will be collected to 
allow for determination of nivolumab anti-drug antibodies (ADA), if deemed appropriate to support PK 
data interpretation. After completion of the analysis, the remaining PK samples may be stored for up to a 
maximum of 15 years after the end of the study and, if required, may be used for metabolic profiling, for 
further bioanalytical investigations (such as method cross-validation and protein binding), for a 
retrospective examination of safety laboratory tests or proteins involved in the metabolism or the 
pharmacological effects of Debio 1143 or nivolumab. 
For all PK samples, exact sampling time must be recorded. PK samples will be taken in both parts of the 
study but will differ depending on the administration schedule of nivolumab (i.e., every 15 days throughout 
the study or every 4 weeks after Cycle 2).  
Sampling days and times for PK are listed in: Table 8-1, Table 8-2 and Table 8-3. 
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 
For the determination of Debio 1143 and Debio 1143-MET1, during Cycle 1 PK samples are to be 
collected for Part A on Days 1, 3, 8 15, 17 and 22 and for Part B on Days 1, 8, 15 and 22. During 
Cycle 3, PK samples will be collected for Part A on Days 1, 3, 15 and 17 and for Part B on Days 1 
and 15. During Cycle 6 on Day 1 (in both parts A and B). On Days 1, 8, 15, and 22 of Cycle 1, and 
on Days 1 and 15 of Cycle 3 there are at least two PK samplings on the same day. Samples will be 
analyzed for Debio 1143 and Debio 1143-MET1 using a validated LC/MS/MS method with a lower 
limit of quantification (LOQ) of 2.5 ng/mL for both compounds. 
 
For the determination of nivolumab, during Cycle 1 PK samples are to be collected for Part A on 
Days 1, 3, 8, 15, 17 and 22 and for Part B on Days 1, 8, 15 and 22. During Cycle 3, PK samples 
will be collected for Part A on Days 1, 3, 15 and 17 and for Part B on Days 1 and 15. During Cycle 
6 on Day 1 (in both parts A and B). On Days 1 and 15 of Cycles 1 and 3 there are at least two PK 
samplings on the same day. Nivolumab serum concentrations will be determined using a validated 
electrochemiluminescence (ECL) immunoassay with a lower LOQ of 100 ng/mL.    
 
For ADA, blood is taken predose on Days 1 and 15 of Cycle 1 and 3, on Day 1 of Cycles 6 and at 
EOT for both Parts A and B. For patients entering the Extended study period, the last nivolumab 
ADA will be collected at C13D1 instead of at EOT.  
If deemed appropriate to support PK data interpretation, samples will be analyzed for serum ADA entities 
using a validated immunoassay following a tiered testing approach. 
For all PK measurements, the windows of tolerance for sample collection are provided in Table 8-5. 
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8.2.4. 
Pharmacodynamics and predictive biomarkers 
Tumor biopsies will be collected as follows: 
1. An archived biopsy collected at diagnosis and before any prior PD-1/PD-L1 therapy will be 
provided, if available. 
2. An archived biopsy collected after prior PD-1/L1 therapy will be provided; if not available a 
percutaneous or endoscopic biopsy will be mandatorily collected during screening. 
3. A percutaneous or endoscopic biopsy will be performed (to collect fresh tumor tissue) at the end of 
Cycle 2, if consented and feasible (optional). 
PDy and potentially predictive biomarkers in tumor biopsies may include, but are not limited to 
 
and markers of cell death and proliferation. 
Blood samples for PDy measurements will be collected on Days 1 (pre- and 4 h post-dose Debio 1143), 8, 
15 and 22 (always predose) of Cycle 1, and on Day 1 of Cycle 3. PDy and potentially predictive biomarkers 
in blood 
 
 
For all PDy and biomarker measurements, the windows of tolerance for sample collection are provided in 
Table 8-5. 
8.2.5. 
Pharmacogenomics and pharmacogenetics  
Blood samples will be collected for mRNA analyses (pharmacogenomics PGx PAX gene) at baseline and 
on Day 15 of Cycle 1 and on Day 1 of Cycle 3. Blood for circulating tumor DNA (PGx ctDNA) will be 
collected on Day 1 of Cycle 1, 3 and 6. A blood sample will be collected at baseline to explore genetic 
variations in DMET genes (pharmacogenetics PGt) associated with differences in the PK disposition of 
Debio 1143 in combination with nivolumab.  
Back-up samples for PDy, PGx, and PGt will be stored in a sample storage facility pending use for further 
investigations within the scope of the above- mentioned procedures. The maximum storage period will be 
15 years. 
DNA and RNA samples for future analyses that are not yet defined will be de-identified and re-coded for 
improved protection of patient confidentiality and stored for 15 years. 
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8.3. 
Study procedures 
8.3.1. 
Study plan 
A visit assessment schedule is presented in Table 8-6 and a detailed timetable for visits, and PK, PDy are 
detailed in Table 8-1, Table 8-2 and Table 8-3. 
Study procedures must be performed according to the planned time schedule with strict adherence to visit 
intervals. All patients enrolled in the study will attend the study visits as indicated in the study plan. 
Prior to conducting any of the screening tests, the Investigator or designee will fully explain the study to 
the prospective patient and provide him/her with a copy of the Patient Information Leaflet/ICF.  
If the patient is willing to participate in the study, s/he and the Investigator or designee will both sign the 
document. Of note, CT or MRI scans done before screening, as part of the patient’s standard of care, if 
within the accepted window up to 8 weeks (±1 week) before C1D1, can be used instead of repeating a new 
assessment at screening even if it was done before ICF signature, with patient specific agreement, if deemed 
clinically appropriate by the Investigator. A separate ICF will be signed for participation in the PGx part of 
the study (section 8.2.4). 
Patients will attend the screening visit(s) within 4 weeks prior to the first treatment cycle. The patient’s 
suitability for the study will be confirmed by the inclusion/exclusion criteria (see section 6). 
 
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*  Examinations should be performed in the following order as applicable: physical examination, vital signs, ECG, safety blood/urine samples, followed by blood sampling for PK/PDy according to specific 
instructions, and other examinations: Note: ECGs always have to be taken before PK/PDy sampling. 
 
Assessments should be performed on schedule, but occasional changes may be allowed. If the study schedule is shifted, both assessments and dosing must be shifted to ensure the collection of data is 
completed prior to dosing. Windows:  Laboratory assessments and clinical examinations: Screening period: -4 days (i.e., day -32); EOT visit: ±5 days; follow up visits ±1week, in case of holidays, vacations; 
other administrative reasons: ± 3 days in all cycles. Window for CT/MRI assessment = ± 1 week 
#  
Assessments for concomitant medications, pregnancy test and AEs will be performed only at the first two FU visits, if applicable. CT scan or MRI assessments will be performed until confirmed iRECIST 
PD, symptomatic PD or any new anticancer treatment or end-of-life hospice care is started or until EOS whichever occurs first.  
µ  
Height only collected at screening. 
1  
Digital triplicate 12-lead ECGs will be recorded after 10 minutes of supine rest at the following 3 time points: pre-, 0.5-2h Debio 1143 post-dose (before starting the nivolumab infusion or after nivolumab 
perfusion was removed)  and 4-6 h post-dose ;There should be at least 1 minute between each ECG and all 3 ECGs should be completed within 10 minutes or less. ECG readings must be performed before 
PK/PDy sampling. ECG reading will be done centrally and also locally for screening purposes. 
2  
Pre-dose (as per section 8.2.2.5) only required if screening test were performed > 7 days prior to C1D1 or if inclusion/exclusion criteria were not met during screening:  
2a  HIV, HCV and HBV serology testing and CPK and Troponins (I or T whichever is applicable): Only at screening, to be repeated if clinically indicated only. 
2b  FSH/LH and total testosterone (in male) or estrogens (in female patients), free-cortisol (at morning) and ACTH: Only at screening and to be repeated if clinically indicated.  
2c  Hemoglobin, hematocrit, platelets and complete blood cell count and differential counts, creatinine, sodium, potassium, calcium, total bilirubin (if >ULN, then also measure direct bilirubin), ALP, 
AST, ALT, amylase, lipase, LDH, total protein, albumin, CRP.  
2d 
Part A patients (only): Total bilirubin (if >ULN, then direct bilirubin should also be measured), ALP, AST, ALT, and creatinine. 
2e  
TSH, FT3 and FT4: At Day 1 and Day 15 in Cycle 1 and every Day 1 of each subsequent cycle. 
2f  CA-125 to be performed at screening within 4 weeks of C1D1, exclusively in applicable patients included in Cohort 4, and to be repeated before start of each new cycle if abnormally elevated 
before treatment start, unless PD, any new anticancer treatment or end-of-life hospice care is started before. 
3  
In women of childbearing potential only: blood test at screening (only required if screening test were performed > 7 days prior to C1D1), then urine dipstick test alone would be sufficient, at the beginning 
of each treatment cycle while on study up to 5 months after EOT.  
4  
Every 8 weeks (±1 week) from first on-treatment scan until Cycle 10, then from Cycle 13, every 12 weeks (± 1 week) until confirmed iRECIST PD, symptomatic PD or any new anticancer treatment or end-
of-life hospice care is started or until the end of the Main study period whichever occurs first. For patients who continue study treatment in the Extended study period, tumor response assessments will be 
performed at the frequency of local institutional care practice until EOT. All patients will have CT or MRI at the time of disease progression, if none previously available. CT or MRI done before screening, 
as part of patient’s standard of care and not older than 8 weeks (+1-week tolerance) before C1D1 can be used instead of repeating a new assessment at screening even if done before ICF signature with 
patient specific agreement, if deemed clinically appropriate by the Investigator. 
 
A contrast enhanced brain CT or MRI is mandatorily at baseline only in SCLC cohort, subsequent brain scans to be done if clinically indicated. 
5  
Up to 3 tumor tissue samples will be collected:  
1) An archived biopsy at diagnosis (before prior PD-1/PD-L1 therapy) = optional;  
2) An archived biopsy if collected after prior PD1/PD-L1 or, if not available a fresh biopsy collected at screening will be mandatory;  
3) A fresh biopsy collected at end of Cycle 2 (day 28=Day 1 of the following cycle) = optional 
6  
Timepoints as specified in Table 8-1, Table 8-2 and Table 8-3 and windows of tolerance as specified in Table 8-5.  
6a  
Patients included in Part A only. 
6b  
Debio 1143 PK, nivolumab PK, and nivolumab ADA sample  at C6D1only. In addition, for patients discontinuing the study at the end of the Main study period, the last nivolumab ADA will be 
collected at EOT, and for patients entering the Extended study period, the last nivolumab ADA will be collected at C13D1 instead of at EOT. 
7  
Timepoints as specified in Table 8-4 and windows of tolerance as specified in Table 8-5.   
7a Only at Cycle 6: PGx ctDNA. 
8  
Debio 1143 will be taken orally on D1-10 and D15-24 on an empty stomach (patients will fast for 2 h before dosing and for at least 1 h after dosing) at approximately the same time each day. Water is 
permitted freely. A missed dose can be taken as soon as the patient remembers but no later than 6 h after the planned dose. If >6 h have elapsed, the missed dose should be skipped and the next dose taken 
according to the regular dosing schedule. A double dose should not be taken to make up for a missed dose. Debio1143 will be  given in the hospital (before nivolumab infusion whenever is applicable) 
during: Cycle 1 on Days 1,3 (only Part A), 8, 15, 17 (only Part A), 22; Cycle 2 on Days 1 and 15; Cycle 3 on Days 1, 3 (only Part A) , 15, and 17 (only Part A); and on Days 1 ± 15  of all subsequent cycles. 
The rest of the days will be taken at home following relevant medical instructions. A patient’s diary to record treatment compliance will be provided as a separate document and it will be reconciled with 
the returning capsules by the study nurse. 
9  
Nivolumab will be administered, as per current prescribing information, at a dose of 240 mg, flat dose by IV infusion over at least 30 minutes on Days 1 and 15, every 4 weeks (i.e., 2 infusions in each 
cycle). 
9a  
From Cycle 3 on, the switch to an administration of 480 mg of nivolumab only on Day 1 of each 28-day cycle is allowed based on the Investigator’s judgment and Sponsor’s agreement. 
± Dispensing of nivolumab will depend on the nivolumab schedule administered from Cycle 3 onwards.   
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10  
Continuous AE monitoring, with Investigator’s assessment and documentation at scheduled study visits up to EOT visit and second follow up visit, if applicable. The SAE reporting period is up to 5 months 
after the last nivolumab administration. Patients continuing in follow-up (FU) after EOT, in the first and/or second FU visits will have final AEs update of any ongoing toxicity at this time, if applicable, 
unless start of new anticancer treatment or end-of-life-care, in which case visit should be scheduled ideally before. 
 11     For Part B, visits on Cycle 1 and Cycle 3 on Days 3 and 17 will not be performed 
12    Including information on current and previous tobacco and alcohol use/consumption 
13    Only applicable for patients treated beyond Cycle 13
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8.3.2. 
Study discontinuation 
For patients prematurely discontinuing the study, date and reason of withdrawal must be recorded in the 
eCRF. Only non-evaluable patients will be replaced, as appropriate. 
8.3.2.1. 
End of treatment 
Treatment with Debio 1143 will be continued until any of the following occurs: 
1. Unacceptable toxicity [including, treatment-related NCI-CTCAE v5.0 grade 4 laboratory 
abnormalities (excluding hematological and/or non-febrile asymptomatic neutropenia/leukopenia)] 
that does not resolve with appropriate standard medical measures; or intercurrent illness that would, 
in the opinion of the Investigator, affect assessments of clinical status to a significant degree or 
compromise the patient’s safety; 
2. Permanent discontinuation of nivolumab; 
3. Treatment delay greater than 4 and 8 weeks (+1-week tolerance) for Debio 1143 and nivolumab, 
respectively; 
4. Need to discontinue Debio 1143 due to toxicity despite dose reduction to 100 mg/d; 
5. Prohibited medication as indicated in section 7.7.2 is required/used during the course of the trial. 
In the event a patient is found to be taking a prohibited medication during the trial, the site should 
immediately contact the medical monitor. The decision to withdraw the patient will be made in 
conjunction with the Sponsor; 
6. If a critical protocol violation occurs that may preclude safety continuation of the study for the 
patient, the Sponsor’s trial manager will be contacted to discuss if the patient has to be withdrawn 
from treatment; 
7. Symptomatic disease progression documented by RECIST v1.1 or by GCIG criteria (Cohort 4, if 
applicable) in RECIST non-evaluable patients. However, patients may continue study treatment if, 
in the Investigator’s opinion, there is reasonable evidence of ongoing clinical benefit or suggestion 
of “pseudoprogression” without excess risk of toxicity or complications for the patients.  
8. Confirmed disease progression as per iRECIST; 
9. Any medical condition that the Investigator or Sponsor determines may jeopardize the patient’s 
safety if he or she continues in the study; 
10. Withdrawal of patient’s consent; 
11. Pregnancy or breast-feeding a baby; 
12. Start of any subsequent anti-neoplastic therapy (excluding palliative symptomatic localized RT up 
to 36 Gy total doses for alleviating symptoms e.g. pain, intracranial hypertension, which may 
continue upon the Sponsor’s agreement, if appropriate). These patients will continue only in the 
OS follow-up. 
Patients who discontinue treatment for any of the reasons above will have an EOT visit performed 30 days 
(± 5 days) after the last Debio 1143 administration date, but prior to any further therapeutic intervention, 
whenever possible, otherwise an EOT visit should be ideally scheduled immediately before these events. 
Results of these assessments are to be recorded in the eCRF, together with the reason for treatment 
discontinuation.  
Patients who are taken off study treatment due to AEs are to be treated and followed up according to 
accepted medical practice. All pertinent information concerning the outcome of such treatment is to be 
recorded in the eCRF. 
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8.3.2.2. 
Follow-up 
Patients with confirmed PD at the EOT visit will have an safety follow-up of 5 months (±15 days) planned 
after the last nivolumab infusion, provided no new cancer treatment or end-of-life care has been started, 
otherwise this visit may be done immediately before if any of these occur. Patients without PD documented 
at the EOT visit will continue in follow-up for efficacy every 12 weeks (± 1-week window) until PD or start 
of new treatment or end-of-life care, whichever occurs first. After PD or new cancer treatment or end-of-
life care starts, patients will not attend more onsite visits, however, they and/or relatives may be contacted 
(by telephone, email or mail) every 4 (± 1) months to update the survival status until the end of the Main 
study period (18 months have elapsed since the LPI was included in the study or 60 days after LPLV, 
whichever occurs first). 
 
Follow-up assessments comprise onsite visits: 
 
Safety: For all patients, one first safety follow-up visit will be conducted 90 days (±15 days) after 
last study treatment; a second safety follow-up visit will be scheduled at 5 months (±15 days) after 
the last nivolumab infusion, provided the first safety follow-up visit did not overlap (± 1 week), and 
if the patient is still alive and no further anticancer treatment has been started yet..  
 
Efficacy: Patients without evidence of PD at EOT will be assessed for PD by appropriate methods 
(CT scan or MRI, and clinically) every 12 weeks (±1 week)  until symptomatic PD or confirmed 
iRECIST PD or start of any new cancer treatment or end-of-life care or the end of the Main study 
period, whichever occurs first. For patients who continue study treatment after the Main study 
period, tumor response assessments will continue at the frequency of local institutional care practice 
until PD, start of any new anti-cancer therapy, death or EOT, whichever occurs first.   
 
Survival calls/contact: All patients alive after symptomatic progression or confirmed iRECIST PD 
or start of new anti-cancer treatment will be contacted (by telephone, e-mail or mail) every 4 (± 1) 
months until the end of the Main study period. In case patients cannot be reached, the primary 
physician or the patient’s partner or family may be contacted by the Investigator or designee. 
 
The following scheme summarizes the temporal relationship between EOT and EOS: 
 
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EOS will occur at the End of Main study period or End of Extended study period, whichever occurs last. 
After the End of Main study period no OS follow-up will be performed for patients in the Extended study 
period. 
 
8.4. 
Study duration and EOS 
The study duration for an individual patient completing 13 cycles, will be 52 weeks plus up to 5 months for 
safety follow-up after EOT, excluding a 4-week screening period. Patients will attend the EOT as well as 
any follow-up visits, if applicable.   
Permission to prolong the study treatment for one additional year can be exceptionally granted by the 
Sponsor, if patients are deriving continuous clinical benefit from the study treatment. Medical justification 
for extending the treatment and the assessment of the risk/benefit balance must be provided by the Study 
Investigator and will be discussed with the Sponsor. The decision to further extend study treatment will be 
re-evaluated on a yearly basis for each patient. 
 
The total number of onsite visits per patient will depend on the total number of cycles delivered which is 
based on disease progression, clinical deterioration, investigator criteria, unacceptable toxicity or death 
whichever occurs first. 
The EOS will occur at the End of Main study period or End of Extended study period, whichever occurs 
last.  
The Sponsor will make every effort to supply Debio 1143 and nivolumab to patients who benefit from 
continued treatment; Safety of the patients will be monitored and Health authorities will be notified per 
regulatory requirements. 
Patients will discontinue the study for any of the following reasons: 
1. Patient withdrawal of consent; 
2. Patient lost to follow-up; 
3. Start of end-of-life care; 
4. Death; 
5. Sponsor or Institutional Review Board (IRB)/ Independent Ethics Committee(s) (IEC) decides to 
terminate early the study; 
6. Completion of Main study period, or completion of Extended study period, as applicable. 
9. ADVERSE EVENTS  
The Investigator is responsible for detection and documentation of events meeting the criteria and definition 
of an AE/SAE as provided in this protocol. At each safety evaluation during the study, the Investigator or 
designee will collect information on unusual manifestations or AEs and SAEs and will record them on the 
AE page of the eCRF. Their nature, severity, duration, treatment, and relationship with the IMPs as assessed 
by the Investigator will be recorded. The Investigator will also indicate whether study treatment was 
discontinued and how the event evolved. 
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9.1. 
Definitions and assessment criteria 
9.1.1. 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical trial patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
Thus, any new sign, symptom or disease, or any clinically significant worsening of an existing sign, 
symptom or disease compared to the condition at the first visit (including disease treated), should be 
considered as an AE. Lack of efficacy is not considered as an AE. 
In particular: 
 
Any new sign or symptom reported by the subject that appears after accidental or intentional 
overdose or misuse should be reported as an AE. 
 
Whenever possible, a diagnosis should be reported on the AE form, instead of signs, symptoms or 
abnormal laboratory values.  
 
Pregnancy is not to be considered as an AE; however, it must be monitored as described in Section 
9.5. 
 
Each new episode of a chronic disease (e.g., hay fever, allergy, etc.) from the screening visit should 
be reported as a new AE. 
AEs are illnesses, signs or symptoms (including abnormal laboratory findings) occurring or worsening in 
the course of the study. AEs can be serious or non-serious. They may or may not lead to the withdrawal of 
the patient from the study.  
9.1.2. 
Serious adverse event 
A SAE is defined as any untoward medical occurrence that at any dose: 
 
Results in death; 
 
Is life threatening (i.e., puts the patient 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, or 
 
Is otherwise medically significant: Important medical events that may not immediately be life 
threatening or result in death or hospitalisation, but that jeopardize the patient or require 
intervention to prevent one of the outcomes listed in the definitions above shall also be considered 
as serious. 
All AEs that do not correspond to the definition of SAE are considered as non-serious. 
9.1.3. 
Unexpected or expected adverse events 
An unexpected AE is an event whose nature or severity is not consistent with information on the condition 
under study and/or not consistent with the applicable product information, i.e. the Investigator Brochure. 
All AEs that are suspected to be related to the IMP(s) and that are both unexpected and serious are 
considered to be Suspected Unexpected Serious Adverse Reactions (SUSARs). 
9.1.4. 
Severity of adverse events  
AEs will be graded by the Investigator or designee according to NCI-CTCAE, version 5.0.  
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If a particular AE’s severity is not specifically graded by this guidance document, the Investigator is to 
revert to the general definitions of grades 1 to 5 and to use his or her best medical judgment: 
 
Grade 1 (mild): Causing no limitation of usual activities, the patient may experience slight 
discomfort. 
 
Grade 2 (moderate): Causing some limitation of usual activities, the patient may experience 
annoying discomfort. 
 
Grade 3 (severe): Causing inability to carry out usual activities, the patient may experience 
intolerable discomfort or pain. 
 
Grade 4: Life-threatening 
 
Grade 5: fatal 
 
9.1.5. 
Relatedness to IMPs  
The Investigator or designee will determine the relationship between the AE and the IMPs according to the 
following criteria: 
Reasonable causal relationship: 
A clinical event, including laboratory test abnormality, 
 
Where time relationship to drug administration is at least reasonable, and  
 
Where other causes (e.g. underlying disease) may not by themselves explain the event, and/or 
 
Where a clinically reasonable response occurs on withdrawal (dechallenge). 
No reasonable causal relationship: 
A clinical event, including laboratory test abnormality, 
 
Where time sequence to drug administration is not reasonable, or 
 
Where other causes (e.g. underlying disease) can by themselves provide plausible explanations. 
9.1.6. 
Adverse events of special interest 
AESIs are  
1. for Debio 1143:  
a. AST or ALT increases >3 ULN associated with total bilirubin >2 ULN and ALP <2 ULN 
b. Lipase or amylase increases >5 ULN  
c. Any QTcF prolongation above 30 ms compared to baseline on at least two consecutive 
readings or other ECG abnormalities such as Torsade de Pointe, ventricular tachycardia, 
ventricular fibrillation, flutter or any other new cardiac abnormality at the ECG or during 
the physical examination considered as clinically significant. 
2. for nivolumab: 
a. Any AEs that are suspected to be immune-related or infusion-related including drug 
hypersensitivity, immune-related pneumonitis, immune-related colitis, immune-related 
hepatitis, immune-related endocrinopathies such as: thyroid disorders, adrenal 
insufficiency, new onset type I diabetes mellitus, pituitary disorders; or immune-related 
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nephritis and renal dysfunction and other immune-related AEs such as: myositis, 
myocarditis, Guillain-Barré syndrome or uveitis of any grade  
All AESIs, occurring after treatment start on C1D1 must be reported to the sponsor in the appropriate eCRF 
pages. When reporting these cases, it has to be specified in the eCRF whether the case is serious or non-
serious. If the AESI(s) is/are serious or considered to be a DLT, then it has to be properly reported within 
24 hours of acknowledgement and all applicable SAEs reporting guidelines should be followed (as 
described in section 9.2) including the reason why it is considered serious. 
 
9.2. 
Reporting of serious adverse events to the Sponsor  
9.2.1. 
Reporting during the study 
The Investigator must notify the Sponsor/Clinical Research Organization (CRO) of all SAEs within 24 
hours of awareness by completing the AE form provided in the eCRF. Once the AE is selected as a Serious 
event and the form is saved in the eCRF an email notification will be sent automatically to the Sponsor’s 
Pharmacovigilance department. 
If for any reasons the eCRF is not available, as a back-up option the SAE can be declared by e-mail using 
the Debiopharm International (DPI) paper 'SAE Report form', or by telephone. 
1. When reported by e-mail, the 'SAE Report form' will be sent to the following e-mail address: 
‘
’ (
) or CRO email 
address if applicable.  
2. When reported by telephone, the DPI Pharmacovigilance Officer will be notified as specified in the 
site study file.  
This should be followed by the completion of the AE form in the eCRF as soon as possible 
The processes are fully described in separate guidelines and will be provided to investigators with the 
protocol. 
Notification of SAEs does not depend on their relationship with the IMP(s). All SAEs regardless of their 
relationship with the study drugs and occurring until the last study visit will be reported as described above.  
9.2.2. 
Reporting post-study 
Any SAE occurring up to 5 months from the last nivolumab infusion date will be reported in the appropriate 
eCRF pages and within one day of SAE awareness as described in section 9.2.1 
9.3. 
Follow-up of serious adverse events 
All SAEs, regardless of severity, must be followed up: 
 
To resolution (the patient's health has returned to the baseline status or all variables have returned 
to normal), or  
 
Until stabilization of the event has occurred (the Investigator does not expect any further 
improvement or worsening of the event), or  
 
Until the event is otherwise explained regardless of whether the patient is still participating in the 
study.  
Some events, such as metastases, are often ongoing; however, once these events have been determined by 
the principal Investigator to be stable or chronic, he/she may consider the event to be resolved or resolved 
with sequelae. 
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The Investigator will notify the Sponsor of any follow-up information in the eCRF pages within 24 hours 
of new information awareness (see section 9.2.1). 
9.4. 
Procedure for SAE communication 
If required by applicable local regulations, the Investigator will promptly notify the relevant IRB/IEC (in 
addition to the Sponsor) of any SAE (including post-study SAEs and follow-up information) that occurred 
at their site or was brought to their attention by the Sponsor. The Investigator will verify that the IRB/IEC 
acknowledges receipt of the notification. 
In case of Suspected Unexpected Serious Adverse Reactions (SUSARs), unusual increase in the frequency 
or the severity of expected SAEs or new safety data which could have an impact on the overall expectedness 
of a SAR or change in the safety profile of the investigational product(s) that requires the informed consent 
to be updated, the Sponsor will prepare investigator safety reports according to regulatory requirements 
relating to safety reporting. 
This report will be communicated by the Sponsor to all the investigators involved in clinical studies with 
Debio-1143 to ensure that any ongoing subjects can be promptly informed. 
9.5. 
Pregnancies 
Pregnancies should be avoided during the study. Any patient who nevertheless becomes pregnant must be 
followed-up until pregnancy outcome is known. 
Pregnancies shall be reported from the Investigational site to the Sponsor using a Pregnancy Report Form. 
The same process and timelines as defined for SAE reporting apply (section 9.2.1). In case of serious 
outcomes experienced by the parent and/or the fetus/child (definition of ‘seriousness’ in section 9.1.2), the 
events should be reported as SAEs using the SAE report form. This procedure applies to pregnancies in 
female patients as well as to those in female partners of male patients. 
10. 
MONITORING AND STUDY COMMITTEES 
10.1. Monitoring 
The study Sponsor is Debiopharm International S.A (DPI), Lausanne, Switzerland. 
A designated Contract Research Organization (CRO) will perform site monitoring.   
At mutually convenient times during the study, the Investigator will let DPI or its representative review all 
eCRFs and related source documentation, i.e., patient office, hospital, clinic, and laboratory records.  
At timely intervals, and at the closing of the study, all IMPs will be accounted for and dispensing records 
made available to DPI or its representative (see also sections 7.3 and 7.6). 
In case eCRFs require support information, DPI may request copies of patient records or other source 
documents. All the necessary steps will then be taken to protect patient identity. Adherence to local and 
national laws governing protection of patient identity will be ensured. 
10.2. Study committees 
10.2.1. 
Data Safety Monitoring Committee  
A Data Safety Monitoring Committee (DSMC) will overview study conduct during both parts A and B. It 
will be composed of at least all actively involved investigators (or their designee), the Sponsor Medical 
Director and the CRO medical monitor as voting members and will meet regularly to overview the clinical 
safety of the patients, laboratory data and the conduct of the study. Ad hoc members may be invited as 
needed. 
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During Part A, calls will be scheduled monthly or according to patient recruitment as necessary. A charter 
will be provided as a separate document. 
During part B the DSMC will meet approximately every three months, but more frequently if needed due 
to rapid recruitment. A charter will be provided separately. 
11. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
11.1. Sample size 
 
Part A  
The sample size will be determined by the number of patients included per dose level and the observed 
toxicities. Given that (i) a maximum number of two dose levels will be explored, (ii) a classical 3+3 design 
will be used and (iii) at least 6 patients need to be treated at the RP2D before the phase II part starts formally, 
between 3-12 evaluable patients will be included. Patients non-evaluable for DLT will be replaced as 
appropriate. 
 
Part B 
The efficacy of Debio 1143 in combination with nivolumab will be assessed in each cohort using the 
Bayesian posterior probability with early stopping rules for futility. The primary efficacy endpoint will be 
the confirmed ORR based on RECIST v.1.1 and/or GCIG (Cohort 4, if applicable). Assuming a futility 
response rate of 5% below which the response is considered not clinically meaningful and a true response 
rate of 15% which is considered clinically meaningful, with a maximum sample size of 15 patients per 
cohort, a cohort will be declared successful if there is at least 80% probability that the true response rate is 
>= 15%, which corresponds to 4 responses or more. A cohort will be declared futile if there is sufficiently 
low probability (20%) that the true response rate exceeds 5%. The first futility assessment will be performed 
after the first 8 patients are assessed and the second one after 11 patients. Futility assessment will be 
performed using the unconfirmed responses. 
The total sample size will be between 32 (if all cohorts are futile) and 60 evaluable patients (if none of the 
4 cohorts is futile) and no patient replacement occurs.  
11.2. Data management and handling  
11.2.1. 
Data capture, verification and validation 
Data entry, verification and validation will be captured using an electronic data capture (EDC) system. EDC 
system is a web-based computerized system designed for the collection of clinical data in electronic format 
(electronic case report forms (eCRF)); accessed via an Internet URL link.  
EDC system access (username and password) will be provided upon completion and confirmation of 
prerequisite training. Username and passwords are personal and confidential and must not be shared. 
The Investigator and/or designee will accurately, completely, and in a timely manner enter the required 
study data into the eCRFs. One eCRF will be completed for each patient. 
Validation of the eCRF data is performed by i) automatic EDC system checks and ii) other data review 
tools, such as data listings. Data validation may result in the generation of queries. A query is a request for 
further information or clarification which may lead to data change. All queries (automatic and manual) will 
be generated and tracked within the EDC system until resolution. Manual queries can be raised directly into 
the EDC system by the clinical study team depending on the assigned EDC role throughout the duration of 
the study. 
CRA review, source data verification, is conducted on an ongoing basis and is confirmed in the EDC system. 
In general, the CRA review is focused on the quality and integrity of the eCRF data. 
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Data management review is conducted on an ongoing basis, includes the review of all automatic system 
generated queries and is confirmed in the EDC system. In general, data management review is focused on 
the completeness and coherency of the eCRF data, and also includes reconciliation of external data versus 
eCRF data. 
Medical review is conducted on an ongoing basis. In general, this review is focused on the completeness 
and coherency of the safety data. 
The EDC system audit trial captures all eCRF data related activities such as: data entry, data modifications, 
data verification, data lock, e-signature etc.   
eCRF data will be extracted from the EDC system into SAS® on a periodic basis and at defined study 
timepoints for statistical analysis. 
11.2.2. 
Missing data handling for statistical analysis 
For missing or partial AEs and concomitant medications dates, conservative conventions will be applied in 
order to assign the events to corresponding periods. AE will be considered as treatment emergent and the 
medications will be considered as concomitant if the missing/partial dates cannot definitively exclude the 
treatment period. 
Dates of remote events (e.g., medical history) may be partially incomplete, as the day and/or month may 
be unknown. Any missing day will be replaced by the 15th and any missing month by June.  
Imputation of missing data will be described in detail in the statistical analysis plan. 
11.3. Handling of values below (or above) a threshold 
To derive PK parameters and for summary statistics (except for calculations involving logarithmic 
transformations), plasma levels reported as below the LOQ will be considered as 0 when they occur before 
the first quantifiable concentration. When a plasma level is below LOQ between two quantifiable 
concentrations within a dosing interval, it will be set to ½ LOQ.  
For summary statistics where calculation involves logarithmic transformations (including geometric mean 
calculation), plasma levels below LOQ will be set to ½ LOQ. 
For pharmacodynamics parameters and safety laboratory tests, values below or above the limit of detection 
will be substituted with the lower/upper limit of detection. 
11.4. Handling of unscheduled assessments or retests 
The unscheduled assessments and the retests performed before the treatment start will be included in the 
definition of the baseline which is the last value before the treatment start between the planned assessments, 
unscheduled assessments and retests. 
After treatment start, the unscheduled assessments and retests will be used only in the derivation of 
endpoints that are not related to a specific timepoint (e.g. worst laboratory parameter level on-treatment). 
In the timepoint analyses, the original/planned values will be used. 
11.4.1. 
Derived parameters and endpoints 
11.4.1.1. 
Efficacy 
Patients without any new anticancer therapy or PD will be assessed for anti-tumor efficacy every 8 weeks 
(±1 week) during the first 10 cycles and then every 12 weeks (± 1 week) from Cycle 13 onwards until PD 
occurs or start of a new cancer treatment or end-of-life-care or until the end of the Main study period 
whichever occurs first. For patients who continue study treatment after the Main study period, tumor 
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response assessments will continue at the frequency of local institutional care practice until PD, start of any 
new anti-cancer therapy, death or EOT, whichever occurs first.   
Response according to RECIST version 1.1 (38) or GCIG criteria (39) (Cohort 4 for RECIST non-evaluable 
patients) will be assessed in the efficacy and ITT populations. CR and PR must be demonstrated by 
objective tumor assessment (CT scan/MRI or CA-125 dosage) and confirmed 4 weeks later. All patients 
will have a CT scan/MRI or CA-125 dosage at the time of PD. Tumor response will also be assessed by 
using the novel modified RECIST v1.1 guideline for immunotherapeutics, iRECIST.(40) These exploratory 
analyses using iRECIST guideline will be presented in detail in the SAP.  
In case of premature discontinuation with SD at the EOS visit, this SD will be included in the derivation of 
efficacy parameters only if the assessment has been performed at least 35 days after treatment start. 
The start of a systemic new anti-cancer therapy without prior disease progression could potentially impact 
the tumor activity observed, hence potentially biasing the evaluation of Debio 1143 anti-tumor activity. As 
a consequence, no further efficacy data will be collected after the start of any new anti-cancer treatment, 
except for OS, at least until study data cut-off. 
The confirmed response will be used in the primary ORR analysis while a secondary analysis will be 
performed using the unconfirmed response. 
 
Objective response is derived as any PR or CR recorded after the start of study treatment until 
disease progression/recurrence is documented, a new systemic anti-cancer therapy is started or 
analysis cut-off, whichever occurs first. 
 
BOR is the best response (CR, PR, stable disease or disease progression) recorded after the start of 
study treatment until disease progression/recurrence is documented, a new systemic anti-cancer 
therapy is started or analysis cut-off, whichever occurs first.  
 
Disease control is derived as any CR, PR or stable disease reported during the study  
 
Duration of response is the time from documentation of tumor response to disease progression, 
start of a systemic new anti-cancer therapy or analysis cut-off, whichever occurs first. 
 
PFS duration is defined as the time elapsed between treatment initiation and tumor progression or 
death from any cause, whichever occurs first. Censoring to the last assessment will be applied in the 
following situations: a) lost to follow-up, b) no progression before analysis cut-off, c) start of a new 
systemic anti-cancer therapy. The median PFS and the PFS rate at 6, 12 and 18 months will be 
derived from the Kaplan-Meier curves.  
 
OS is defined as the time elapsed between treatment initiation and death from any cause. In the main 
analysis, censoring to the last assessment will be applied in the following situations: a) lost to follow-
up, b) alive at analysis cut-off. A sensitivity analysis will be performed by censoring the OS at the 
time of start of a new systemic anti-cancer therapy. The median OS and the OS rate at 12 months 
will be derived from the Kaplan-Meier curves. 
11.4.1.2. 
Safety  
A TEAE is any new, related or non-related, undesirable medical occurrence or change of an existing 
condition in a patient that occurs during the treatment-emergent period, starting or worsening on or after 
the first study drug administration and up to 5 months (±15 days) after last nivolumab infusion, or the 
earliest date of new anticancer therapy – 1 day, whichever occurs first. 
11.4.1.3. 
Pharmacokinetics  
Based on sparse plasma concentrations, Debio 1143 and Debio 1143-MET1 PK parameters will be 
evaluated from the population PK disposition model available to date (36) via a population approach with 
nonlinear mixed effects modelling using NONMEM® (ICON Solutions). If appropriate, post-hoc estimates 
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of AUCs, Cmax and Cmin will be derived for Debio 1143 and Debio 1143-MET1. Inter- and intra-individual 
PK variability will be assessed by pooling data of this study with those of other clinical trials. 
For nivolumab, serum concentration versus time profiles will be analyzed. If deemed appropriate, 
nivolumab concentrations will be integrated in a population PK model (37) to estimate relevant PK 
parameters.   
These population PK analyses will be described in a separate analysis plan and reported separately. 
If data allow, a non-compartmental PK analysis for Debio 1143 and Debio 1143-MET1 may also be 
performed using Phoenix™ WinNonlin® (Certara L.A.). As appropriate, this analysis will also be described 
in a separate analysis plan. 
11.4.1.4. 
Coding 
Medical history, AEs, concomitant treatments and/or procedures, and surgeries will be coded per SOC and 
PT using the last available version of the Medical Dictionary for Regulatory Activities (MedDRA). Past 
and concomitant medications will be coded per anatomical therapeutic chemical (ATC) class levels 2 and 
4 using the last available World Health Organization (WHO) Drug Dictionary.  
11.5. Selection of patients for statistical analysis 
11.5.1. 
RP2D population (part A only) 
Patients will be considered as not evaluable for DLTs and excluded from the RP2D population, if they did 
not receive at least 70% of Debio 1143 (i.e., a maximum of 6 missed Debio 1143 doses) and at least one 
nivolumab dose as planned in Cycle 1 for any reason other than DLT. 
Patients not evaluable for DLT will be replaced if there are less than 3 evaluable patients by cohort. 
If a treatment modification during the DLT period leads to a potentially non-evaluable patient, the final 
decision regarding the patient’s evaluability will be taken only at the end of his/her DLT period. If the 
patient experiences a DLT, he/she will be considered as evaluable regardless his/her exposure.   
11.5.2. 
Safety population  
The safety population is defined as enrolled patients who received at least one dose of any study drug.  
11.5.3. 
ITT population  
The intention-to-treat (ITT) population will include all enrolled patients who took at least one dose of any 
study drug. This is to exclude the patients who took no trial medication. Therefore, the ITT population is 
identical with the current Safety population. 
11.5.4. 
Efficacy population  
The efficacy population is defined as patients who have: 
 
measurable disease according to RECIST v1.1 and/or GCIG criteria (Cohort 4, if applicable) 
and 
 
a baseline tumor assessment and at least one post-baseline tumor assessment, either CT or MRI for 
RECIST evaluable patients, or CA-125 dosage performed after baseline, if applicable,  
or  
 
treatment discontinuation occurred before the efficacy assessment was done due to treatment 
failure, defined as: death, unacceptable toxicity, clinical deterioration and/or symptoms worsening 
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Patients with treatment failure will not be replaced and will be included in the efficacy population.  
In case of non-permitted concomitant treatments or critical protocol violations that may affect the patient 
benefit/risk balance (i.e., non-eligibility criteria), efficacy data assessed after such protocol violations will 
be excluded from the efficacy analysis, as appropriate, but the patient will be kept in the efficacy population. 
This will be described in detail in the statistical analysis plan (SAP).  
11.6. Statistical analysis 
The statistical analysis described below corresponds to what is foreseen during the planning of this study. 
If during the study, circumstances should arise that render this analysis inappropriate, or if in the meantime 
improved methods of analysis should come to light, a different analysis may be performed. Therefore, the 
definitive statistical analysis will be described in the SAP. Any deviations from this plan, reasons for such 
deviations, and all alternative or additional statistical analyses that may be made, will be described in the 
final report. 
Ordinal and continuous data will be presented, in the form of descriptive statistics, as number of patients, 
mean, standard deviation, minimum, median, maximum, and 95% confidence interval (CI). In addition, for 
PK parameters (see section 11.6.4.5), the geometric mean, 90% CIs of geometric means, the standard 
deviation of the geometric means, and geometric coefficient of variation (CV%) will be presented if 
applicable. Categorical data will be presented, using contingency tables with absolute and relative 
frequencies. 
For Part A, the results will be reported overall and by dose, while for Part B, the results will be reported by 
cohort and overall (except for efficacy in case of heterogeneous data and futile cohorts). 
All data analyses will be performed using the statistical softwares SAS®, R, NONMEM®, and Phoenix™ 
WinNonlin®. 
11.6.1. 
Part A 
Due to the nature and design of the study, the statistical analysis of the dose-optimization part will be mostly 
descriptive unless otherwise specified.  
11.6.2. 
Part B 
Part B of the study is an exploratory basket trial intended to assess the preliminary efficacy of Debio 1143 
in combination with nivolumab in four indications and promising efficacy results should be further 
evaluated in subsequent trials. Due to the exploratory nature of the trial, there will be no formal hypotheses 
testing. 
Bayesian posterior probability will be used for the early stopping rules for futility and to assess the efficacy. 
The claim of efficacy will be based on the primary endpoint (confirmed ORR), while the futility stopping 
rules will use the unconfirmed ORR.  
Recruitment will be stopped in the futile cohorts. A homogeneity test will be conducted in the non-futile 
cohorts showing a confirmed response rate of at least 15%. In case of homogeneous response rates across 
the cohorts, efficacy data will be pooled and all the efficacy endpoints will be reported overall and by 
cohort. Otherwise, the efficacy will be reported by cohort only. The efficacy of the futile cohorts and of the 
cohorts with less than 15% response rate will be reported separately.  
All other endpoints such as demographics, baseline characteristics, safety, PK, PDy, etc. will be presented 
overall and for each cohort.  
 
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11.6.3. 
Interim analyses 
Part A 
No formal interim analysis will be performed during the dose-optimization part; review of ongoing data 
will be done when dose increase, repeat or decrease is to be decided at DSMC meetings.  
Part B 
There will be two interim futility analyses in each cohort. The cut-off for the futility analyses is defined as 
the time when the last ongoing patient from the first 8/11 evaluable patients has at least 2 post-baseline 
tumor assessments or prematurely discontinued. 
No formal interim analysis will be performed during the futility monitoring. Only the number of patients 
with, at least, unconfirmed responses as per RECIST v1.1 and/or GCIG criteria (if applicable) will be 
checked vs. the futility boundaries in each cohort independently.  
Bayesian posterior probability of the unconfirmed objective rate will be used for the early stopping rules 
for futility.  
 A general confirmed response rate of 15% is considered as promising, justifying further development. This 
corresponds to approximatively 17% unconfirmed response rate. On the other hand, 5% is considered to be 
the general futility response rate (unconfirmed). 
Assuming a probability confidence threshold for futility stopping of 20%, and a maximum sample size of 
15 patients by cohort, the futility stopping boundaries are defined for each cohort as follows:   
 
0 unconfirmed response out of 8 evaluable patients for the first interim analysis and  
 
≤1 unconfirmed response out of 11 evaluable patients for the second interim analysis.  
Consequently, if no unconfirmed objective response is documented as per RECIST v1.1 and/or GCIG 
criteria (if applicable) after the 8th evaluable patient is assessed, futility will then be concluded and the 
recruitment will be stopped in the corresponding cohort. In case at least one unconfirmed response is 
documented in the first 8 evaluable patients, recruitment shall continue up to 11 evaluable patients and a 
second futility analysis will be conducted. If at least two unconfirmed responses are documented in the first 
11 evaluable patients, the recruitment will continue up to 15 evaluable patients; otherwise the recruitment 
will be stopped. The early stopping for futility is binding.  
11.6.4. 
Final analysis 
The final analysis will be performed within one year of the End of the Main study period (which lasts until 
18 months after LPI or 60 days after last LPLV, whichever occurs first). 
Data collected after the Main study period for patients entering the Extended study period, will be 
summarized using descriptive statistics and included in an addendum to the Final CSR. 
The main study results will be presented separately for both study parts. An exploratory analysis will be 
conducted by pooling demographics, baseline characteristics and safety, data from both study parts. In 
addition, if homogeneity tests allow, and any specific cohort population is adequately represented in Part 
A, efficacy data form both study parts may be pooled exploratory, as appropriate. 
In Part B, according to the Bayesian posterior probability used in each non-futile cohort at the final efficacy 
assessment conducted in the 15 evaluable patients, the first proof of efficacy will be claimed if at least four 
confirmed responses are reported in these 15 evaluable patients. This efficacy boundary was derived 
assuming a confirmed ORR of 15% and a probability confidence threshold of efficacy of 80%. 
A homogeneity test of the primary endpoint will be conducted in the non-futile cohorts showing a confirmed 
response rate of at least 15%. In case of homogeneous response rates across the cohorts, efficacy data will 
be pooled and all the efficacy endpoints will be reported overall and by cohort. Otherwise, the efficacy will 
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be reported by cohort only. The efficacy of the futile cohorts and of the cohorts with less than 15% response 
rate will be reported separately.  
All other endpoints such as demographics, baseline characteristics, safety, PK, PDy, etc. will be presented 
overall and for each cohort. 
11.6.4.1. 
Disposition of patients, demographic and baseline data 
Disposition of patients enrolled and treated will be presented with reasons for patient discontinuation if 
applicable. The number of patients at each study visit will be tabulated. Frequency distribution of adherence 
to the visit schedule and assessments will be given according to the protocol schedule. 
Demographic and baseline data will be summarized overall and by dose for each study population. Ordinal 
and continuous data will be presented as descriptive statistics, i.e. median, mean, standard deviation, min-
max and 95% CI. Characteristics of baseline categorical parameters will be presented as contingency tables 
with absolute frequencies and percentages, and with 95% CI where applicable. 
Medical history and prior anti-cancer treatments will be presented for the safety population as the 
number/proportion of patients and the number of mentions. Medical history and prior anti-cancer treatments 
will be classified by the MedDRA dictionary, per SOC and PT and/or by the WHO drug dictionary by ATC 
class levels 2 and 4.   
11.6.4.2. 
Investigational medicinal product, concomitant medication, 
and illnesses 
Extent of exposure  
Extent of exposure will be summarized in the safety, efficacy and RP2D populations for Debio 1143 as 
follows:  
• 
The number of administrations and total cumulative dose will be summarized as descriptive 
statistics; 
• 
Treatment delays and dose reductions will be summarized as descriptive statistics; 
For nivolumab, the extent of exposure will be summarized in the safety, efficacy and RP2D populations as 
follows: 
• 
The number of cycles and total cumulative dose will be summarized as descriptive statistics; 
• 
Treatment delays and dose reductions will be summarized as descriptive statistics; 
• 
The treatment-specific window used for the selection of the “exposure on-treatment period” safety 
and efficacy assessments is defined as: 
• 
Debio 1143: last administration + 5 half lives (~32 hours) 
• 
Nivolumab: last administration + 14 or 28 days as applicable (depending on nivolumab schedule 
used in last cycle) 
Concurrent diseases, concomitant medications, procedures and surgeries will be presented in the Safety 
population as the number/proportion of patients and the number of mentions. Concomitant procedures and 
surgeries will be classified by the MedDRA dictionary, per SOC and PT. Concomitant medications will be 
presented using the WHO drug dictionary by ATC class levels 2 and 4.  
Concomitant medications will be split into three categories: pre-medications (medications administered 
only before treatment start), co-medications (medications administered during investigational product 
administration) and post-medications (new anticancer therapies started after treatment stop). If applicable, 
procedures and surgeries will be split as pre-, concomitant, and post-treatment. 
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ECOG-PS 
ECOG-PS will be presented as contingency tables by assessment timepoint. 
ECG 
Digital High-Quality ECG will be obtained by triplicate at pre-treatment, on-treatment, and change from 
pre-treatment to on-treatment will be analyzed centrally and will be presented as descriptive statistics, as 
appropriate. The number and percentage of patients with significant QTcF prolongation will be reported as 
contingency tables. Significant QTcF prolongation is defined as an interval >500 ms or an interval which 
increases by 60 ms over baseline. Several QTc prolongation analyses using different categories limits 
(>450, >480 and >500 ms, as well as increases from baseline of >30 ms and >60 ms) will be performed as 
per ICH-E14 guidelines. 
11.6.4.5. 
Pharmacokinetics  
PK concentrations will be presented by timepoint and by dose (Part A) and overall and by cohort (Part B) 
as descriptive statistics for Debio 1143 and Debio 1143-MET1.  
Descriptive statistics will include the number of patients, arithmetic mean, standard deviation, minimum, 
median, maximum, CV%, geometric mean, standard deviation of the geometric mean, geometric CV%, 
and 90% CI of geometric mean. 
Graphic displays of plasma concentration vs. time curves will be presented individually by patient and as 
arithmetic means ± arithmetic standard deviations using linear/linear scales and as geometric means ± 
geometric standard deviations using log10/linear scales. 
PK parameters will be listed by patient and summarized as descriptive statistics. 
PK data will be presented similarly for nivolumab, when applicable.  
The relationship between PK disposition and clinical response, PDy, QTcF variations, safety and genetic 
variations in DMET genes will be analyzed by regression methods or association analyses. 
11.6.4.6. 
Pharmacodynamics 
 
Pharmacodynamics at baseline, at any scheduled visit, and the corresponding fold changes (log2) from 
baseline will be presented using descriptive statistics. The maximum increase on-treatment will be similarly 
presented, along with its fold change from baseline. 
Graphics displaying PDy parameters absolute values and fold changes from baseline will be presented as 
individual curves and mean curves (±standard deviation) vs. time.  
Exploratory data analyses will be conducted to investigate the relationship between PDy biomarkers and 
efficacy and safety parameters by using regression methods. 
11.6.4.7. 
Pharmacogenetic factors and predictive biomarkers 
Pharmacogenetic factors and predictive biomarkers assessments are exploratory. The relationship between 
efficacy, pharmacogenetic factors and predictive biomarkers will be analyzed by regression methods. 
12. 
SPONSOR AND INVESTIGATOR OBLIGATIONS 
12.1. Good Clinical Practice and Declaration of Helsinki 
This trial will be conducted in compliance with the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines (and the ethical principles that have their origin in the Declaration of 
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Helsinki see Appendix A in Section 14.1 and its subsequent amendments) as well as with all the applicable 
local regulations for clinical trials involving human subjects. 
12.2. Institutional Review Board / Independent Ethics Committee 
The study protocol, ICF, and any other relevant study documentation must be reviewed and approved by 
an appropriate IRB/IEC that conforms to local laws, prior to enrolment of patients into the study. It is the 
responsibility of the Investigator to assure that all aspects of the institutional review are conducted in 
accordance with local regulations and applicable ICH GCP. A letter documenting IRB/IEC approval (in 
which the protocol [title and protocol number is specifically identified) and a list of IRB/IEC members and 
affiliations must be received by the Sponsor prior to initiation of the study. If applicable, the Investigator is 
responsible for submitting an Investigator Progress Report to the IRB/IEC in time for the IRB/IEC to carry 
out review prior to the expiration date of the current IRB/IEC approval. This is required as long as the study 
is ongoing. 
The Investigator will inform the IRB/IEC of the completion or early termination of the study.  
Every serious or unexpected AE that might affect patient safety must be brought to the attention of the 
IRB/IEC by the Investigator. Similarly, every report from the Sponsor concerning an AE must be brought 
to the attention of the IRB/IEC by the Investigator if applicable as per local guidelines. 
12.3. Informed consent 
The Investigator or designee will ensure that signed ICF in accordance with the Declaration of Helsinki, 
local laws, and all applicable regulatory requirements, is obtained from each potential patient prior to any 
study related procedure. The informed consent process will be documented.  
Each patient will be given oral and written information in an easily understandable language describing the 
nature and duration of the study. This must take place under conditions where the patient has adequate time 
to consider the risks associated with study participation.  
A least one original of the ICF will be signed by the patient (and/or legal authorized representative 
[guardian, next of kin, or other authorized individual] if applicable) and the Investigator or designee. One 
signed original or a copy of the original will be given to the patient and the original one will be kept in the 
Investigator file at the study site.  
12.4. Patient confidentiality 
The Investigator will ensure that patient reports and samples are identified only by a patient identifier to 
maintain patient confidentiality. All patient study records will be kept safely in an access-controlled area. 
Identification code lists linking the patient names to identifiers shall be stored separately from patient 
records. Clinical information will not be released without written permission from the patient, except for 
monitoring and/or audit by Regulatory Authorities or the study Sponsor. 
12.5. Data reporting and electronic case report forms 
The Investigator and/or designee will accurately, completely, and in a timely manner enter data resulting 
from execution of the protocol into eCRFs made available by the Sponsor via an EDC system, i.e. a web-
based computerized system designed for the collection of clinical data in electronic format. One eCRF will 
be completed for each patient and must be electronically signed and dated by the principal Investigator or 
may be signed by the study Co-investigator on behalf of the principal Investigator. Corrections in eCRFs 
will be recorded in an audit trail. The data will be extracted from the eCRF database periodically after 
interim and final database locks. At the EOS, each site will be given a CD-ROM with all study data entered 
by EDC. 
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12.6. Retention of data 
The Investigator will maintain adequate study records including the CD-ROM with electronically collected 
study data, medical records, laboratory reports, ICFs, drug disposition records, safety reports, information 
regarding participants who discontinued and other pertinent data, such as letters and administrative 
documents exchanged between the Sponsor and the center. Records can be in paper or electronic format. 
All study records must be retained by the Investigator for the maximum period of time authorized by the 
hospital, institution or surgery but in no case for less than 15 years after study completion. 
To avoid any possible errors, the Investigator must contact the Sponsor prior to the destruction of any study 
records or if leaving the institution where the study was conducted. The Investigator will notify the Sponsor 
in the event of accidental loss or destruction of any study records. 
12.7. Deviations from the protocol/protocol amendments 
As per Sponsor’s standard practice, in general, no waivers will be granted. In case of medical emergencies, 
the Investigator will use medical judgment and will remove the participant from immediate hazard. The 
Sponsor and/or the CRO medical monitor and the IRB/IEC will be immediately notified of the type of 
emergency and course of action taken. Permanent changes to or deviations from the protocol will be 
formalized in an amendment to the protocol. 
The amendment must be approved by the Sponsor, Health Authorities and the respective IRB/IEC prior to 
implementation. If the change implies a modification of treatment or of patient evaluation tests, a new 
version of the ICF must be prepared and submitted for approval to the IRB. The Sponsor will assume any 
responsibility or liability resulting from a change in the protocol, only if the change has been approved in 
writing by himself and the IRB/IEC. 
The Sponsor will promptly notify the relevant Health Authorities, IRB/IEC and/or Investigators, as 
applicable, of any confirmed serious protocol deviations that may have an impact on subject safety or 
increase the risk/benefit ratio as a result for any participating subjects. 
12.8. IMP accountability 
The Investigator must maintain accurate records of the IMP(s) received from the Sponsor. These records 
will include receipt, preparation (for nivolumab), and dispensing dates, and dates of return and/or 
destruction of unused supplies.  
At trial termination, clinical supplies must be accounted for and a written clarification provided in case of 
discrepancies. All unused supplies must be properly destroyed at the study site or returned promptly to the 
Sponsor; written authorization from the Sponsor must be obtained prior to destruction which must be 
documented.  
When the above tasks are delegated to a pharmacist, the Investigator remains ultimately responsible for the 
maintenance of accurate drug dispensing records. 
12.9. Study monitoring 
At agreed times during the study and after the study has been completed, the Investigator will let Sponsor 
representatives periodically review the eCRF and corresponding office, hospital, and laboratory records 
(source documents) of each study patient. The eCRFs must be completed by the Investigator on a regular 
basis and prior to each monitoring visit. 
Monitoring visits allow the Sponsor or a mandated CRO to evaluate study progress, verify accuracy and 
completeness of eCRFs, resolve any inconsistencies in the trial records, and ensure that all protocol 
requirements, applicable local laws, ICH guidelines, and Investigator obligations are fulfilled. 
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12.10. Sponsor audits 
During the study or after the study has been completed, the Investigator will allow Sponsor representatives 
or external auditors to conduct an audit of the study. The purpose of the audit is to evaluate compliance 
with GCP guidelines, applicable regulations, the study protocol and the Sponsor's procedures, and to assess 
accuracy of the study data.  
Before the audit, the Investigator will be contacted by the monitor to arrange a convenient time for the visit. 
Investigator and staff are expected to be present, co-operate with the auditors, and allow access to all patient 
records supporting the eCRFs, and other study-related documents. 
12.11. Regulatory agency inspections  
The Investigator may undergo a Regulatory Agency/IRB/IEC inspection during the study or after the study 
has been completed. The purpose of such an inspection is to conduct an official review of documents, 
facilities, records, and any other resources that are deemed by the authority (ies) to be related to the clinical 
trial.  
The Investigator and staff are expected to be available for the inspection and allow access to patient records 
supporting the eCRFs and other study-related documents. If given advance notice of this inspection, the 
Investigator must contact the Sponsor immediately. 
12.12. Publications 
A scientific communication/paper related to this study will be published as agreed between the Sponsor and 
the Investigator and after review of the final draft by the Sponsor.  
The Investigator will inform the Sponsor in advance about any plans to publish or present data from the 
trial. Any publications and presentations of the results (abstracts in journals or newspapers, oral 
presentations, etc.), either in whole or in part, by Investigators or their representatives will require pre-
submission review by the Sponsor. 
12.13. Insurance policy 
The Sponsor will subscribe a liability insurance covering his and the Investigator's responsibility as well as 
the responsibility of any person involved in the conduct of the study, provided there is proper adherence to 
the protocol. An insurance certificate will be provided by the Sponsor to the IRB/IEC if required. 
12.14. Premature study termination 
The trial may be prematurely terminated by the Sponsor, the Investigator, or the IRB/IEC at any time. If 
the study is prematurely terminated, the Investigator must promptly inform the study patients and ensure 
that they receive appropriate therapy and follow-up. All procedures and requirements pertaining to study 
closure as defined by the Sponsor will be carried out.  
If the Investigator terminates the trial, he/she should promptly inform the Sponsor and the IRB/IEC and 
provide a detailed written explanation of the termination. If the Sponsor terminates the trial, the Investigator 
should promptly inform the IRB/IEC and provide a detailed written explanation of the termination. If the 
IRB/IEC terminates the trial or suspends its approval, the Investigator should promptly inform the Sponsor 
and provide a detailed written explanation of the termination. 
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13. 
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23. Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, et al. A potent and orally 
active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical 
development for cancer treatment. Journal of Medicinal Chemistry. 2011;54(8):2714-26. 
24. Barkhouse D, Tao Z, Myers CJ, al e. The SMAC mimetic Debio 1143 synergizes with 
radiotherapy and immune checkpoint inhibitors to enhance antitumor activity. Mol Cancer Ther ; 
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25. Hurwitz HI, Smith DC, Pitot HC, Brill JM, Chugh R, Rouits E, et al. Safety, pharmacokinetics, 
and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: 
results of a first-in-man study. Cancer chemotherapy and pharmacology. 2015;75(4):851-9. 
26. Ray-Coquard I, Le Tourneau C, Isambert N, al e. Clinical safety, pharmacokinetics and early 
evidence of activity of the oral IAP inhibitor Debio 1143 in combination with carboplatin and 
paclitaxel: a phase 1 study. Mol Cancer Ther. 2015;14(12 suppl. 2):abstr C2. 
27. Le Tourneau C, Tao Y, Delord J-P, Brienza S, Vuagniaux G, Sablin MP, et al. A phase I/II 
randomized study of Debio1143 combined with concurrent chemoradiation therapy (CCRT) in 
patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). J 
Clin Oncol. 2014;32(5s (suppl)):abstr TPS6097. 
28. Tao Y, Le Tourneau C, Bouchaab H, al e. Phase 1 study of Debio 1143 with concurrent chemo-
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29. Juergens RA, Chu QS, Renouf DJ, Laurie SA, Purcea D, McWhirter E, et al. A dose-finding 
study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients 
with advanced solid malignancies. Journal of Clinical Oncology. 2019;37(15_suppl):2599-. 
30. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the 
rational design of their combinations in cancer immunotherapy. Annals of oncology : official 
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31. George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, et al. Safety and 
Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond 
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32. Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, et al. Nivolumab for 
Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical 
Trials. JAMA Oncol. 2017;3(11):1511-9. 
33. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line Nivolumab 
in Stage IV or Recurrent Non-Small-Cell Lung Cancer. The New England journal of medicine. 
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34. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 
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publication of the International Association for the Study of Lung Cancer. 2015;10(9):1243-60. 
35. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. 
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint 
Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin 
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36. Rouits E, Csajka C. Debio 1143 population pharmacokinetic analysis. Debiopharm studies 
Debio 1143-101, Debio 1143-102 and Debio 1143-103.; 2016. 
37. Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-Based Population 
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41. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New 
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14. 
APPENDICES 
14.1. Appendix A: World Medical Association Declaration of Helsinki  
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
PREAMBLE 
 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material 
and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied 
without consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
GENERAL PRINCIPLES 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will 
be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act 
in the patient's best interest when providing medical care." 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are dedicated to the 
fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the causes, development 
and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures 
and treatments). Even the best proven interventions must be evaluated continually through research for their 
safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, 
right to self-determination, privacy, and confidentiality of personal information of research subjects. The 
responsibility for the protection of research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics 
and scientific education, training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to participation 
in research. 
14. Physicians who combine medical research with medical care should involve their patients in research only to 
the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician 
has good reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research 
must be ensured. 
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RISKS, BURDENS AND BENEFITS 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks 
and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to 
them and to other individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are confident that 
the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study. 
VULNERABLE GROUPS AND INDIVIDUALS 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or 
priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group 
should stand to benefit from the knowledge, practices or interventions that result from the research. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
21. Medical research involving human subjects must conform to generally accepted scientific principles, be based 
on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be 
respected. 
22. The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding 
funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who are harmed as a consequence 
of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
RESEARCH ETHICS COMMITTEES 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned 
research ethics committee before the study begins. This committee must be transparent in its functioning, must 
be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in which the research is to be 
performed as well as applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to the 
protocol may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the study’s findings and 
conclusions. 
PRIVACY AND CONFIDENTIALITY 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
INFORMED CONSENT 
25. Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual 
capable of giving informed consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential 
subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information needs of individual 
potential subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in 
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writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented 
and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome and 
results of the study. 
27. When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. 
In such situations the informed consent must be sought by an appropriately qualified individual who is 
completely independent of this relationship.  
28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed 
consent from the legally authorised representative.These individuals must not be included in a research study 
that has no likelihood of benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent 
to decisions about participation in research, the physician must seek that assent in addition to the consent of 
the legally authorised representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informedconsent is a necessary characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such representative is available and if 
the research cannot be delayed, the study may proceed without informed consent provided provided that the 
specific reasons for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research ethicscommittee. 
Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorised 
representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal 
of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely 
affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data contained 
in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or 
reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for 
such research. In such situations the research may be done only after consideration and approval of a research 
ethics committee. 
USE OF PLACEBO 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
proven intervention(s), except in the following circumstances:  
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or  
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy 
or safety of an intervention and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result 
of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
POST-TRIAL PROVISIONS 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for 
post-trial access for all participants who still need an intervention identified as beneficial in the trial. This 
information -must also be disclosed to participants during the informed consent process. 
RESEARCH REGISTRATION AND PUBLICATION AND DISSEMINATION OF RESULTS 
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly available 
the results of their research on human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as 
well as positive results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not 
in accordance with the principles of this Declaration should not be accepted for publication. 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
37. In the treatment of an individual patient, where proven interventions do not exist or other known interventions 
have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a 
legally authorised representative, may use an unproven intervention if in the physician's judgement it offers 
hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be 
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