Conditions: Solid Tumor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the efficacy of Debio 1347 in terms of objective response rate (ORR) in participants with solid tumors harboring fibroblast growth factor receptor (FGFR)1-3 gene fusion/rearrangement.

Detailed description:

Arms:
arm 1: Participants with biliary tract cancer were included in this cohort to receive Debio 1347 80 milligrams (mg) tablets, orally, once daily (QD), from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 20 weeks). arm 2: Participants with urothelial cancer were included in this cohort to receive Debio 1347 80 mg tablets, orally, QD, from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 5.86 weeks). arm 3: Participants with all other solid tumor histologies were included in this cohort to receive Debio 1347 80 mg tablets, orally, QD, from Day 1 to Day 28 in 28-day cycles until the occurrence of disease progression or unacceptable toxicity (up to a median duration of 8.14 weeks).

Interventions: intervention 1: Debio 1347
Intervention descriptions: intervention 1: Debio 1347 oral tablets.

Protocol document:
Prot_000.pdf: 
 
Official Title: A Phase II Basket Study of the Oral Selective Pan-FGFR Inhibitor 
Debio 1347 in Subjects With Solid Tumors Harboring a Fusion of 
FGFR1, FGFR2 or FGFR3 
NCT Number: NCT03834220 
Document Date: Protocol Version 3.0: 16 July 2020 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
 
 
A Phase II basket study of the oral selective pan-FGFR inhibitor Debio 1347 in 
subjects with solid tumors harboring a fusion of FGFR1, FGFR2 or FGFR3 
"The FUZE Clinical Trial" 
Clinical Development Phase: II 
 
Investigational Medicinal Product: Debio 1347  
 
EudraCT number: 2018-003584-53 
 
IND number: 118244 
 
Debiopharm International SA Study Number: Debio 1347-201  
 
 
 
SPONSOR: 
Debiopharm International SA 
Forum “après-demain” 
Chemin Messidor 5-7 
P.O. Box 5911 
CH-1002 Lausanne  
Switzerland  
 
 
 
Protocol version N° 3 dated 16 July 2020 integrating amendment Nº 1 & 2 
 
 
The information in this protocol is confidential. It is provided to every potential 
Investigator and his/her team, as well as to the Independent Ethics Committee or 
Institutional Review Board that must statute on the trial. No information can be 
provided to a third party without the written agreement of  
Debiopharm International SA, except for the medical personnel directly concerned  
by the trial and for the information needed by the subject and his/her family. 






Protocol 
 
IV/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
TABLE OF CONTENTS 
1. INTRODUCTION 
16 
2. RATIONALE 
17 
3. PHARMACEUTICAL AND BACKGROUND INFORMATION 
17 
3.1. 
DEBIO 1347 CHEMICAL STRUCTURE, FORMULA, AND MOLECULAR WEIGHT 
17 
3.2. 
INTERNATIONAL NON-PROPRIETARY NAME, BRAND NAME, AND CODE NAME 
18 
3.3. 
BRIEF SUMMARY OF NON-CLINICAL AND CLINICAL DATA 
18 
3.3.1. 
NON-CLINICAL DATA 
18 
3.3.2. 
CLINICAL DATA 
20 
3.3.3. 
RISK-BENEFIT ASSESSMENT 
21 
4. OBJECTIVES 
24 
4.1. 
OBJECTIVES 
24 
4.1.1. 
PRIMARY OBJECTIVE 
24 
4.1.2. 
SECONDARY OBJECTIVES 
24 
 
24 
5. STUDY DESIGN AND TREATMENT 
24 
5.1. 
STUDY DESIGN 
24 
5.2. 
STUDY TREATMENT 
25 
5.3. 
DOSE MODIFICATIONS 
25 
5.3.1. 
DEBIO 1347 DOSE ADJUSTMENT 
25 
5.3.2. 
GUIDELINE FOR SIGNIFICANT QTCF PROLONGATION 
26 
6. STUDY POPULATION 
27 
6.1. 
INCLUSION CRITERIA 
27 
6.2. 
EXCLUSION CRITERIA 
29 
6.3. 
SUBJECT REPLACEMENT 
30 
7. CLINICAL SUPPLIES 
31 
7.1. 
INVESTIGATIONAL MEDICINAL PRODUCT – DEBIO 1347 
31 
7.2. 
PACKAGING AND STORAGE OF INVESTIGATIONAL MEDICINAL PRODUCT 
31 
7.2.1. 
PACKAGING 
31 
7.2.2. 
LABELLING 
31 
7.2.3. 
STORAGE 
31 
7.3. 
DISPENSING AND ACCOUNTABILITY OF INVESTIGATIONAL PRODUCT 
31 
7.4. 
SUBJECT NUMBERING 
32 
7.4.1. 
PRE-SCREENING NUMBER IN THE CASE OF CENTRAL FGFR ASSESSMENT 
32 
7.4.2. 
SCREENING NUMBER 
32 
7.5. 
BLINDING AND UNBLINDING METHODS 
32 
7.6. 
METHOD OF ADMINISTRATION AND COMPLIANCE 
32 
7.7. 
CONCOMITANT THERAPY 
33 
7.7.1. 
PERMITTED MEDICATIONS 
33 


Protocol 
 
V/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
7.7.2. 
SUPPORTIVE CARE 
34 
7.7.3. 
PROHIBITED MEDICATIONS 
35 
7.7.4. 
REPORTING OF PRIOR AND CONCOMITANT THERAPY/MEDICATIONS 
35 
8. STUDY ENDPOINTS, ASSESSMENTS AND PROCEDURES 
35 
8.1. 
ENDPOINTS 
35 
8.1.1. 
PRIMARY ENDPOINT 
35 
8.1.2. 
SECONDARY ENDPOINTS 
35 
 
36 
8.2. 
ASSESSMENTS 
36 
8.2.1. 
ASSESSMENT OF FGFR FUSION/REARRANGEMENT 
36 
8.2.2. 
EFFICACY ASSESSMENTS 
37 
8.2.3. 
SAFETY ASSESSMENTS 
37 
 
38 
8.2.5. 
PHARMACOKINETIC ASSESSMENTS 
38 
 
 
 
 
39 
8.2.7. 
FOLLOW-UP ASSESSMENTS 
39 
8.3. 
STUDY PROCEDURES AND PLAN 
40 
8.3.1. 
RE-SCREENING 
40 
8.4. 
END-OF-TREATMENT AND OVERALL END-OF-STUDY 
46 
8.4.1. 
END-OF-TREATMENT CRITERIA 
46 
8.4.2. 
END-OF-STUDY CRITERIA 
46 
8.4.3. 
OVERALL END-OF-STUDY 
46 
9. ADVERSE EVENTS 
47 
9.1. 
DEFINITIONS AND ASSESSMENT CRITERIA 
47 
9.1.1. 
ADVERSE EVENT 
47 
9.1.2. 
SERIOUS ADVERSE EVENT 
47 
9.1.3. 
SEVERITY OF ADVERSE EVENTS 
48 
9.1.4. 
RELATIONSHIP WITH THE INVESTIGATIONAL MEDICINAL PRODUCT(S) 
48 
9.1.5. 
ADVERSE EVENTS OF SPECIAL INTEREST 
49 
9.2. 
REPORTING OF SERIOUS ADVERSE EVENTS TO THE SPONSOR 
49 
9.2.1. 
REPORTING DURING THE STUDY 
49 
9.2.2. 
REPORTING POST-STUDY 
49 
9.3. 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS 
49 
9.4. 
PROCEDURE FOR SERIOUS ADVERSE EVENT NOTIFICATION TO INDEPENDENT ETHICS COMMITTEES 50 
9.5. 
PROCEDURE FOR REPORTING ADVERSE EVENTS OF SPECIAL INTEREST 
50 
9.6. 
DETERMINATION OF EXPECTEDNESS - REFERENCE DOCUMENT 
50 
9.7. 
PREGNANCIES 
50 
10. MONITORING AND STUDY COMMITTEES 
51 
10.1. 
MONITORING 
51 
10.2. 
DATA MONITORING COMMITTEE 
51 
11. DATA MANAGEMENT AND STATISTICAL ANALYSIS 
52 
11.1. 
SAMPLE SIZE 
52 
11.2. 
DATA MANAGEMENT AND HANDLING 
52 
11.2.1. 
DATA CAPTURE, VERIFICATION, AND VALIDATION 
52 
11.2.2. 
CODING 
53 
11.3. 
ANALYSIS POPULATION 
53 


Protocol 
 
VI/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
11.4. 
TIMING OF STATISTICAL ANALYSIS 
53 
11.5. 
STATISTICAL ANALYSIS 
54 
11.5.1. 
GENERAL ANALYSIS METHODS 
54 
11.5.2. 
HANDLING OF MISSING DATA 
54 
11.5.3. 
INTERIM ANALYSIS 
54 
11.5.4. 
DISPOSITION OF SUBJECTS, DEMOGRAPHIC AND BASELINE DATA 
55 
11.5.5. 
EXTENT OF EXPOSURE 
55 
11.5.6. 
EFFICACY 
55 
11.5.7. 
SAFETY 
56 
 
 
 
57 
11.5.9. 
PHARMACOKINETICS 
57 
 
 
 
58 
12. SPONSOR AND INVESTIGATOR OBLIGATIONS 
59 
12.1. 
GOOD CLINICAL PRACTICE AND DECLARATION OF HELSINKI 
59 
12.2. 
INDEPENDENT ETHICS COMMITTEE 
59 
12.3. 
INSTITUTIONAL REVIEW BOARD 
59 
12.4. 
INFORMED CONSENT 
59 
12.5. 
SUBJECT CONFIDENTIALITY 
60 
12.6. 
DATA REPORTING AND ELECTRONIC CASE REPORT FORMS 
60 
12.7. 
RETENTION OF DATA 
60 
12.8. 
DEVIATIONS FROM THE PROTOCOL 
60 
12.9. 
INVESTIGATIONAL MEDICINAL PRODUCT DRUG ACCOUNTABILITY 
61 
12.10. STUDY MONITORING 
61 
12.11. SPONSOR AUDITS 
61 
12.12. REGULATORY AGENCY INSPECTIONS 
61 
12.13. DISCLOSURE OF RESULTS AND PUBLICATION POLICY 
61 
12.14. INSURANCE POLICY 
62 
12.15. PREMATURE STUDY DISCONTINUATION 
62 
13. REFERENCES 
64 
14. APPENDICES 
67 
 
TABLE OF TABLES 
 
Table 1-1 
Frequency of FGFR fusions in solid cancers ...................................................... 16 
Table 5-1  
Debio 1347 dose adjustment............................................................................... 26 
Table 8-1 
Study Plan ........................................................................................................... 42 
 
 
 


Protocol 
 
VII/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
STUDY SYNOPSIS 
 
STUDY TITLE  
A Phase II basket study of the oral selective pan-FGFR inhibitor Debio 1347 in subjects with solid tumors 
harboring a fusion of FGFR1, FGFR2 or FGFR3. 
STUDY NUMBER  
Debio 1347-201  
STUDY PHASE 
II 
STUDY DESIGN 
Multicentre, basket, two stage, adaptive single arm Phase II study in subjects with solid tumors 
harboring FGFR1-3 gene fusion/rearrangement. Three cohorts will be included consisting of subjects 
with biliary tract cancer (Cohort 1), urothelial cancer (Cohort 2) and all other solid tumor histologies 
not included in Cohorts 1-2 such as NSCLC, head and neck cancer, thyroid cancer, oral cancer, breast 
cancer, prostate cancer and others but excluding primary brain tumors (Cohort 3). 
STUDY OBJECTIVES 
Primary objective 
To assess the efficacy of Debio 1347 in terms of ORR in subjects with solid tumors harboring FGFR1-
3 gene fusion/rearrangement. 
Secondary objectives 
1. To evaluate the efficacy of Debio 1347 in terms of DoR, DCR, PFS and OS. 
2. To assess the safety of Debio 1347.  
3. To assess exposure-response relationships vs efficacy and safety (notably QTcF).  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
ENDPOINTS 
  
Primary endpoint 
ORR (defined as the proportion of subjects with a BOR of partial or complete response) as centrally 
measured by RECIST 1.1 criteria. 
Secondary endpoints 
1. DoR (defined as the time from the date of the initial partial or complete response to date of the first 
documented progression or death due to any cause).  
2. DCR (defined as the proportion of subjects with a BOR of CR or PR or SD). 
3. PFS (defined as the time from the start date of treatment to date of the first documented progression 
or death due to any cause).  
4. OS (defined as the time from the start date of treatment to date of death due to any cause).  
5. Proportion of subjects with TEAEs assessed by NCI-CTCAE v5.0 and SAEs. 
6. Debio 1347 plasma exposure (Ctrough, AUC and any other PK parameters as deemed appropriate) 
and relationships with efficacy and safety endpoints; Debio 1347 plasma concentration (C)-QTcF 
relationship based on ECG and PK matching time-points. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
STUDY POPULATION 
Subjects with locally advanced (unresectable) or metastatic tumors with FGFR1-3 gene 
fusion/rearrangement who require systemic therapy and who have radiologic and/or clinical 
progression following at least one prior standard treatment or who have no satisfactory alternative 


Protocol 
 
VIII/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
treatment options will be included in this study. Approximately 125 males or females ≥ 18 years will 
be recruited in North America, EU, the Middle East, South America and the Asia Pacific region.  
INCLUSION CRITERIA 
1. Written informed consent given according to ICH/GCP guidelines and local regulations.  
2. Cytologically or histologically confirmed advanced solid tumor. 
3. Radiographic progression on prior systemic therapy; prior localized therapy (i.e., radiation, 
ablation, embolization) is allowed provided radiographic progression out-of-field or in the 
treatment field is shown. 
4. Male or female ≥18 years of age. 
5. Locally-advanced (unresectable) or metastatic disease harboring an FGFR1-3 gene 
fusion/rearrangement potentially leading to a functional FGFR aberrant protein, identified through 
local and/or central molecular assay.  
6. The subject must have received at least one prior line of standard therapy appropriate for tumor 
type and stage of disease (if available), and, in the opinion of the Investigator, s/he would have 
been unlikely to tolerate or derive clinically meaningful benefit from further appropriate standard 
of care therapy. In particular: 
a. Biliary tract cancer subjects must have progressed on/after gemcitabine-based 
chemotherapy (including subjects who progressed within 6 months of gemtabicine-based 
adjuvant chemotherapy). Subjects can have received additional chemotherapy after 
documented intolerance to gemcitabine. 
b. Urothelial cancer subjects must have progressed on/after cisplatin-based or carboplatin-
based chemotherapy either given for advanced disease or within 12 months from completion 
if given as neoadjuvant or adjuvant therapy and anti-PD1/PDL1 therapy (unless not 
available, contraindicated for some reasons or refused by the patient). 
c. NSCLC subjects must have progressed on chemotherapy and anti PD1/PDL1 therapy 
(unless contraindicated for some reasons). Subjects with known EGFR mutations, ALK 
rearrangement or BRAF V600E mutation must have received the relevant target therapy 
(unless not available). 
d. For all other tumor types, subjects must have progressed on/after appropriate SOC therapy 
(evidence-based level 1). Subjects who harbor genomic aberrations for which approved 
target therapy is available must have received such therapy. HER2+ or ER/PR+ breast 
cancer subjects should have received at least one line of HER2-targeted or ER-targeted, 
respectively. 
7. Measurable disease according to RECIST criteria version 1.1.  
8. ECOG PS of 0 to 1. 
9. Screening laboratory values as follows: 
a. ANC ≥ 1,000/mm3 [1.0 x 109/L]. 
b. Platelet count ≥ 75,000/mm3 [75 x 109/L]. 
c. Hemoglobin ≥ 8.0 g/dL. 
d. Total bilirubin ≤ 2 x UNL [biliary stent allowed]. A subject with an isolated elevation of 
indirect bilirubin is eligible. 
e. AST and ALT ≤ 2.5 x UNL (5 x UNL in the presence of liver metastases).  
f. Calculated or measured creatinine clearance ≥ 30 mL/min (creatinine clearance measured 
based on 24-hour urine collection should be considered to help assess eligibility). 
g. Serum phosphate < 1.5 x UNL. 
10. Female subjects of child-bearing potential must have a negative serum pregnancy test (minimum 
sensitivity of 25 mIU/mL) at screening and be willing to practice the highly effective 
contraception methods listed below from the time of study entry up to 6 months after the last day 
of treatment: 
a. IUD  
b. IUS 
c. Bilateral tubal occlusion 
d. Vasectomized partner 
e. Sexual abstinence if corresponds to usual and preferred lifestyle of subject. 
For hormonal contraceptives see Section 7.7.1 
Of note:  
- 
Female subjects of non-childbearing potential are defined as either pre-menopausal with a 
documented tubal ligation or hysterectomy or post-menopausal with 12 months of 
spontaneous amenorrhea. 
- 
Female subjects of child-bearing potential must refrain from donating egg(s) during the 
clinical study and for 6 months after Debio 1347 discontinuation. 
- 
Male subjects must agree to use a condom from study entry and up to 6 months after the last 
day of treatment. The subject’s female partner should use highly effective contraception 


Protocol 
 
IX/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
methods, which may include hormonal contraceptives or any of the methods outlined above, 
during this period. 
- 
Male subjects must refrain from donating sperm during the clinical study and for 6 months 
after Debio 1347 discontinuation. 
11. Available fresh tumor sample (preferably) or, if no fresh sample can be obtained, archived tumor 
sample (slides or block) for central analysis of FGFR status or retrospective central confirmation 
in case of local screening.  
Of note: A "liquid biopsy", e.g., ctDNA based test is acceptable for subject eligibility but then a 
pre-study treatment tissue sample is required for post-hoc confirmation of the fusion.  
12. Life expectancy ≥ 3 months. 
EXCLUSION CRITERIA 
1. History of hypersensitivity to any of the excipients in the Debio 1347 formulation (lactose hydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate 
and magnesium stearate). 
2. Prior treatment with a FGFR1-3 selective inhibitor. 
3. History and/or current evidence of ectopic mineralization/calcification, including but not limited 
to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes, lung 
nodules and asymptomatic vascular or cartilage/tendon calcifications. 
4. Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic 
examination. 
5. Chemotherapy, radiotherapy or small molecule anti-cancer agents within 2 weeks prior to initial 
dosing with Debio 1347 (3 weeks for immune checkpoint inhibitors).  
6. Administration of any investigational agent within 2 weeks prior to initial dosing with Debio 1347 
(3 weeks for immune checkpoint inhibitors). 
7. Surgery requiring general anesthesia, except diagnostic biopsy or local procedure, within 3 weeks 
prior to initial dosing with Debio 1347 and/or if the subject has not fully recovered from the 
surgery. 
8. Grade > 1 NCI-CTCAE v5.0 AEs or toxicities from previous treatments except: 
a. Albumin (≥ 2.5 g/dL is allowed). 
b. AST and ALT in subjects with liver metastases ( 5 × ULN is allowed). 
c. ALP in subjects with bone metastases ( 5 × ULN is allowed). 
d. Any grade of alopecia is allowed. 
e. Other Grade 1-2 clinically insignificant laboratory abnormalities are allowed. 
9. Symptomatic or unstable brain metastases < 1 month (Of note: Subjects with asymptomatic stable 
and treated brain metastases are eligible). 
10. Total corrected and/or ionized serum calcium ≥ 1.5 x UNL (corrected calcium = [0.8 x (normal 
albumin - subject albumin)] + serum calcium level). 
11. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, gastric 
resection, significant bowel obstruction, active ulcerative colitis, active Crohn’s disease). 
12. Concomitant treatment with a prohibited medication. 
13. Subjects with a known history of uncontrolled or unstable angina or myocardial infarction within 
the last 6 months, unstable cardiac arrhythmias despite treatment (subjects with a history of atrial 
fibrillation stabilized under treatment are allowed), unexplained recurrent syncope, family history 
of sudden death from cardiac-related causes, congestive heart failure greater than NYHA class II, 
uncontrolled diabetes, uncontrolled psychiatric disorders, severe ongoing infections or any other 
medical condition that might be aggravated by the treatment on evaluation.  
14. Prolongation of QTcF interval to greater than 480 msec. 
15. History of congenital long QT syndrome 
16. History of another malignancy other than the primary tumor within the last 2 years, with the 
exception of completely resected basal or squamous cell skin cancer or any successfully treated 
in-situ carcinoma, or clinically insignificant prostate cancer without any treatment intent (either 
treated or on active surveillance/watchful waiting). Other cancers within the last 2 years that are 
considered clinically insignificant by the treating physician should be discussed with the study 
Sponsor to assess eligibility. 
17. Known infection requiring the systemic use of, for example, an antibiotic or antiviral agent. 
18. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit 
compliance with study requirements. 
19. If female, pregnant or breast feeding. 
20. Unable to swallow and retain oral medications.  
21. Known contraindication to enhanced MRI and/or CT scan. 
INVESTIGATIONAL 
MEDICINAL PRODUCT 
Debio 1347 formulated as 20 mg tablets for oral administration. 


Protocol 
 
X/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
TREATMENT DURATION  Subjects will be treated with Debio 1347 daily in 28-day cycles until the occurrence of disease 
progression (clinical or radiologic) or unacceptable toxicity (other treatment discontinuation criteria 
are described in Section 8.4.1). 
PARTICIPANT 
DURATION 
See above. 
STUDY VISITS 
Subjects will attend a pre-secreening visit (only those who undergo central assessment of FGFR status), 
a screening visit, a variable number of on-treatment visits depending on the number of treatment cycles, 
an EOT visit and a variable number of follow-up visits/contacts. 
For all subjects who will remain on treatment with Debio 1347 after the implementation of Protocol 
Amendment Nº 2, the assessments and procedures defined in the study protocol will no longer be in 
force and will be replaced by standard institutional care practice. Subects must be followed regularly 
(at least every 2 months) to assess the potential occurrence of safety events, as described in the Table 
8.1b. 
STUDY 
PERIOD/DURATION 
18 months = estimated period and time in months from FPFV (first patient first visit) to LPLV (last 
patient last visit). 
As of the implementation date of Protocol Amendment Nº 2, subjects showing clinical benefit may 
continue treatment with Debio 1347 until a condition to stop treatment is met. The LPLV (last patient 
last visit) will occur 30 days after the end of treatment (EOT) for the last subject in the study. 
 
STATISTICAL METHODS  Sample size 
A basket two stage adaptive design will be used to assess the efficacy of Debio 1347 in terms of ORR. 
With 27 evaluable subjects in Stage 1 and 86 evaluable subjects in Stage 2, the study will have 
approximately 90% power to reject the null hypothesis that ORR ≤ 15% when the true ORR is 30% in at 
least one of the baskets, using a one-sided exact binomial test at an overall significance level of 5%. The 
sample size for Stage 2 is for a pooled sample across baskets in case homogeneity is shown at end of 
Stage 1, or for one active basket taken into Stage 2 in case of heterogeneity. Sample size and design 
operating characteristics were determined using simulations.  
Assuming homogeneity across baskets and a 10% drop out the study would enroll approximately 
125 subjects.  
Based on an initial statistical review of pooled data, the antitumor activity for Debio 1347 is lower than 
initially assumed at the time the protocol was developed. Debiopharm decided to permanently halt the 
enrollment in the study after consultation with the DMC on June 10th, 2020.  
Randomisation 
Not applicable. 
Interim analysis 
An interim analysis will be conducted at end of Stage 1 to assess ORR homogeneity across baskets as 
well as futility. A minimum of 4 subjects per basket and a maximum of 13 subjects per basket will be 
required for the end of Stage 1 analysis. ORR homogeneity will be assessed using a pre-defined cut-off 
for the critical value of the exact test for contingency tables. If homogeneity is declared, the next analysis 
steps will be conducted using combined data from all baskets; if heterogeneity is declared, data will be 
analyzed separately for each individual basket. 
The interim analysis at end of Stage 1 will be conducted by the DMC.  
Details on the roles and responsibilities of the DMC will be provided in the DMC charter. 
 
Based on initial review and monitoring of efficacy data, the interim analysis is cancelled. 
Efficacy analysis 
The ITT population will be the primary analysis population for efficacy analysis. Efficacy analyses will 
be repeated on the mITT population and the PP population as supportive analyses. The efficacy analysis 
will be conducted using centrally measured response as primary analysis and repeated on locally 
measured response as sensitivity analysis.  
The statistical testing for primary analysis will be conducted on ORR as centrally measured using a one-
sided exact binomial test. The hypothesis tested will be: 
• 
Scenario 1: If the ORR homogeneity assumption is met at the interim analysis, then the 
hypothesis will be 
H0: ORR ≤ 15% against H1: ORR > 15 % at alpha level of 5% 
• 
Scenario 2: If the ORR homogeneity assumption is not met at the interim analysis, then a 
decision will be made at the time of interim analysis to further continue the study with only 1 
cohort or 2 cohorts. Then the hypothesis tested at final stage will be.  
H0: ORR ≤ 15% against H1: ORR > 15 % in each chosen cohort 


Protocol 
 
XI/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
o 
Scenario 2a: In the case 1 cohort has been selected the statistical comparison will be 
conducted at an alpha level of 5%.  
o 
Scenario 2b: In the case 2 cohorts have been selected the statistical comparison will 
be conducted at a Bonferroni adjusted alpha level of 2.5% for each cohort.  
ORR, DCR and BOR will be summarized using frequencies and percentages. Confidence intervals will 
be presented overall and by cohort. DoR, PFS and OS will be analysed using the Kaplan Meier method.  
Safety analysis 
AEs: Treatment-emergent adverse events, TEAEs related to study drug, TEAEs by severity, TEAEs 
leading to treatment discontinuation and SAEs will be tabulated and listed by MedDRA system organ 
class and preferred term. All on study deaths and reasons will be listed.  
Laboratory parameters: Safety laboratory parameters and corresponding changes from baseline will be 
presented as descriptive statistics by cohort and by timepoint. Shift tables will be produced.  
 
ECGs: 12-lead ECG parameters and corresponding changes from baseline will be summarized by cohort 
and by visit as descriptive statistics. No central reading of the original ECGs will be performed. Central 
tendency, categorical and morphological analyses will be performed for all available parameters. 
Subordinated to the safety and efficacy outcome and data availability, an exposure-response (C-QTcF) 
analysis may be performed by linear mixed effect modeling based on ECG and PK matching time-points, 
if deemed appropriate. 
 
Pharmacokinetic analysis 
Individual Debio 1347 concentrations will be listed by gender, subject and time point. Graphic displays 
of plasma concentration vs time will be presented individually by subject, arithmetic means and 
geometric means. Pharmacokinetic parameters will be listed by subject and summarized by cohort and 
overall, as descriptive statistics and will be derived by population PK data analysis using a nonlinear 
mixed-effects modeling approach. If deemed appropriate, based on safety and efficacy outcome, 
relationships between exposure vs efficacy and safety may be evaluated. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Protocol 
 
XII/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area under the plasma concentration-time curve over the dosing interval  
 
 
BOR 
Best overall response 
BP 
Blood pressure 
 
 
 
 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CoA 
Certificate of analysis 
CR 
Complete response 
CRO 
CSR 
Clinical research organisation 
Clinical study report 
CT 
Computerised tomography 
 
 
Ctrough 
Trough concentration 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
 
 
DMC 
Data monitoring committee 
DCR 
Disease control rate 
DoR 
Duration of response 
 
 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EOT 
End-of-treatment 
 
FPFV 
 
First patient first visit 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast growth factor receptor 
FGFR1-3 
FGFR1, FGFR2 or FGFR3 
 
 
GnHR 
Gonadotrophin-releasing hormone receptor 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
 
 
HDPE 
High-density polyethylene 
Hpf 
High power field 
 
 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
 
LPLV 
 
 
Last patient last visit 
MATE1 
Multidrug and toxin extrusion protein 1 
MEDRA 
Medical Dictionary for Regulatory Activities 


Protocol 
 
XIII/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
mmHg 
Millimetres of mercury 
MRI 
Magnetic resonance imaging 
MRT 
Mean residence time 
ms 
Millisecond 
MSRA  
Methicillin-Resistant Staphylococcus Aureus 
mITT 
Modified intent-to-treat 
 
 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
 
 
OCT2 
Organic cation transporter 2 
ORR 
Objective response rate 
OS 
Overall Survival 
 
 
PD 
Progressive disease 
PDX 
Patient-derived xenograft 
PDy 
Pharmacodynamics 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
 
 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Partial response 
 
 
PS 
Performance status 
PTF 
Peak-to-Trough fluctuation 
 
 
QD 
Once daily 
 
 
QTcF 
QT interval corrected for heart rate using Fridericia 's formula 
 
 
RD 
Recommended dose 
RECIST 
Response evaluation criteria in solid tumours 
 
 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Stable disease 
SOC 
Standard of care 
 
 
t½ 
Apparent terminal half-life 
TACC 
Transforming acidic coiled-coil 
TEAE 
Treatment emergent adverse event 
tmax 
Time to maximum concentration 
 
 
ULN 
Upper normal limit  
 
 
Vz/F 
Apparent volume of distribution during the terminal phase 
 
 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
WMA 
World Medical Association 
 
 
λz 
Apparent elimination rate constant during the terminal phase 
 
 
 


Protocol 
 
XIV/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
 
DEFINITION 
 
Investigational Medicinal 
Product (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 authorised form, or when used for an 
unauthorised indication, or when used to gain further information about the authorised form. 
 
According to the above definition, the Debiopharm International SA active substance being 
tested during the study is considered as IMP. 
 
 
 


Protocol 
 
XV/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
RATIONALE FOR PROTOCOL AMENDMENT Nº 2 
 
The results of an initial statistical review of pooled data showed that the antitumor activity of Debio 1347 
is lower than initially assumed at the time the protocol was developed. Considering that further enrolment 
is unlikely to substantially change the magnitude of the efficacy observed up to now, Debiopharm decided 
to permanently halt the enrolment in the study after consultation with the DMC on June 10th, 2020.   
 
Despite the lower than expected efficacy, there are ongoing subjects who are deriving benefit from the 
treatment, as per the opinion of their treating physician. For ethical reasons, the Sponsor intends to continue 
supplying study medication to these subjects until disease progression, unacceptable toxicity, subject 
withdrawal, or loss to follow up. 
 
For all subjects who will remain on treatment with Debio 1347 after the implementation of Protocol 
Amendment Nº 2, the assessments and procedures defined in the study protocol will no longer be in force 
and will be replaced by standard institutional care practice. Subjects must be followed regularly (at least 
every 2 months) to assess the potential occurrence of safety events and conduct safety laboratory analyses, 
as described in Table 8.1b. Only safety data will be collected in the electronic case report form (eCRF). 
 






Protocol 
18/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
Chemical name:  
 
Molecular weight:  
490.47l 
Molecular formula: 
C20H16N6O•C4H6O5 
3.2. International Non-proprietary Name, Brand Name, and Code Name  
INN (International Non-proprietary Name) 
Not applicable  
Brand name: 
Not applicable 
Company code name: 
Debio 1347 malate (malate salt) 
 
Debio 1347 (free base) 
Former code name: 
 CH5183284 
3.3. Brief Summary of Non-clinical and Clinical Data  
3.3.1. 
Non-clinical data  
FGFRs are expressed on many different cell types and regulate key cell behaviours such as proliferation, 
differentiation and survival, and render FGF signalling susceptible to subversion by cancer cells.40 
Activation of FGFRs as a result of amplification/mutation/translocation of FGFR genes, over-expression 
of FGFR proteins or overproduction of ligands has been shown to be oncogenic in many cancer cell types. 
Alterations in FGF/FGFR signalling ultimately lead to up regulation of the MAPK and PI3K-Akt signalling 
pathways. Dysregulation of FGFR-dependent signalling can contribute to tumour growth and angiogenesis 
through a variety of mechanisms.41 FGFR alterations are thus promising therapeutic targets in cancer. 
The orally-active small molecule Debio 1347 is an ATP competitive and highly selective inhibitor of 
FGFR1-3 at the low nanomolar level in cell-free systems (IC50: 7.6 – 22 nM). Preclinical studies have shown 
that Debio 1347 is effective in multiple tumour models of different origins with FGFR alterations. 
Pharmacology – in vitro 
Debio 1347 is an ATP competitive inhibitor of FGFR1-3 tyrosine kinases at the low nanomolar level (IC50: 
7.6–22 nM) with less potent inhibitory activity on FGFR4 (290 nM) in cell-free systems. The compound is 
highly selective and does not act on VEGF receptor kinase KDR as demonstrated in vascular endothelial 
cells. 
Debio 1347 has predominant activity against FGFR1-3 and has been shown in vitro to display 
anti-proliferative activity in tumor cell lines with either amplification, mutation or fusion/rearrangement of 
the FGFR1-3 genes or overexpression of FGFR(s). 
No anti-proliferative activity was observed for cell lines without FGFR genetic alterations or high 
expression. More specifically, out of 327 cell lines tested, 31 harboured a FGFR gene alteration, of which 
20 (64.5%) were classified as sensitive to Debio 1347 (with an IC50 below or equal to 1μM). Looking more 
closely at the different types of alterations, 100% of cell lines (5/5) that harboured FGFR fusions were 
sensitive to the inhibitor whereas, in the presence of mutation or amplification, only 50% (5/10) and 62.5% 
(10/16) of the tested cell lines were found to be sensitive to Debio 1347. This suggests that cancer cell lines 
harbouring FGFR fusions are the most sensitive to FGFR inhibition.37 
Pharmacology – in vivo 
Debio 1347 potently inhibits cell growth in a dose-dependent manner in multiple tumour models of various 
origins with FGFR genetic alterations and in particular in models harbouring FGFR fusions. For example, 
Debio 1347 showed potent anti-tumoral activity in patient-derived xenograft (PDX) models of gastric 
cancer harbouring FGFR2-WDR11 fusion and lung cancer with FGFR2-MCU fusion. Debio 1347 


Protocol 
19/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
administration induced tumor regressions in PDX models of liver cancer harbouring FGFR2-CCDC6 
fusion, in a brain cancer model harbouring FGFR3-TACC3 fusion and a breast PDX model harbouring 
FGFR2-GAB2 fusion at non-toxic doses. 
Overall, the results suggest that subjects with FGFR1-3 fusions/rearrangements could benefit from targeted 
FGFR1-3 inhibitors such as Debio 1347.  
Please refer to the Investigator’s Drug Brochure for more information. 
Toxicology and Safety Pharmacology  
The toxicology profile of Debio 1347 was assessed after single and repeated oral administration in Wistar 
rats and Cynomolgus monkeys for up to 4 weeks and in a battery of safety pharmacology tests in vitro and 
in vivo. 
In the 4-week GLP-compliant repeated-dose toxicity study in rats (0, 3, 10, 30 mg/kg/day), no deaths 
occurred at any Debio 1347 dose up to the highest dose of 30 mg/kg/day. At 30 mg/kg/day, thoracic 
deformity was seen in the general condition observations, and changes in cartilage and bone including the 
sternum were seen in the histopathological examinations. Mineralisation in multiple organs, changes in 
epithelial tissues and changes in parameters of blood and urine related to renal function were also observed. 
The above-mentioned histopathological changes were not seen at 10 mg/kg/day or less, mainly changes in 
parameters of blood and urine that suggested effects on bone were observed. At the lowest dose of 
3 mg/kg/day, high blood TRACP-5b (tartrate-resistant acid phosphatase 5b, a bone resorption marker) was 
seen, so the no observed adverse effect level was judged to be less than 3 mg/kg/day. The no observed 
adverse effect level (NOAEL) was considered to be lower than 3 mg/kg/day. 
In the 4-week GLP-compliant repeated-dose toxicity study in monkeys (0, 0.4, 1.3, and 4 mg/kg/day), no 
deaths occurred at any Debio 1347 dose up to the highest dose of 4 mg/kg/day. At 4 mg/kg/day, very slight 
histopathological changes in bone and cartilage and related changes in parameters of blood and urine were 
seen, and in one female, very slight histopathological changes in kidneys were observed. At the middle 
dose of 1.3 mg/kg/day, only high urinary excretion of inorganic phosphorus in females was seen. No effects 
were observed at the lowest dose of 0.4 mg/kg/day, so that was judged to be the no observed adverse effect 
level in this study. On the basis of these results, the HNSTD (highest non-severely toxic dose for monkeys) 
was set at 4 mg/kg/day (NOAEL: 0.4 mg/kg/day). 
The principal target organs of Debio 1347 toxicity in rats and monkeys were bone/cartilage, epithelial 
tissues and the kidneys. In addition, effects on lymphohematopoietic tissues, liver and the gastrointestinal 
tract were observed. Mineralisation in multiple organs was also seen, with a broader range of organs and 
tissues affected in rats than in monkeys. On the other hand, periosteal changes occurred only in monkeys 
but not in rats. Except for thoracic deformity and mineralisation in multiple organs in rats, the changes seen 
in rats and monkeys in the 4-week repeated-dose toxicity studies either reversed or tended to reverse over 
the 4-week recovery period. 
Debio 1347 was not considered to be genotoxic on the basis of bacterial reverse mutation, chromosomal 
aberration in vitro and micronucleus and Comet assays in vivo in rats.  
Debio 1347 may have an in vivo phototoxic risk based on 1) an in vitro phototoxicity test using a fibroblast 
cell line (absorbance wavelengths of 200 nm to 400 nm) and 2) a whole-body autoradiography in rats 
suggesting a slower elimination rate of Debio 1347 from skin compared with blood. Subjects should avoid 
excessive exposure to sun/UV light while undergoing treatment with Debio 1347. 
Although dedicated reproductive and developmental toxicity studies of Debio 1347 have not been 
conducted so far, some changes such as thinning of vaginal mucosal epithelium and atrophic changes in 
testes, epididymides, prostate gland, seminal vesicles and uterus were observed at lethal dose in preliminary 
dose-repeated toxicity in rats. From the above findings and those on bone and cartilage, it is inferred that 
Debio 1347 may affect reproduction and development. 
Results of safety pharmacology studies performed with Debio 1347 showed that the compound had no 
effects on the central nervous or respiratory systems in rats at doses up to 100 mg/kg. Although a significant 


Protocol 
20/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
hERG inhibition (IC50, 677 ng/mL) was seen in vitro, there were no effects on blood pressure (BP), heart 
rate, electrocardiogram (ECG) or body temperature in monkeys at doses up to 10 mg/kg. According to 
calculations based on free Debio 1347 (plasma protein binding around 99%), the plasma concentrations 
required to induce a given level of inhibition would be about 100 times greater than the concentration 
inducing the same level of inhibition in vitro. The ratio of 50% inhibitory concentration (IC50) for the hERG 
assay 
to 
the 
free 
plasma 
concentration 
of 
drug 
required 
for 
clinical 
efficacy  
(i.e., 25 ng/mL of unbound Cmax, based on 99.0% protein binding and mean Cmax of 2486 ng/mL at 
steady-state of the RD of 80 mg/day in study Debio 1347-101 – dose-escalation phase) was used as an index 
of proarrhythmic potential; the ratio was 27, giving a significant apparent safety margin. 
No carcinogenicity studies or local tolerance studies have been conducted to date. 
Please refer to the Investigator’s Brochure for more information. 
Rationale for dose selection 
The dose of 80 mg/day to be administered in this study is based on the RD determined in the previous study 
Debio 1347-101. 
3.3.2. 
Clinical data  
The dose-escalation part of the first-in-human, multicenter, open-label study Phase I study of Debio 1347 
(study Debio 1347-101) was recently completed.39A total of 58 subjects with genomically activated 
advanced solid tumours were included and treated with Debio 1347 at doses from 10 to 150 mg/day. All 
were assessable for safety. Of these, 57 were evaluable for efficacy. Median treatment duration was 7.3 
weeks (range 0.1 – 72). 
All 58 treated subjects experienced ≥ 1 treatment emergent adverse event (TEAE) of which the highest 
severity was Grade 1 in 4 (6.9%), Grade 2 in 17 (29.3%), Grade 3 in 28 (48.3%), Grade 4 in 2 (3.4%) and 
Grade 5 in 7 (12.1%) subjects. The most common TEAEs with an incidence > 25% were 
hyperphosphatemia, diarrhea, nausea, fatigue, constipation, decreased appetite and dry mouth. Nail changes 
(includes nail bed disorder, nail discoloration, nail dystrophy, onychalgia, onychoclasis and 
onychomadesis) were reported in 11 subjects. The most severe TEAEs were Grade 5 disease progression 
in 4 (6.9%) subjects and respiratory failure, sepsis and a new neoplasm (endometrial cancer) each in one 
subject (1.7%). They were not drug-related. Hyperphosphatemia, anemia, hyponatremia and dyspnea were 
most often severe (i.e., Grade > 2). A total of 54 (93%) subjects experienced TEAEs considered as related 
to Debio 1347. 
Twenty subjects experienced 39 serious adverse events (SAEs), most commonly dyspnea, but only two 
SAEs were deemed possibly study drug related and thus dose limiting toxicities (DLTs), i.e., Grade 3 
hyperamylasemia (80 mg) and Grade 3 stomatitis (110 mg). DLTs occurred in 3 other subjects, i.e., Grade 2 
dry mouth and eyes (60 mg) in one subject; Grade 3 asymptomatic hypercalcemia (80 mg); Grade 3 
bilirubin increase and hyperphosphatemia (110 mg) in one subject. The subject with hyperamylasemia died 
from disease progression. The remaining 4 subjects recovered after Debio 1347 interruption and/or dose 
modification. As there were only ≤ 2 DLTs at the same dose level, the MTD (maximum tolerated dose) was 
not formally reached. No further dose-escalation was carried out. 
Decreased left ventricular ejection fraction (LVEF) was reported in 1 subject (Grade 2) and 3 subjects 
experienced non-clinically significant Grade 1 (n = 2) and Grade 2 (n = 1) ECG QTc prolongation. 
Overall, 21 subjects died from disease progression; no death was considered drug-related. 
Although a cohort of 3 subjects completed the first treatment cycle at 150 mg once daily without 
experiencing any DLT, the safety data showed an increased incidence of adverse events (AEs) and Grade 3 
AEs during dose-escalation from 80 to 110 to 150 mg. The 80 mg dose once daily was therefore selected 
as the recommended Phase 2 dose and hence the dose level to be administered in the expansion part of the 
study. The expansion part is still ongoing. 


Protocol 
21/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
No trend towards QTc prolongation was evident from the local ECG measurements collected during the 
study. An additional exposure-response analysis based on ECG central reading was not fully conclusive 
regarding the QTcF prolonging potential of Debio 1347, but indicate that the potential increase (predicted 
upper bound of the 90% CI for QTcF was 11.44 and 12.55 milliseconds at the recommended dose of 
80 and the highest dose of 150 mg, respectively) would remain below the 20 milliseconds threshold 
usually considered for oncology products. Furthermore, there were no relevant changes for the other ECG 
intervals of interest (QRS, RR, PR) after Debio 1347 and no relevant changes were evident from the 
categorical analysis or from the analysis of morphological abnormalities. 
A total of 57 subjects were evaluable for tumor response. One subject had no measurable disease. Best 
overall response was progressive disease (PD) in 35 subjects and stable disease (SD) in 16 subjects, of 
whom 10 showed reduced target lesion size at least once post-dose; the remaining 6 subjects had PR 
(2 unconfirmed). Of these six PRs, two had urothelial carcinoma (80, 150 mg), the others endometrial 
(30 mg), cervical (80 mg), inflammatory bowel disease-associated colorectal cancer or cholangiocarcinoma 
(both 110 mg). For the latter the independent centralized radiological review changed response from partial 
to confirmed complete response (CR) and of the 2 unconfirmed PRs one became confirmed. Among 10 
subjects with confirmed FGFR fusions treated at doses ≥ 60 mg/day, 3 achieved PRs and 5 disease 
stabilization. This represents a DCR in this subpopulation of 80% (vs 38.6% overall). The median treatment 
duration in subjects with disease control was 34 weeks (range: 24-47). 
Upon oral dosing in fasted conditions, Debio 1347 was rapidly absorbed with a median tmax of 3 hours, 
followed by a mono-exponential decrease of plasma levels with a mean half-life of 11.5 hours. Mean 
apparent oral clearance was 7 L/h and mean volume of distribution 110 L. Inter-individual pharmacokinetic 
(PK) variability was 32 to 48%. The increase of Debio 1347 plasma exposure was approximately dose-
proportional over doses from 10 to 150 mg. In line with the half-life and 24-hour dosing intervals, a limited 
accumulation was observed at the end of the first treatment cycle, with on average 1.9 and 1.7 times higher 
AUC and Cmax after 28 days of repeated once daily dosing, respectively. Trough levels indicated that 
steady-state was achieved in the majority of subjects during the first week of treatment. Overall, Debio 
1347 PK is linear and supports a once daily dosing regimen. 
Please refer to the Investigator’s Brochure for more information. 
3.3.3. 
Risk-benefit Assessment 
In the non-clinical setting, Debio 1347 exhibits high anti-tumour activity both in vitro and in vivo in cancers 
with amplification, mutation or translocation/fusion of the FGFR1, 2 or 3 genes, and cancers with 
overexpression of FGFR(s). This compound is regarded as an innovative therapeutic opportunity for cancer 
patients with genetic alterations in the FGFR1-3 genes or overexpression of the FGFR1-3 proteins. 
In non-clinical safety studies of Debio 1347 in rats and monkeys, the principal target organs of toxicity 
were bone/cartilage, epithelial tissues and the kidneys. In addition, effects on lymphohaematopoietic 
tissues, liver and the gastrointestinal tract were observed. Mineralisation in multiple organs was also seen 
(such as trachea, stomach, kidneys, eyes in rats), with a broader range of organs and tissues affected in rats 
than in monkeys. On the other hand, periosteal changes occurred only in monkeys but not in rats. Except 
for thoracic deformity and mineralisation in multiple organs in rats, the changes seen in rats and monkeys 
in the 4-week repeated-dose toxicity studies either reversed or tended to reverse over the 4 week recovery 
period. 
As a result, soft-tissue mineralisation, bone/cartilage effects, lymphohaematopoietic abnormalities, 
gastrointestinal and hepatic disorders, and ophthalmological disorders (mainly corneal mineralisation) are 
under close monitoring in the clinical setting. Subjects with phosphate/calcium homeostasis impairment are 
contraindicated. In addition, subjects with osteoporosis should be closely monitored. Investigators should 
reassess the risk-benefit ratio for each of their subjects. 
Debio 1347 may have an in vivo phototoxic risk based on an in vitro phototoxicity test using a fibroblast 
cell line, where the compound was suggested as a phototoxic substance; and a whole-body autoradiography 
in rats after single oral dose of 1 mg/kg of [14C] Debio 1347 suggesting a slower elimination rate of Debio 


Protocol 
22/80 
Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
1347 from skin compared with blood. On the basis on these findings, subjects should avoid excessive 
exposure to sun/UV light. 
Although reproductive and developmental toxicity studies of Debio 1347 have not been conducted, some 
changes in the reproductive organs, such as thinning of vaginal mucosal epithelium and atrophic changes 
in testes, epididymides, the prostate gland, seminal vesicles and the uterus were observed at the lethal dose 
in preliminary dose-repeated toxicity studies in rats. From these findings and those reported above on bone 
and cartilage, it is inferred that Debio 1347 may affect reproduction and development; 
pregnancy/breastfeeding are therefore strictly contraindicated. 
In safety pharmacology studies, no effects on the central nervous system or respiratory system were seen 
in rats at Debio 1347 doses up to 100 mg/kg. Debio 1347 was a potent hERG inhibitor in vitro, but the 
compound did not modify blood pressure, heart rate, and ECG or body temperature at doses up to 10 mg/kg 
in the monkey telemetry study. Although Debio 1347 potential for affecting cardiac function is considered 
to be low based on the study in monkeys, this potential risk is under close monitoring in the ongoing Phase 
I trial. 
Based on current knowledge, Debio 1347 is deemed to have a limited risk of being victim of PK interaction 
from other drugs. In contrast, as per in vitro results available so far, Debio 1347 is considered at possible 
risk for perpetrating DDIs towards sensitive substrates of CYP1A2, CYP3A, P-gp, BCRP, MATE1 and 
OCT2 through inhibition and/or induction of drug metabolism or transport. In addition, BSEP may be 
inhibited as well. 
The clinical impact of these in vitro observations is not known. Subjects who are taking concurrent drugs 
that are known substrates of either CYP3A, CYP1A2, P-gp, BCRP, MATE1 or OCT2 should be carefully 
monitored. In addition, potential changes in bile salts plasma concentration should be monitored during 
treatment with Debio 1347.  
Carcinogenicity studies or local tolerance studies have not been conducted to date. 
Concerning efficacy, clinical activity of Debio 1347 started at the dose of 30 mg. In the dose escalation 
portion of the Phase I trial, a total of 57 subjects were evaluable for tumor response. One subject had no 
measurable disease. Best overall response was PD in 35 subjects and SD in 16 subjects, of whom 10 showed 
reduced target lesion size at least once post-dose; the remaining 6 subjects had PR (2 unconfirmed). Of 
these six PRs, two had urothelial carcinoma (80, 150 mg), the others endometrial (30 mg), cervical (80 mg), 
inflammatory bowel disease-associated colorectal cancer or cholangiocarcinoma (both 110 mg). For the 
latter the independent centralized radiological review changed response from partial to confirmed CR and 
of the 2 unconfirmed PRs one became confirmed. Among 10 subjects with confirmed FGFR fusions treated 
at doses ≥ 60 mg/day, 3 achieved PRs and 5 disease stabilization. This represents a DCR in this 
subpopulation of 80% (vs 38.6% overall). The median treatment duration in subjects with disease control 
was 34 weeks (range: 24-47). 
The safety population comprised 58 subjects of which 20 reported 39 SAEs. Two of these were considered 
as having a reasonable causal relationship with Debio 1347. One subject developed NCI-CTCAE Grade 3 
hyperamylasaemia 23 days after intake of the first dose of Debio 1347. The Investigator considered 
causality as possibly related to the study drug, even though the subject presented with dilatation of the main 
pancreatic duct, suggesting previously unknown chronic pancreatitis. Moreover, concomitant medications 
(pravastatin, captopril, ranitidine and codein) could have contributed to the occurrence of this event. One 
subject experienced NCI-CTCAE Grade 3 stomatitis, which decreased to Grade 1 after holding the drug for 
8 days. 
The most common AEs (> 25%) irrespective of relationship with the study drug were hyperphosphatemia, 
diarrhea, nausea, fatigue, constipation, decreased appetite and dry mouth, all of which were generally mild 
and manageable. Nail changes (includes nail bed disorder, nail discoloration, nail dystrophy, onychalgia, 
onychoclasis and onychomadesis) were reported in 11 subjects.  
Decreased LVEF was reported in 1 subject (Grade 2) and 3 subjects experienced non-clinically significant 
Grade 1 (n = 2) and Grade 2 (n = 1) ECG QTc prolongation. Data are limited and ECG monitoring is 
warranted for all subjects included in clinical studies of Debio 1347.  


Protocol 
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Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
No trend towards QTc prolongation was evident from the local ECG measurements collected during the 
study. An additional exposure-response analysis based on ECG central reading was not fully conclusive 
regarding the QTcF prolonging potential of Debio 1347, but indicate that the potential increase (predicted 
upper bound of the 90% CI for QTcF was 11.44 and 12.55 milliseconds at the recommended dose of 80 
and the highest dose of 150 mg, respectively) would remain below the 20 milliseconds threshold usually 
considered for oncology products. Furthermore, there were no relevant changes for the other ECG intervals 
of interest (QRS, RR, PR) after Debio 1347 and no relevant changes were evident from the categorical 
analysis or from the analysis of morphological abnormalities. 
To mitigate the inherent risks in the current clinical study of Debio 1347, subjects are closely monitored 
while they are receiving treatment. 
Debio 1347 seems to be generally well tolerated and the observed toxicity profile to date has been consistent 
with the expected effect of a selective and potent inhibitor of the FGFR pathway, the benefit/risk profile is 
assessed as positive. Further clinical research with Debio 1347 is therefore warranted.  
 
 




Protocol 
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Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
 
Subjects will be treated with Debio 1347 daily in 28-day cycles until the occurrence of disease progression 
(clinical or radiologic) or unacceptable toxicity (other treatment discontinuation criteria are described in 
Section 8.4.1). Subject safety (AEs) and survival will be followed-up respectively for 30 days after the last 
Debio 1347 dose and every 12 weeks from treatment end until death or loss to follow-up but no longer than 
for a total of 2 years after the last subject has discontinued treatment. Disease status will be followed-up 
every 12 weeks only in subjects without PD from treatment end until PD, death or loss to follow-up but no 
longer than for a total of 2 years after the last subject has discontinued treatment.  
 
 
5.2. Study Treatment  
Subjects will receive Debio 1347 tablets at the dose of 80 mg once daily from Day 1 to Day 28 in 28-day 
cycles until occurrence of any of the criteria described in Section 8.4.1. 
Debio 1347 method of administration is described in Section 7.6. 
5.3. Dose Modifications 
5.3.1. 
Debio 1347 dose adjustment 
Individual dose adjustment of Debio 1347 may be considered and applied as per Table 5-1 below if required. 
Non-treatment related or unexpected toxicities may also require treatment interruption at the discretion of 
the Investigator and Medical Monitor. For guidance on toxicity management, please refer to appendices E, 
F, and G. 
 
 
 
 
Enroll and treat Stage 1 patients
Assess heterogeneity of treatment
effectacross baskets
Applybasket-
specific futility
stopping rule
Futility testing
using one-
sample
Stop trial for 
individual baskets
Enroll and treat
Stage 2 patients 
for individual
baskets
Individual test(s) for 
efficacy with correction for 
multiple comparisons
Stop trial 
(for all baskets)
Enroll and treat
Stage 2 patients 
(all baskets 
combined)
One-sample test 
for efficacy
Encouraging
Futile
Heterogeneous
Homogeneous
Futile
Encouraging




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Debio 1347-201 – Phase II basket trial in solid tumors harboring a fusion of FGFR1-3 
 
Protocol version N° 3 dated 16 July 2020 
Copyright by Debiopharm International SA 
integrating amendment Nº 1 & 2 
Lausanne, Switzerland  
6. 
STUDY POPULATION 
Subjects with locally advanced (unresectable) or metastatic tumors with FGFR1-3 gene 
fusion/rearrangement who require systemic therapy and who have radiologic and/or clinical progression 
following at least one prior standard treatment or who have no satisfactory alternative treatment options. 
6.1.  Inclusion Criteria 
Potential participants who fulfil the criteria below will be included: 
1. Written informed consent given according to International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP) guidelines and local regulations.  
2. Cytologically or histologically confirmed advanced solid tumor. 
3. Radiographic progression on prior systemic therapy; prior localized therapy (i.e., radiation, 
ablation, embolization) is allowed provided radiographic progression out-of-field or in the 
treatment field is shown. 
4. Male or female ≥18 years of age. 
5. Locally-advanced (unresectable) or metastatic disease harboring an FGFR1-3 gene 
fusion/rearrangement potentially leading to a functional FGFR aberrant protein, identified through 
local and/or central molecular assay.  
6. The subject must have received at least one prior line of standard therapy appropriate for their 
tumor type and stage of disease (if available), and, in the opinion of the Investigator, s/he would 
have been unlikely to tolerate or derive clinically meaningful benefit from further appropriate 
standard of care therapy. In particular: 
a. Biliary tract cancer subjects must have progressed on/after gemcitabine-based 
chemotherapy (including subjects who progressed within 6 months of gemtabicine-based 
adjuvant chemotherapy). Subjects can have received additional chemotherapy after 
documented intolerance to gemcitabine. 
b. Urothelial cancer subjects must have progressed on/after cisplatin-based or 
carboplatin-based chemotherapy either given for advanced disease or within 12 months 
from completion if given as neoadjuvant or adjuvant therapy and anti-PD1/PDL1 therapy 
(unless not available, contraindicated for some reasons or refused by the subject).  
c. NSCLC subjects must have progressed on chemotherapy and anti-PD1/PDL1 therapy 
(unless contraindicated for some reasons). Subjects with known EGFR mutations, ALK 
rearrangement or BRAF V600E mutation must have received the relevant target therapy 
(unless not available). 
d. For all other tumor types, subjects must have progressed on/after appropriate standard of 
care (SOC) therapy (evidence-based level 1). Subjects who harbor genomic aberrations for 
which approved target therapy is available must have received such therapy. HER2+ or 
ER/PR+ breast cancer subjects should have received at least one line of HER2-targeted or 
ER-targeted, respectively. 
7. Measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) criteria 
version 1.1.  
8. Eastern Cooperative Oncology Group (ECOG) (see Appendix A) performance status (PS) of  
0 to 1. 
9. Screening laboratory values as follows: 
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3 [1.0 x 109/L]. 
b. Platelet count ≥ 75,000/mm3 [75 x 109/L]. 


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c. Hemoglobin ≥ 8.0 g/dL. 
d. Total bilirubin ≤ 2 x upper normal limit (UNL) [biliary stent allowed]. A subject with an 
isolated elevation of indirect bilirubin is eligible. 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x UNL (5 x 
UNL in the presence of liver metastases).  
f. Calculated or measured creatinine clearance ≥ 30 mL/min (creatinine clearance measured 
based on 24-hour urine collection should be considered to help assess eligibility). 
g. Serum phosphate < 1.5 x UNL. 
10. Female subjects of child-bearing potential must have a negative serum pregnancy test (minimum 
sensitivity of 25 mIU/mL) at screening and be willing to practice the highly effective contraception 
methods listed below from the time of study entry up to 6 months after the last day of treatment:  
a. Intrauterine device (IUD)  
b. Intrauterine hormone-releasing system (IUS) 
c. Bilateral tubal occlusion 
d. Vasectomized partner 
e. Sexual abstinence if corresponds to usual and preferred lifestyle of subject. 
For hormonal contraceptives see Section 7.7.1. 
Of note:  
- 
Female subjects of non-childbearing potential are defined as either pre-menopausal with a 
documented tubal ligation or hysterectomy or post-menopausal with 12 months of spontaneous 
amenorrhea. 
- 
Female subjects of child-bearing potential must refrain from donating egg(s) during the clinical 
study and for 6 months after Debio 1347 discontinuation. 
- 
Male subjects must agree to use a condom from study entry and up to 6 months after the last 
day of treatment. The subject’s female partner should use highly effective contraception 
methods, which may include hormonal contraceptives or any of the methods outlined above, 
during this period. 
- 
Male subjects must refrain from donating sperm during the clinical study and for 6 months after 
Debio 1347 discontinuation. 
11. Available fresh tumor sample (preferably) or, if no fresh sample can be obtained, archived tumor 
sample (slides or block) for central analysis of FGFR status or retrospective central confirmation 
in case of local screening.  
Of note: A "liquid biopsy", e.g., ctDNA based test is acceptable for subject eligibility but then a 
pre-study treatment tissue sample is required for post-hoc confirmation of the fusion.  
12. Life expectancy ≥ 3 months. 
 
 


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6.2. Exclusion Criteria 
Any of the following would render a subject ineligible for inclusion: 
1. History of hypersensitivity to any of the excipients in the Debio 1347 formulation (lactose hydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate 
and magnesium stearate). 
2. Prior treatment with a FGFR1-3 selective inhibitor. 
3. History and/or current evidence of ectopic mineralization/calcification, including but not limited to 
soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes, lung nodules 
and asymptomatic vascular or cartilage/tendon calcifications. 
4. Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic 
examination. 
5. Chemotherapy, radiotherapy or small molecule anti-cancer agents within 2 weeks prior to initial 
dosing with Debio 1347 (3 weeks for immune checkpoint inhibitors).  
6. Administration of any investigational agent within 2 weeks prior to initial dosing with Debio 1347 
(3 weeks for immune checkpoint inhibitors). 
7. Surgery requiring general anesthesia, except diagnostic biopsy or local procedure, within 3 weeks 
prior to initial dosing with Debio 1347 and/or if the subject has not fully recovered from the surgery. 
8. Grade > 1 (National Cancer Institute Common Terminology Criteria for Adverse Events 
NCI-CTCAE v5.0) AEs or toxicities from previous treatments except: 
a. Albumin (≥ 2.5 g/dL is allowed). 
b. AST and ALT in subjects with liver metastases ( 5 × ULN is allowed). 
c. Alkaline phosphatase (ALP) in subjects with bone metastases ( 5 × ULN is allowed). 
d. Any grade of alopecia is allowed. 
e. Other Grade 1-2 clinically insignificant laboratory abnormalities are allowed. 
9. Symptomatic or unstable brain metastases < 1 month (Of note: Subjects with asymptomatic stable 
and treated brain metastases are eligible). 
10. Total corrected and/or ionized serum calcium ≥ 1.5 x UNL (corrected calcium = [0.8 x (normal 
albumin - subject albumin)] + serum calcium level). 
11. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, gastric 
resection, significant bowel obstruction, active ulcerative colitis, active Crohn’s disease). 
12. Concomitant treatment with a prohibited medication. 
13. Subjects with a known history of uncontrolled or unstable angina or myocardial infarction within 
the last 6 months, unstable cardiac arrhythmias despite treatment (subjects with a history of atrial 
fibrillation stabilized under treatment are allowed), unexplained recurrent syncope, family history 
of sudden death from cardiac-related causes, congestive heart failure greater than New York Heart 
Association (NYHA) class II, uncontrolled diabetes, uncontrolled psychiatric disorders, severe 
ongoing infections or any other medical condition that might be aggravated by the treatment on 
evaluation.  
14. Prolongation of QTcF interval to greater than 480 msec. 
15. History of congenital long QT syndrome 
16. History of another malignancy other than the primary tumor within the last 2 years, with the 
exception of completely resected basal or squamous cell skin cancer or any successfully treated in-
situ carcinoma, or clinically insignificant prostate cancer without any treatment intent (either 


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treated or on active surveillance/watchful waiting). Other cancers within the last 2 years that are 
considered clinically insignificant by the treating physician should be discussed with the study 
Sponsor to assess eligibility. 
17. Known infection requiring the systemic use of, for example, an antibiotic or antiviral agent. 
18. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance 
with study requirements. 
19. If female, pregnant or breast feeding. 
20. Unable to swallow and retain oral medications.  
21. Known contraindication to enhanced magnetic resonance imaging (MRI) and/or computerised 
tomography (CT) scan. 
6.3. Subject Replacement 
No subjects will be replaced. 
 


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7. CLINICAL SUPPLIES  
7.1. Investigational Medicinal Product – Debio 1347 
Composition: 
Debio 1347 20 mg tablets containing the following excipients: lactose hydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium 
lauryl sulfate, and magnesium stearate. 
Dosage form: 
White coated tablets.  
Presentation: 
28 tablets in 
 blisters. 
Expiry date: 
Shelf life will be updated when new stability data are available. 
Storage: 
Mentioned on labels. 
A certificate of analysis (CoA) will be provided with the product. 
7.2. Packaging and Storage of Investigational Medicinal Product 
7.2.1. 
Packaging 
Debio 1347 tablets packed in 
 blisters will be delivered to study site pharmacies by the 
Sponsor. Each blister will contain 28 tablets of Debio 1347 20 mg.  
The site Pharmacist will deliver to the subjects the number of Debio 1347 blisters required.  
7.2.2. 
Labelling 
Labelling will be open and will comply with the health authority regulations of each participating country. 
7.2.3. 
Storage 
Storage conditions will be specified on the labels. 
7.3. Dispensing and Accountability of Investigational Product 
The IMP and CoA will be provided to the Investigator(s) by and under the responsibility of the Sponsor, 
who will also ensure release of the IMP as per current GMP (Good Manufacturing Practice) guidelines. 
Any documentation required by local health authorities for import of the IMP will be appropriately 
submitted. 
The Investigator/Pharmacist at each study site will inventory and acknowledge receipt of all shipments of 
IMP. The IMP 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 IMP accidentally or deliberately destroyed.  
At timely intervals and study closure, the IMP will be reconciled by the Sponsor’s monitor/representative 
according to the Sponsor's standard operating procedure (SOP) unless otherwise agreed. Unused IMP will 
be counted and destroyed only after formal written agreement has been received from the Sponsor. Any 
discrepancies between the IMP returned and the expected balance must be justified. 
Unused IMP must not be used for any purpose other than the present study. 


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7.4. Subject Numbering 
7.4.1. 
Pre-screening number in the case of central FGFR assessment 
Only subjects who require a central assessment of FGFR status will be manually assigned a unique 
pre-screening number by the site. The pre-screening number consists of a unique 7-digit identifier 
(###9###). The first 3 digits represent the number of the study centre, the hardcoded “9” refers to the 
pre-screening process and digits 5-6-7 identify the pre-screening order of the subject at the centre (starting 
at 001). Pre-screening # 1069001, for example, identifies the first subject (001) pre-screened at study 
centre 106. The second subject pre-screened at the same study centre will be given  
Pre-screening # 1069002, etc.  
The above subjects will not be recorded in the electronic case report form (eCRF) if their eligibility is not 
confirmed by the pre-screening FGFR fusion/rearrangement assessment (see Section 8.2.1.1). Conversely, 
eligible subjects will proceed with the scheduled screening procedures and will be assigned a screening 
number as described below. The pre-screening number will then be entered in a specific field of the eCRF 
via the internet-based application. The pre-screening number described above is different and separate from 
the screening number described in the next section.  
Each site must keep the pre-screening log to document the subjects who have been pre-screened at their 
site. 
7.4.2. 
Screening number 
At the first screening visit between Days -28 and -1 prior to study start, each potential study subject 
will be identified by a unique Screening number (#) which is automatically displayed when the subject is 
initially recorded in the IWRS (Interactive Web Response System) via the internet-based application, and 
the subject will be created with the same Screening # in the e-CRF by an automated data integration from 
the IWRS. The Screening # allows entry of subject data in the eCRF.  
The Screening # consists of a unique 6-digit identifier. The first 3 digits represent the number of the study 
centre and digits 4-5-6 identify the screening order of the subject at the centre (starting at 001). 
Screening # 106001, for example, identifies the first subject (001) screened at study centre 106. The second 
subject screened at the same study centre will be given Screening # 106002, etc.  
7.5. Blinding and Unblinding Methods 
Not applicable. 
7.6. Method of Administration and Compliance 
Debio 1347 tablets will be administered orally at the dose of 80 mg once daily from Day 1 to Day 28 in 28-
day cycles (see study plan in Section 8.3) until occurrence of any of the criteria described in Section 8.4.1. 
Debio 1347 will mostly be self-administered by subjects at home and should be taken at approximately the 
same time each day as follows: 
1. Debio 1347 must be taken early in the morning. Subjects must fast (only water permitted freely) 
for 4 hours before and 2 hours after intake. 
2. If a dose is not administered for reasons other than toxicity, the subject may take the dose later in 
the day but no later than 6 hours after normal intake time. If the delay exceeds 6 hours, the subject 
must wait until the next scheduled administration.  
3. If the subject vomits after Debio 1347 intake, another dose should not be administered, rather wait 
until the next scheduled dose.  
Subjets will also be instructed by study staff on how to take Debio 1347.  


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Dose adjustments are permitted as described in Section 5.3.  
Subject compliance will be verified by a) means of a diary card or equivalent electroninc tool to be filled 
out after each dose when taken at home and b) direct visual supervision at dosing by the Investigator or 
designee when the drug is administered at the study site. Compliance will be checked by the Investigator 
or designee at each study visit and the number of returned tablets and date will be recorded when applicable.  
7.7. Concomitant Therapy 
7.7.1. 
Permitted medications 
1. Supportive therapies against pain, nausea, vomiting, constipation and diarrhea are allowed as per 
the Investigator’s decision, as well as granulocyte colony-stimulating factors (G-CSF). Treatment 
of pain should be administered according to severity and recommended drugs. Study specific 
guidelines will be provided separately. 
2. Gonadotrophin-releasing hormone receptor (GnHR) agonists and antagonists for prostate cancer 
are permitted (if prostate cancer is the reason for eligibility). 
3. Bisphosphonates and denosumab: Concomitant use is allowed. 
4. Radiotherapy: Concomitant radiotherapy may only be given for the control of bone pain or as 
indicated to ≤ 30% of the bone marrow. Irradiated lesions will not be evaluable for response. 
Radiotherapy should start no sooner than 24 hours after the previous dose of Debio 1347 and study 
treatment may be resumed with the resolution of any radiation toxicity to ≤ Grade 1. 
The following medications and/or treatments are permitted with caution and should be monitored during 
the study: 
1. Contact lenses: In non-clinical studies, Debio 1347 has been found to affect the cornea. Since 
corneal disorders may occur when contact lenses are worn and use of Debio 1347 may exacerbate 
these symptoms, caution should be exercised when administering Debio 1347 in a subject wearing 
contact lenses. The subject should be monitored.  
2. Drugs with a known risk of QTc prolongation: Considering the QTc prolongation potential (not yet 
fully characterized) and the risk of hypokalemia associated with Debio 1347, caution should be 
exercised when using Debio 1347 with drugs having a known risk of QTc prolongation (see 
Arizona CERT database at website: http://www.crediblemeds.org). Monitoring of electrolyte levels 
is strongly recommended. 
3. Drugs that are known substrates of either CYP3A, CYP1A2, P-gp, BCRP, MATE1 or OCT2:  
Per in vitro results available so far and Debio 1347 plasma exposure observed in subjects, 
Debio 1347 is considered at possible risk of perpetrating drug-drug interactions through CYP3A 
inhibition, CYP3A induction (some transporters such as P-gp might also be co-induced), CYP1A2 
repression, or inhibition of several transporters (P-gp, BCRP, MATE1, OCT2). The clinical impact 
of these in vitro observations is not known and subjects who are taking concurrent drugs that are 
known substrates of either CYP3A, CYP1A2, P-gp, BCRP, MATE1 or OCT2 should be carefully 
monitored. A list of such drugs can be consulted in: 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School 
of 
Medicine 
(2007) 
(http://medicine.iupui.edu/clinpharm/ddis/ 
); 
and 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm 
It should be noted that the potential for drug-drug interactions with CYP3A or CYP1A2 substrates 
(and possibly also with P-gp substrates) is time-dependent; it may increase with time as subjects 
continue to take Debio 1347 and may persist for some days after Debio 1347 discontinuation. 


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3. Gastric mucosal protectants (e.g. histamine receptor antagonists and antacids but not proton pump 
inhibitors which are prohibited - see Section 7.7.3) must be taken at least 2 hours after Debio 1347 
intake since they may interfere with its absorption. 
4. Hormonal contraceptives should be used with caution. Based on in vitro data, Debio 1347 has the 
potential to induce and/or inhibit CYP3A4 and, as such, exposure and efficacy of hormonal 
contraceptives might be altered.  
Any other medication necessary for the well-being of the subject (with the exception of those mentioned as 
prohibited medications, see Section 7.7.3 below) may be given at the Investigator’s discretion.  
7.7.2. 
Supportive care 
7.7.2.1. 
Dermatological toxicity - prophylaxis and management 
Prophylaxis and treatment of dermatological toxicities are described in Appendix F. 
7.7.2.2. 
Gastrointestinal disorders 
For nausea, vomiting, diarrhea or constipation, treatment may include antiemetics, antidiarrheals or laxative 
bowel regimens consistent with SOC. Since drugs that alter gastric pH may interfere with the absorption of 
Debio 1347, proton pump inhibitors are prohibited during the study (see Section 7.7.3) and other gastric 
mucosal protectants (e.g. histamine receptors antagonists, antacids) should be administered at least 2 hours 
after Debio 1347 administration. 
7.7.2.3. 
Hematological support 
The use of red blood cell transfusions will be permitted as clinically indicated during the study. 
The use of bone marrow colony stimulating factors (such as granulocyte colony-stimulating factor or 
granulocyte-macrophage colony-stimulating factor) is permitted as clinically indicated. Prophylactic use is 
prohibited. 
7.7.2.4. 
Hypercalcemia management 
Subjects with asymptomatic hypercalcemia do not require immediate treatment if calcium remains  
< 12 mg/dL (3 mmol/L). However, the subject should be advised to avoid factors that can aggravate 
hypercalcemia (such as thiazide diuretics, volume depletion, prolonged bed rest or inactivity and a high 
calcium diet [> 1000 mg/day]).  
Adequate hydration (at least 6 glasses of water per day) is recommended to minimise the risk of 
nephrolithiasis.  
Hypercalcemia treatment guidelines are described in Appendix G. 
7.7.2.5. 
Hyperphosphatemia management 
Subjects will be treated according to the guidelines available in Appendix E. 
All enrolled subjects should receive adequate instructions concerning dietary phosphate restriction. 
Phosphate is a mineral widely found in most foods. The main natural sources of phosphate are: 
• 
Dairy products (milk, cheese, ice-cream, yogurt)  
• 
Meat 
• 
Dried beans 
• 
Peas 
• 
Nuts and peanut butter 
• 
Wholegrains 
• 
Cola 


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7.7.2.6. 
Infections 
1. CR-BSI (Catheter-Related Bloodstream Infection) should be managed according current Clinical 
Practice Guidelines.43  
2. Febrile neutropenia: Antibacterial and antifungal prophylaxis for fever and treatment of 
neutropenia should be managed according to current clinical practice guidelines.44,45 
3. MSRA (Methicillin-Resistant Staphylococcus Aureus) infection should be managed according to 
current clinical practice guidelines.46 
7.7.3. 
Prohibited medications  
1. Other antineoplastic agents are prohibited except GnHR agonists and GnHR antagonists for 
prostate cancer. 
2. Other investigational agents are not to be used within 2 weeks (3 weeks for immune checkpoint 
inhibitors) of initial dosing or while receiving Debio 1347. 
3. Concurrent radiation treatment, except for palliation or symptom relief. If palliative radiation is 
indicated for bone metastases, palliative radiation may start within 24 hours of last dose of 
Debio 1347, unless, in the judgment of the Investigator, subject safety will require a longer washout 
period prior to palliative therapy and dosing of Debio 1347 may resume with the resolution of any 
radiation toxicity to ≤ Grade 1. 
4. Chronic immunosuppressant (e.g., cyclosporine following transplantation or systemic e.g., oral, 
intravenous (IV), intramuscular (IM), subcutaneous (SC)) steroid dose equivalent to > 10 mg 
prednisone daily); however, a transient steroid dose equivalent to > 10 mg prednisone daily might 
be allowed after discussion with the Sponsor. 
5. Fibroblast growth factor injections, cosmetics containing FGF. 
6. Proton pump inhibitors. 
If treatment with a prohibited medication is necessary, the subject will be withdrawn from the study after 
discussion with the Sponsor. 
7.7.4. 
Reporting of Prior and Concomitant Therapy/Medications 
Administration of medications to and therapies taken by the subject during the study period must be reported 
on the prior and concomitant medications page of the eCRF using the World Health Organization Drug 
Dictionary (WHO-DD) classification.  
Information to be reported on the eCRF includes: i) international non proprietary name and the trade name, 
ii) dosage information (i.e. total daily dose, unit(s), frequency and route), iii) dates of administration, and 
iv) reasons for use. 
8. 
STUDY ENDPOINTS, ASSESSMENTS AND PROCEDURES  
8.1. Endpoints 
8.1.1. 
Primary endpoint 
ORR (defined as the proportion of subjects with a BOR of partial or complete response) as centrally 
measured by RECIST 1.1 criteria. 
8.1.2. 
Secondary endpoints 
1. DoR (defined as the time from the date of the initial partial or complete response to date of the first 
documented progression or death due to any cause).  
2. DCR (defined as the proportion of subjects with a BOR of CR or PR or SD). 


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3. PFS (defined as the time from the start date of treatment to date of the first documented progression 
or death due to any cause).  
4. OS (defined as the time from the start date of treatment to date of death due to any cause).  
5. Proportion of subjects with TEAEs assessed by NCI-CTCAE v5.0 and SAEs. 
6. Debio 1347 plasma exposure (Ctrough, AUC and any other PK parameters as deemed appropriate) 
and relationships with efficacy and safety endpoints; Debio 1347 plasma concentration (C)-QTcF 
relationship based on ECG and PK matching time-points. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
8.2. Assessments 
As per Protocol Amendment Nº 2, the assessments and procedures plan defined in the study protocol 
(section 8.2) will no longer be in force and will be replaced by standard institutional care practice. Subjects 
must be followed up regularly (at least every two months) to assess the potential occurrence of safety events 
and conduct the safety laboratory analyses, as described in Table 8.1b. 
Pregnancy, AEs, AESI, and SAE will be collected and documented in the study eCRF. The dedicated report 
forms should be completed by the Investigator and sent to the Sponsor as specified in section 9.2 of this 
Protocol. 
Subjects showing clinical benefit may remain on treatment with Debio 1347 until a condition to stop 
treatment is met for the last subject in the study. 
 
8.2.1. 
Assessment of FGFR fusion/rearrangement  
8.2.1.1. 
Pre-screening 
Pre-screening for tumor FGFR fusion/rearrangement will be made either locally at the study site in a 
certified laboratory or in a central laboratory using RNA or DNA-based NGS techniques. Only subjects 
harboring FGFR fusions/rearrangements potentially leading to a functional FGFR aberrant protein may 
undergo the complete clinical screening required for study participation. 
The test will be made on adequate fresh tumor tissue slides (preferably) or, only if not possible, adequate 
unstained archival slides or tumor block, prior to or during the 28-day screening period. 


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Of note: A "liquid biopsy", e.g., ctDNA based test is acceptable for subject eligibility but then a pre-study 
treatment tissue sample is required for post-hoc confirmation of the fusion.  
8.2.1.2. 
Post-hoc confirmatory test 
Tumor FGFR fusion/rearrangement will be confirmed by a central laboratory in case pre-screening is 
performed locally at the study site. Central analysis of FGFR fusion/rearrangement is not required for 
eligibility. Functional gene fusions involving FGFR1-3 and containing an intact FGFR kinase domain will 
be confirmed by RNA sequencing. 
8.2.2. 
Efficacy Assessments 
As per Protocol Amendment Nº 2, the efficacy assessments described in section 8.2.2 will no longer be 
be in force and efficacy data will not be collected. Central radiological review will no longer be 
performed. The patient will be followed for efficacy by the Investigator as per institutional practice. 
 
8.2.2.1. 
Tumour assessments 
Of note: An imaging review will be conducted by a central radiological review board to confirm the tumor 
assessments of all subjects enrolled in the trial regardless of response. 
8.2.2.1.1. 
Screening 
1. Subjects will be examined and the tumor staged using the appropriate system.  
2. A CT scan or MRI of the involved regions and tumour assessment according to RECIST version 
1.1 guidelines47 (see Appendix B) will be performed. The choice of the radiological method will 
depend on the tumour site.  
For each subject, the same radiological method must be used throughout the study.  
8.2.2.1.2. 
On-treatment 
1. A CT scan or MRI and tumour assessment of the target/non target lesions will be performed 
according to RECIST version 1.1 guidelines47 (see Appendix B) at the end of Cycles 2, 4 and 6 
followed by every 3 cycles (end of cycle) for up to 24 months. In the case of response, imaging will 
be repeated 4 (± 3 days) weeks later. 
2. A CT scan or MRI and tumour assessment of the target/non target lesions will be performed 
according to RECIST version 1.1 in all subjects at the time of disease progression and/or EOT.  
8.2.3. 
Safety Assessments 
1. Adverse events will be monitored throughout the study as of signature of informed consent and 
will be graded according to NCI-CTCAE v5.0 (see Appendix C). 
2. Demographics, medical history and height measurement will be collected at screening. 
3. Physical examination, vital signs (BP and heart rate after at least 5 minutes of supine rest), rating 
of ECOG PS (see Appendix A) and weight measurement will be performed at: 
• 
All clinical visits as part of the standard institutional practice 
• 
EOT/progression 
4. As per Protocol Amendment Nº 2, central ECG reading will not be performed. ECGs (with PR, 
RR, QRS and QTcF intervals) after at least 5 minutes of supine rest will be recorded as part of the 
ongoing safety assessments.  
• 
All clinical visits as part of the standard institutional practice  
• 
EOT/progression 
5. As per Protocol Amendment Nº 2, central analytical laboratory testing will not be performed. 
Laboratory tests will also be conducted according to standard institutional practice to support the 




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 The 
concentration of Debio 1347 in plasma will be determined using a validated LC-MS/MS method 
 
. 
Detailed instructions on sample drawing, handling and shipping to the central laboratory will be provided 
in a separate laboratory manual. After completion of the analysis (if applicable), 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 
a retrospective examination of safety laboratory tests, of proteins involved in body disposition or the 
pharmacological effects of Debio 1347, for metabolic profiling or for further bioanalytical investigations 
(such as method cross-validation) to validate data for the development of Debio 1347. 
 
8.2.6. 
, Tumour and 
 Assessments 
 
  
 
 
 
 
8.2.6.2. 
Tumour biopsy assessments 
A tumour biopsy will be collected at pre-screening/screening (if biopsy not possible adequate unstained 
archival slides or tumor block must be made available) for the assessment of predictive biomarkers and 
. The biopsy may be also used to 
generate information needed for research and development of tests allowing to detect FGFR alterations. 
 
 
As per Protocol Amendment Nº 2, no further tumor biospies will be collected at time of progression. 
 
 
 
 
 
 
 
 
 
  
 
8.2.7. 
Follow-up Assessments 
As per Protocol Amendment Nº 2, patients who discontinue study treatment will only undergo a safety 
follow-up (i.e. during 30 days post last Debio 1347 dose administration). Patients will not be followed for 
disease status and survival follow up. Sub-section “a”  below applies exclusively.  After treatment 
discontinuation (= EOT visit), subjects will be followed up for: 
a. Safety (AEs/SAEs) for 30 days from the date of the last Debio 1347 dose; after this period, 
the Investigator should report to the Sponsor any unusual safety information or any safety 
information that appears to be related to the study drug;  


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b. Survival every 12 weeks (± 14 days) from the date of the last Debio 1347 dose until death 
or loss to follow-up but no longer than for a total of 2 years after the last subject 
discontinued treatment;  
c. Disease 
status 
only 
in 
subjects 
without 
PD 
every 
12 
weeks  
(± 14 days) from the date of the last Debio 1347 dose until PD, death or loss to follow-up 
but no longer than for a total of 2 years after the last subject discontinued treatment;  
d. Pregnancy screening every 28 days for 6 months after the last Debio 1347 dose. All 
pregnancies detected during the 6-month post-EOT follow-up period should be reported 
according to the standard process described in Section 9.7 
8.3. Study Procedures and Plan 
Assessments are described in detail in Section 8.2. A study plan including timing of tests and evaluations is 
presented below in Table 8-1.  
All eligible subjects will attend the study visits indicated in the study plan. Study procedures must be 
performed according to the planned time schedule with strict adherence to visit intervals. 
Prior to conducting any of the screening tests, the Investigator or his/her designee will explain the study fully 
to the prospective subject and provide him/her with a copy of the Patient Information Leaflet/Informed 
Consent Form for the entire study. If the subject is willing to participate in the study, s/he and the Investigator 
or his/her designee will each sign two copies of the Informed Consent Form of which the subject keeps one.  
Subjects who are confirmed at the pre-screening assessment as harboring FGFR fusions/rearrangements (see 
Section 8.2.1.1) will attend the full screening visit within 28 days prior to the first treatment cycle. Subject 
suitability will be confirmed by the inclusion/exclusion criteria in Section 6. A subject may be re-screened on 
the conditions described below. 
Of note: Subjects who require a central assessment of FGFR status (pre-screening test, see Section 8.2.1.1) 
will be asked to sign a pre-screening Informed Consent Form to this intent.  
As per Protocol Amendment Nº 2, the updated study plan is presented in Table 8-1b.  
All subjects will be followed by the Investigator as per standard institutional care practice. Subjects will 
receive Debio 1347 for as long as they are benefitting from the study drug and there is no safety concern as 
per Investigator’s judgment. Pregnancy, AEs, AESI, SAEs, will be documented and collected in the study 
eCRF, and reported using dedicated forms described in section 9.2 of this protocol. 
8.3.1. 
Rescreening 
In certain circumstances subjects may be re-screened for inclusion into the study despite an initial screening 
showing them to be ineligible, e.g.: 
• 
A subject consented to participate, met the eligibility criteria but was delayed in starting due to a 
change in situation (i.e., family issues, request for attending a private matter, etc.). 
• 
A subject failed eligibility due to an acute event that resolved or was stabilized with medications. 
• 
Reversible causes of screening failure that were adequately treated, e.g., anemia precluding subject 
participation was treated by transfusion. 
In these situations: 
• 
A new eCRF will be used. 
• 
A new identification number will be assigned to the subject.  
• 
The subject will be flagged as having been re-screened in the eCRF and on the site master list. 


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• 
The eCRF will be completed with the new screening data; data from the initial screening must not be 
copied from the initial eCRF into the new eCRF; the latter must be completed based on the current 
clinical situation as documented by the subject's clinical notes. 
• 
The subject may need to sign a new consent form as part of the screening procedure. 
A subject who failed to meet the eligibility criteria in a first attempt should not be re-screened if no changes 
or treatments indicate that the subject may possibly be suitable. 






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k) A tumour biopsy will be collected a) at pre-screening/screening (necessary for inclusion and assessment of biomarkers pre-treatment if biopsy not possible adequate unstained archival slides or tumor block 
must be made available) and b) at disease progression whenever feasible. 
l) The examination will be interpreted by a qualified ophthalmologist, including visual acuity testing, slit-lamp ophthalmoscopy and indirect ophthalmoscopy. At the EOT visit, only slit lamp ophthalmoscopy 
will be performed. 
 
 
 
n) After treatment discontinuation (= EOT visit) subjects will be followed-up for: 
1) Safety (AEs/SAEs) for 30 days from the date of the last Debio 1347 dose. After this period, the Investigator should report to the Sponsor any unusual safety information or any safety information that 
appears to be related to the study drug.   
2) Survival every 12 weeks (± 14 days) from the date of the last Debio 1347 dose until death or loss to follow-up but no longer than for a total of 2 years after the last subject discontinued treatment.  
3) Disease status only in subjects without PD every 12 weeks (± 14 days) from the date of the last Debio 1347 dose until PD, death or loss to follow-up but no longer than for a total of 2 years after the last 
subject discontinued treatment. 
4) 
 
 
5) Urinary pregnancy test post-EOT: Every 28 days for 6 months (home pregnancy test is acceptable). All pregnancies detected during the 6-month post-EOT follow up period should be reported according 
to the standard process described in Section 9.7   
 
 
 
 


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Table 8-2b 
Study Plan ( applicable to subjects with Debio 1347 treatment ongoing after the implementation of Protocol Amendment Nº 2) 
 
Ongoing Treatment* 
EOT  
EOS (30 days after last 
study drug intake)  
Cycle 
any 
 
 
Written informed consent (amendment Nº2) 
● 
 
 
Physical examination 
● 
● 
● 
Vital signs 
● 
● 
● 
ECGa 
● 
● 
 
Hematology, fasting biochemistryb 
● 
● 
● 
Urinary pregnancy test 
● 
● 
● 
Urinalysis 
● 
● 
● 
Adverse eventsc 
● 
● 
● 
*For all subjects with Debio 1347 treatment ongoing and who consented to participate in the study after the date of implementation of Protocol Amendment Nº 2, the assessments and procedures plan defined in 
the study protocol will no longer be in force and will be replaced by standard institutional care practice (at least every 2 months) 
a) ECG trace (PR, RR, QRS and QTcF intervals) will be recorded after at least 5 minutes of supine rest. 
b) Hematology: Complete blood count with differential (including ANC), hemoglobin, platelet count.  
 
Chemistry: Total protein, albumin, indirect and total bilirubin, AST, ALT, ALP, electrolytes (sodium, potassium, calcium, magnesium), serum phosphate, serum creatinine, creatinine clearance. The assessment 
will be performed in a local laboratory.  
 
Note regarding safety laboratory asessments: In case of a significant laboratory abnormality or clinical or laboratory evidence of toxicity, the Investigator will collect additional samples for repeat or 
additional analyses at appropriate intervals. The subject will be closely followed until sufficient information has been obtained to determine the cause of the abnormality or the value has returned to an 
acceptable level. Appropriate remedial measures should be taken, and the response recorded. Any clinically relevant change from baseline onwards must be recorded on the AE page of the eCRF. 
c) AEs, AESI, SAEs must be documented in the study eCRF and in the dedicated report forms as specified in section 9.2 of this protocol. 
 
 


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8.4. End-of-treatment and Overall End-of-study 
8.4.1. 
End-of-treatment Criteria 
Treatment with Debio 1347 will continue until any of the following occurs: 
1. Subject withdraws consent. In this case, the subject will be discontinued from the trial and will be 
followed up according to the study plan. 
2. Disease progression documented by CT scan/MRI, physical examination or any other method of 
evaluation or measurement t. An exception can be made for subjects who progress due to brain 
and/or bone metastases who may continue treatment with Debio 1347 if, in the Investigator’s 
opinion, there is a reasonable evidence of clinical benefit. The Medical Monitor must be informed. 
3. Unacceptable toxicity. 
4. Pregnancy. 
5. In the subject's interest as judged by the Investigator.  
6. The Sponsor or Independent Ethics Committee (IEC) decides to terminate the study. 
Subjects who are removed from study treatment due to AEs are to be treated and followed-up according to 
accepted medical practice and all pertinent information concerning the outcome of the treatment is to be 
recorded in the eCRF. 
8.4.2. 
End-of-study Criteria 
1. Withdraws consent. 
2. Adverse event, e.g. intercurrent illness that would, in the judgment of the Investigator, affect 
assessments of clinical status to a significant degree; or intercurrent illness that, in the opinion of 
the Investigator or the study Medical Monitor, compromises the subject’s safety. 
3. Subject non-compliance. 
4. Subject lost to follow-up. 
5. If, in the Investigator’s opinion, continuation in the trial would be detrimental to the subject’s 
wellbeing. 
6. A major protocol violation occurs. If a minor protocol violation occurs, the Sponsor’s Trial 
Manager will be contacted to discuss if the subject has to be withdrawn. 
7. Prohibited medication as indicated in Section 7.7.3 is required/used during the course of the trial. 
In the event a subject is found to be taking a prohibited medication during the trial, the site should 
immediately contact the Medical Monitor. The decision to withdraw the subject will be made in 
conjunction with the Sponsor. 
8. Non-drug related reason; e.g. subject relocates too far from study centre. 
9. Sponsor or IEC decides to terminate the study. 
8.4.3. 
Overall End-of-study  
The study will be considered as completed 30 days  after the last subject discontinued treatment. 
 
 


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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 IMP(s) as 
assessed by the Investigator will be recorded. The Investigator will also indicate whether study treatment 
was disontinued and how the event evolved. 
9.1. Definitions and Assessment Criteria 
9.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
Adverse events are signs of illness (including abnormal laboratory findings) or symptoms occurring or 
worsening in the course of the study. Adverse events can be serious or non-serious. They may or may not 
lead to the withdrawal of the subject from the study. 
Events meeting the definition of an AE include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or other safety 
assessments (e.g., ECGs, vital sign measurements…) including those that worsen from baseline 
and assessed to be clinically significant in the medical and scientific judgment of the Investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments that 
are associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• 
A medical or surgical procedure (e.g., endoscopy); the condition that leads to the procedure is an 
AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing diseases(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
Reporting of disease progression: Disease progression/recurrence, symptoms and signs related to tumour 
progression/recurrence, e.g., hospitalisation due to a tumour progression, should not be reported as an AE 
or SAE 
9.1.2. 
Serious Adverse Event 
A SAE is 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; 
Of note: In general, hospitalization signifies that the subject has been detained (at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. Complications that occur during 


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hospitalisation are AEs. If a complication prolongs hospitalization or fulfils any other serious 
criteria, the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; 
Of note: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., strained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
• 
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 jeopardise the patient/subject or require 
intervention to prevent one of the outcomes listed in the definitions above shall also be considered 
as serious. 
Non-serious: All AEs that do not correspond to the definition of SAE are considered as non-serious. 
Reporting of disease progression: Disease progression/recurrence, symptoms and signs related to tumour 
progression/recurrence, e.g., hospitalisation due to a tumour progression, should not be reported as an AE 
or SAE. 
9.1.3. 
Severity of Adverse Events 
Adverse events will be graded according to the NCI-CTCAE v5.0 criteria. 
Hyperphosphatemia, which is not included in the NCI-CTCAE v5.0, will be graded as follows: 
1. Serum phosphate levels > ULN but < 5.5 mg/dL (~ equivalent to Grade 1); 
2. Serum phosphate levels 5.5 - 6.9 mg/dL (~ equivalent to Grade 2); 
3. Serum phosphate levels 7 - 9.9 mg/dL (~ equivalent to Grade 3, as this is the expected level at 
which soft tissue calcifications might develop); 
4. Serum phosphate levels > 10 mg/dL with or without renal impairment (~ equivalent to Grade 4). 
9.1.4. 
Relationship with the Investigational Medicinal Product(s) 
The Investigator or designee will determine the relationship between the AE and the IMP(s) 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. 


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9.1.5. 
Adverse Events of Special Interest 
The following cardiac-related events will be considered as AEs of special interest (AESIs): 
• 
Episodes of ventricular tachycardia or fibrillation,  
• 
Syncope and seizures, 
• 
AEs resulting in subject discontinuation from the study. 
All of the above listed AESIs require appropriate reporting (including narrative summary) within 24 hours 
of becoming aware of the event.  
The procedure for AESI reporting is outlined in Section 9.5 of the protocol. 
9.2. Reporting of Serious Adverse Events to the Sponsor 
9.2.1. 
Reporting during the study 
The Investigator must notify the Clinical Research Organisation (CRO)/Sponsor of all SAEs within 
24 hours of awareness by fax or email using the Debiopharm 'SAE Report form'. 
1. When reported by fax, the 'SAE Report form' will be filled in and sent with the provided fax cover 
page entitled 'Serious Adverse Event Report transmittal form' 
to the following 
number:
 
2. When reported by email, the 'SAE Report form' will be sent to the Sponsor at the following email 
address
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.  
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual 
signs/symptoms. 
9.2.2. 
Reporting post-study 
Any SAE occurring within 30 days of the last IMP administration will be reported by fax, email within 24 
hours of SAE awareness as described in Section 9.2.1.  
After this period, all unusal safety information or any safety information that appears to be related to Debio 
1347 will be reported within 24 hours by fax 
, email 
; new SAEs that are spontaneously reported by Investigators to the CRO/Sponsor 
will be recorded and regarded for expedited reporting purposes. 
9.3. Follow-up of Serious Adverse Events 
All SAEs, regardless of severity, must be followed up: 
• 
To resolution (subject health has returned to his/her baseline status or all variables have returned to 
normal), or  
• 
Until stabilisation 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 subject 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 by fax or e-mail within 24 hours of 
new information awareness (see Section 9.2.1 above). 
9.4. Procedure for Serious Adverse Event Notification to Independent 
Ethics Committees 
If required by applicable local regulations, the Investigator will promptly notify the relevant 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 IEC 
acknowledges receipt of the notification. 
9.5. Procedure for Reporting Adverse Events of Special Interest 
For any AESI (as defined in Section 9.1.5) occurring during the clinical trial period, whether related or not 
to the study drug and whether expected or not, the Investigator must notify the Sponsor within 24 hours of 
awareness by fax or email using the SAE form as described in Section 9.2.1. 
All AESIs, regardless of severity, must be followed-up until: 
• 
Resolution (the subject's health has returned to the baseline status or all variables have returned to 
normal), or 
• 
Stabilization of the event has occurred (the Investigator does not expect any further improvement 
or worsening of the event), or 
• 
The event is otherwise explained whether the subject is still participating in the study or not. 
Some events are often ongoing; however, once these events have been determined by the Investigator to be 
stable or chronic, s/he may consider the event to be resolved or resolved with sequelae. 
The Investigator will notify the Sponsor of any follow-up information by fax or email within 24 hours of 
new information awareness as described above. 
9.6. Determination of Expectedness - Reference Document 
In the European Community, for regulatory reporting purposes, expectedness of an event will be assessed 
according to the applicable reference document. 
Debio 1347:   Investigator’s Drug Brochure, current version. 
9.7. Pregnancies 
Pregnancies should be avoided during the study. Any subject who nevertheless becomes pregnant must be 
followed-up until pregnancy outcome is known. 
The Investigator must notify the Sponsor within 24 hours of awareness of any pregnancy occurring from 
date of Informed Consent until 6 months after EOT by fax or email using the Pregnancy Report Form. 
Individual cases with an abnormal outcome associated with a medicinal product following exposure 
during pregnancy are classified as serious reports and should be reported in an expedited manner.  
 
 


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10. 
MONITORING AND STUDY COMMITTEES 
10.1. Monitoring 
The study Sponsor is Debiopharm International SA, Lausanne, Switzerland. 
At mutually convenient times during the study, the Investigator will let Debiopharm or its representative 
review all eCRFs and related source documentation, i.e., subject 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 Debiopharm or its representative (see also Sections 7.3 and 7.6). 
In case eCRFs require support information, Debiopharm may request copies of subject records or other 
source documents. All the necessary steps will then be taken to protect subject identity. Adherence to local 
and national laws governing protection of subject identity will be ensured. 
Copies of all diagnostic imaging films used to determine subject status must be available for Debiopharm 
International SA and external consultants. If requested, copies of the above films are to be produced for the 
files of Debiopharm International SA. 
10.2. Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be assembled prior to study start and will be comprised of 
independent experts in the field of oncology and biostatistics. The DMC will be responsible for the review 
of safety and efficacy data during the course of the study. The DMC will perform the planned interim 
analysis at end of stage 1 and provide recommendations to the sponsor as defined in the DMC charter. 
The roles and responsibilities of the DMC and meetings frequency will be defined in the DMC charter. 
Following the implementation of Protocol Amendment Nº 2, the DMC is no longer required. 
 
 


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11. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
The general data management and statistical plan described in this section is applicable to all patients 
enrolled in the trial since the study start date until the implementation of the Protocol Amendment Nº 2. 
Following Protocol Amendment Nº 2, only safety data will be captured.  
11.1. Sample Size 
A basket two stage adaptive design42 will be used to assess the efficacy of Debio 1347 in terms of ORR. 
With 27 evaluable subjects in Stage 1 and 86 evaluable subjects in Stage 2, the study will have 
approximately 90% power to reject the null hypothesis that ORR ≤ 15% when the true ORR is 30% in at 
least one of the baskets, using a one-sided exact binomial test at an overall significance level of 5%. The 
sample size for stage 2 is for a pooled sample across baskets in case homogeneity is shown at end of Stage 
1, or for one active basket taken into Stage 2 in case of heterogeneity. Sample size and design operating 
characteristics were determined using simulations.  
Assuming homogeneity across baskets and a 10% drop out the study would enroll approximately 
125 subjects.  
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 eCRFs) accessed via an Internet URL link.  
EDC system accesses (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 subject. 
Validation of 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, i.e., SDV (source data verification), is conducted on an ongoing basis and is confirmed in the 
EDC system. In general the CRA review is focussed on the quality and integrity of the eCRF data. 
The 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, the data management review is focussed 
on the completeness and coherency of the eCRF data, and also includes reconciliation of external data vs 
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's audit trail captures all eCRF data related activities such as data entry, data modifications, 
data verification, data lock, e-signatures etc.  
The eCRF data will be extracted from the EDC system into SAS® datasets on a periodic basis and at 
defined study time points for statistical analysis. 


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11.2.2. 
Coding 
Medical history, tumour characteristics and AEs will be coded per system organ class and preferred term 
using the last available version of the MedRA (Medical Dictionary for Regulatory Activities). Prior and 
concomitant medications will be coded per anatomical therapeutic chemical (ATC) class levels 2 and 4 
using the last available WHO-DD.  
11.3. Analysis Population 
Intent-To-Treat Population  
The intent-to-treat (ITT) population consists of all subjects who received study drug. 
Safety Population  
The safety population consists of all subjects who received study drug. 
Modified Intent-to-Treat Population  
The modified intent-to-treat (mITT) population consists of all subjects in the ITT population whose gene 
fusion/rearrangement has been confirmed by post hoc central testing. 
Per Protocol (PP) population 
The per protocol (PP) population consists of all subjects in the ITT population who have undergone 
radiographic assessment at baseline (i.e., tumor assessment screening visit), received at least one dose of 
study drug, had both baseline and post-baseline disease and had no critical protocol deviation that may have 
an impact on efficacy endpoints. 
PK population  
The PK population will include subjects who received one or more doses of Debio 1347 and have at least 
one PK concentration result available.  
C-QT population  
The C-QT population will include subjects in PK population who has at least one matching ECG evaluation 
and PK sampling.  
The window for matching ECG evaluation and PK sampling will be fully described in the statistical analysis 
plan. 
11.4. Timing of Statistical Analysis 
The statistical analysis will be performed at the following time points: 
• 
An interim analysis will be conducted at end of Stage 1 to assess ORR homogeneity across baskets 
as well as futility. A minimum of 4 subjects per basket and a maximum of 13 subjects per basket 
will be required for the end of Stage 1 analysis. 
As per Protocol Amendment N° 2, this analysis will not be conducted due to the lower than 
expected antitumor activity reported during an initial statistical review of pooled data. 
• 
The main analysis will be conducted with all the safety and efficacy data after the  last subject has 
consented to Protocol Amendment Nº 2. The data from this analysis will be used to write an 
abreviated clinical study report (CSR). 
• 
A final descriptive analysis focused on safety will be conducted after the last subject has completed 
the EOS visit. 


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11.5. Statistical Analysis 
11.5.1. 
General analysis methods 
The statistical analysis will be described in detail in a SAP. Any deviations from the SAP, reasons for such 
deviations and all alternative or additional statistical analyses that may be performed, will be described in 
the final report.  
Ordinal and continuous data will be presented in the form of descriptive statistics, as number of subjects, 
mean, standard deviation, minimum, Q1, median, Q3, maximum. In addition, for PK endpoints, the 
geometric mean, 90% confidence interval (CIs) on geometric mean, the standard deviation of the geometric 
mean, and geometric coefficient of variation (CV) % will be presented. 
Categorical data will be presented using contingency tables with absolute and relative frequencies.  
Baseline is defined as the last measurement prior to the first study drug administration.  
All data analyses will be performed using SAS® statistical software and WinNonlin® Professional. 
11.5.2. 
Handling of missing data  
Missing data will not be imputed unless otherwise stated. Handling of missing tumour assessment is 
described in section . 
For adverse events, partially missing dates will be imputed for the purpose of classifying an event as 
treatment-emergent, dates as collected will be presented in data-listings. Adverse events with completely 
unknown start dates will be considered as treatment emergent. In case of a missing start day, if the AE start 
month and year is the month and year of the first administration of stuy drug, the AE will be considered as 
treatment emergent, otherwise, the missing day will be replaced by the 1st. In case of missing start day and 
month, if the AE start year is the year of the first administration of stuy drug, the AE will be considered as 
treatment emergent, otherwise the missing day and month will be imputed by the January1st. 
11.5.3. 
Interim analysis 
An interim analysis will be conducted at end of Stage 1 to assess ORR homogeneity across baskets as well 
as futility. A minimum of 4 subjects per basket and a maximum of 13 subjects per basket will be required 
for the end of Stage 1 analysis. ORR homogeneity will be assessed using a pre-defined cut-off for the 
critical value of the exact test for contingency tables. If homogeneity is declared, the next analysis steps 
will be conducted using combined data from all baskets; if heterogeneity is declared, data will be analyzed 
separately for each individual basket.  
After homogeneity assessment, a futility analysis will be conducted (for all baskets combined in case of 
homogeneity or per individual basket in case of heterogeneity). Futility will be assessed using a pre-defined 
minimum number of responses required at end of Stage 1.  
In case of homogeneity, the study will continue to Stage 2 if 3 or more responses are observed at end of 
Stage 1, otherwise the study will stop for futility.  
In case of heterogeneity, futility will be assessed in each basket separately. Baskets with 1 or more responses 
at end of Stage 1 will be eligible to continue to Stage 2.  
The interim analysis at end of stage 1 will be conducted by the DMC. At end of stage 1 The DMC will 
provide recommendation to continue or terminate the study for futility or to terminate individual cohorts 
for futility based on the criteria defined above. 
Details on the roles and responsibilities of the DMC will be provided in the DMC charter. 
Based on initial review and monitoring of efficacy data the interim analysis is cancelled. 


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11.5.4. 
Disposition of subjects, demographic and baseline data 
Disposition of subjects screened and treated will be summarized with reasons for study and treatment 
discontinuation by cohort and overall.  
Demographic and baseline data including age, gender, race, ethnicity, weight, height and BMI (body mass 
index) will be listed and summarized by cohort and overall. Baseline tumour characteristics, including 
primary location of tumour and tumour stage will be summarized by cohort and overall. Medical history 
will be summarized by system organ class and by preferred term. 
11.5.5. 
Extent of exposure 
Extent of exposure including treatment duration and number of cycles will be listed and summarized by 
cohort and overall. 
Incidence of treatment interruption and dose reductions will be summarized by cohort and overall. 
11.5.6. 
Efficacy 
The ITT population will be the primary analysis population for efficacy analysis. Efficacy analyses will be 
repeated on the mITT population and the PP population as supportive analyses. The efficacy analysis will 
be conducted using centrally measured response as primary analysis and repeated on locally measured 
response as sensitivity analysis.  
Best overall response is defined as the best confirmed response observed from first administration of study 
drug until disease progression. A PR or CR response needs to be confirmed in the following assessment 
performed at least 4 weeks later. For subjects who experience clinical progression, a radiological 
assessment will be performed to confirm the progression and the results of radiological assessement will be 
used in the efficacy derivation. 
11.5.6.1. 
Primary efficacy endpoints 
Objective response rate is defined as the proportion of subjects with a BOR of partial or complete response 
as centrally measured by RECIST 1.1 criteria.  
The primary analysis will be conducted at the main analysis and the hypothesis tested will be according to 
the decision taken at interim analysis: 
• 
Scenario 1: If the ORR homogeneity assumption is met at the interim analysis, then the hypothesis 
will be  
H0: ORR ≤ 15% against H1: ORR > 15 % 
The statistical comparison will be conducted using a one sided binomial exact test at an alpha level 
of 5%.  
• 
Scenario 2: If the ORR homogeneity assumption is not met at the interim analysis, then a decision 
will be made at the time of interim analysis to further continue the study with only 1 cohort or 
2 cohorts. Then the hypothesis tested at final stage will be  
H0: ORR ≤ 15% against H1: ORR > 15 % in each chosen cohort 
o Scenario 2a: In the case 1 cohort has been selected the statistical comparison will be 
conducted using a one sided Binomial exact test at an alpha level of 5%.  
o Scenario 2b: In the case 2 cohorts have been selected the statistical comparison will be 
conducted using a one sided binomial exact test at a Bonferroni adjusted alpha level of 
2.5% for each cohort.  
As such, the overall FWER (family wise error rate) for the study will be 5%.  


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Objective response rate measured centrally using RECIST v1.1 will be summarized by cohort and overall 
using frequencies and percentages. The CI will be presented overall or by cohort. In addition, BOR will be 
tabulated by cohort. 
A sensitivity analysis will be performed using ORR as assessed by the Investigator using RECIST v1.1. 
The analysis will be performed as for the centrally measured ORR.  
  
11.5.6.2. 
Secondary efficacy endpoints 
Disease control rate is defined as the proportion of subjects with a BOR of CR, PR or SD. Disease control 
rate will be summarized by cohort and overall using frequencies and percentages. The 95% clopper Pearson 
CI will be presented overall and by cohort.  
Duration of response is defined as the time from the date of the first documented PR or CR to date of the 
first documented disease progression or death due to any cause, whichever occurs first. It will be calculated 
only for subject with a best overall response of CR or PR. 
Progression-free survival is defined as the time from the start date of treatment to date of the first 
documented disease progression or death due to any cause, whichever occurs first. It will be expressed in 
months. 
The following censoring rules will be applied on PFS and DOR for subject with no documented disease 
progression or death: 
• 
Subjects who do not experience death or PD, nor initiate a new anti-cancer therapy will be right-
censored at the date of their last adequate tumor assessment (i.e. a tumor assessment not showing 
NE). 
• 
Subjects having initiated a new anti-cancer therapy before experiencing death or PD will be right-
censored at the date of their last adequate tumor assessment prior to initiation of a new anti-cancer 
therapy. 
• 
Subjects who experienced death or PD after two or more consecutive missing or inadequate tumor 
assessments will be right-censored at their latest adequate assessment before death or PD. 
Overall survival is defined as the time from the start date of treatment to date of death due to any cause. 
Subjects with no documented death will be censored at the last date known to be alive. 
Duration of response, PFS and OS will be summarized using the Kaplan Meier method. Median survival 
time and the associated CI will be estimated. Duration of response rate and PFS rate at 6 month and 1 year, 
and OS rate at 1 year and 2 years and the corresponding CIs will be estimated using the Kaplan Meier 
method.  
11.5.7. 
Safety 
The safety analysis will be conducted in the safety population. 
Adverse events  
Treatment emergent adverse events are defined as AEs that start on or after the first administration of study 
drug and within 30 days of last administration of study drug. 
Treatment-emergent adverse events, TEAEs related to study drug, TEAEs by severity, TEAEs leading to 
treatment discontinuation and SAEs will be tabulated and listed by MedDRA system organ class and 
preferred term.  
All study deaths and reasons will be listed.  
Laboratory parameters 


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Safety laboratory parameters and corresponding changes from baseline will be presented as descriptive 
statistics by cohort and overall by timepoint. Shift tables based on the NCI-CTCAE v5.0 toxicity grading 
(and ad hoc grading criteria for hyperphosphatemia) will be presented for each laboratory parameter 
between baseline and the highest post-baseline NCI-CTCAE v5.0 toxicity grade or the highest post-baseline 
ad hoc grading criteria for hyperphosphatemia. Any clinically significant abnormalities in laboratory values 
will be listed.  
12-lead ECG 
12-lead ECG parameters and corresponding changes from baseline will be summarized by cohort and by 
visit as descriptive statistics.  
The number (and percentage) of subjects satisfying the following conditions will be summarized by cohort 
and overall. 
• 
450 ms < QTcF ≤ 480 ms  
• 
480 ms < QTcF ≤ 500 ms  
• 
QTcF > 500 ms  
• 
An increases from baseline of > 30 ms and ≤ 60 ms 
• 
An increases from baseline of > 60 ms  
• 
QTcF > 500 ms or an increases from baseline of > 60 ms. 
No central reading of the original ECGs will be performed. Central tendency, categorical and morphological 
analyses will be performed, if deemed applicable.  
Other safety parameters 
Vital signs and corresponding changes from baseline will be summarized by cohort and by visit as 
descriptive statistics.  
ECOG PS will be presented as contingency tables by cohort and by time point. 
Prior and concomitant medications and will be tabulated by ATC level 2 and 4 and by cohort. 
 
 
 
 
 Pharmacokinetics 
Individual Debio 1347 concentrations will be listed by gender, subject and time point. Concentrations will be 
summarized as the number of subjects, arithmetic mean, standard deviation, minimum, median, maximum, 
25th percentile (Q1), 75th percentile (Q3), CV%, geometric mean, standard deviation of the geometric mean, 
geometric CV%, and 90% CI by time point and by cohort.  
Graphic displays of plasma concentration vs time will be presented individually by subject and as arithmetic 
means ± arithmetic standard deviations using linear/linear scales and as geometric means ± geometric standard 
deviations using log10/linear scales.  
Based on sparse sample plasma concentrations (that were defined by D-optimal design using the population 
PK model available so far), pharmacokinetic parameters (Ctrough, AUC and any other PK parameters as 
deemed appropriate) will be derived by population PK data analysis using a nonlinear mixed-effects 
modeling approach. Pharmacokinetic parameters will be listed by subject and summarized by cohort and overall 
as descriptive statistics. Inter- and intra-individual PK variability will be assessed by pooling data of this 
study with those of other clinical trial(s). 
If deemed appropriate based on safety and efficacy outcome, relationships between exposure vs efficacy 
(clinical response and/or any tumor metrics) and safety may be evaluated. Notably, the C-QTcF relationship 
based on ECG and PK matching time-points may be analysed by linear mixed effects modeling. 
 


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Subordinated to the safety and efficacy outcome and data availability, if applicable, the C-QTcF analysis 
will be fully described in the statistical analysis plan. Population PK data analysis (including covariate 
analysis if deemed appropriate), and,if applicable, exposure-response analyses for safety and efficacy will 
be described in separate analysis plans and reported separately in dedicated reports. If applicable, data may 
be pooled and analysed with data from other clinical trial(s). 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 


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12. 
SPONSOR AND INVESTIGATOR OBLIGATIONS 
12.1. Good Clinical Practice and Declaration of Helsinki 
This trial will be conducted in compliance with the ICH GCP guidelines and the ethical principles that have 
their origin in the Declaration of Helsinki (see Appendix D) and its subsequent amendments. 
12.2. Independent Ethics Committee 
The protocol and informed consent and any other relevant study documentation as outlined in the guidance 
document of Directive 2001/20/EC for this study must be reviewed and approved by an appropriate IEC 
which conforms to the Declaration of Helsinki (see Appendix D) and local laws prior to enrolment of 
participants into the study. A letter documenting IEC approval (in which the protocol title and number are 
specifically identified) and a list of IEC members and affiliations must be received by the Sponsor prior to 
initiation of the study.  
Within 90 days of completion of the study (last subject, last visit) or 15 days of early termination of the 
study, the IEC will be informed of the end of the study by the Investigator, Sponsor or designee.  
Every serious or unexpected AE that might affect subject safety must be brought to the attention of the IEC 
by the Investigator if required by his/her IEC regulations. 
12.3. Institutional Review Board  
The study protocol, informed consent and any other relevant study documentation must be reviewed and 
approved by an appropriate IRB that conforms to local laws prior to enrolment of subjects into the study. 
It is the responsibility of the Investigator to ensure that all aspects of the institutional review are conducted 
in accordance with local regulations and applicable ICH GCP. A letter documenting IRB approval (in which 
the protocol title and number are specifically identified) and a list of IRB members and affiliations must be 
received by the Sponsor prior to initiation of the study. The investigator is responsible for submitting an 
Investigator Progress Report to the IRB in time for the IRB to carry out review prior to the expiration date 
of the current IRB approval. This is required as long as the study is ongoing. 
The IRB will be informed by the Investigator of the completion or early termination of the study.  
Every serious or unexpected AE that might affect subject safety must be brought to the attention of the IRB 
by the Investigator. Similarly, every report from the Sponsor concerning an AE must be brought to the 
attention of the IRB by the Investigator. 
12.4. Informed Consent 
The Investigator or designee will ensure that signed informed consent* in accordance with the Declaration 
of Helsinki, local laws and all applicable regulatory requirements, is obtained from each potential subject 
prior to any study related procedure. The informed consent process will be documented.  
Each subject 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 subject has adequate time 
to consider the risks associated with study participation.  
Two originals of the informed consent will be signed by the subject (and/or legal authorised representative 
[guardian, next of kin or other authorised individual] if applicable) and the Investigator or designee. One 
signed original will be given to the subject and one will be kept in the Investigator file at the study site.  
*Exceptions to the above occur, when, for instance, a subject is not able to give consent  
(e.g., stroke trials, emergency indication). In such cases, the informed consent procedure must be described 
in detail, including the possibility to obtain delayed consent or consent from a relative or legal guardian. 
Applicable regulations must be strictly enforced and referred to.  


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12.5. Subject Confidentiality 
The Investigator will ensure that subject reports and samples are identified only by a subject identifier to 
maintain subject confidentiality. All subject study records will be kept safely in an access controlled area. 
Identification code lists linking the subject names to identifiers should preferably be stored separately from 
subject records. Clinical information will not be released without written permission from the subject, 
except for monitoring by Regulatory Authorities or the study Sponsor. 
12.6. 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 computerised system designed for the collection of clinical data in electronic format. One eCRF 
will be completed for each subject and must be electronically signed and dated by the Principal Investigator 
or the Co-investigator responsible for subject care during the study. 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 end of the study, each site will be given a CD-ROM with all study data entered by 
EDC. 
12.7. Retention of Data 
The Investigator will maintain adequate study records including the CD-ROM or equivalent with 
electronically collected study data, medical records, laboratory reports, informed consent forms, 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 centre. Records 
can be in paper or electronic format. 
All study records must be retained by the Investigator for the maximum period of time authorised 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. 
12.8. Deviations from the Protocol 
The Investigator will not deviate from the protocol. In case of medical emergencies, the Investigator will 
use medical judgment and will remove the participant from immediate hazard. The Sponsor and the 
IEC/IRB will be notified regarding the type of emergency and course of action taken. Any permanent 
changes or deviations in the protocol will be validated in an amendment to the protocol. 
For European studies: The amendment must be approved by the Sponsor and, if substantial as defined in 
directive 2001/20/EC, submitted for approval to the Health Authorities and IEC prior to being implemented. 
If the change implies a modification of treatment or subject evaluation tests, a new version of the informed 
consent form must be prepared and submitted for approval to Health Authorities and the IEC. 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, the Health Authorities, and the IEC.  
For IND studies: The amendment must be approved by the Sponsor and the IRB prior to implementation. 
If the change implies a modification of treatment or subject evaluation tests, a new version of the informed 
consent form 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.  


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12.9. Investigational Medicinal Product Drug Accountability 
The Investigator must maintain accurate records of the IMP(s) received from the Sponsor. These records 
will include receipt 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 authorisation 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. 
12.10. 
Study Monitoring 
At agreed upon 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 subject. The eCRFs must be completed by the Investigator on a 
regular basis (within 3 working days after each subject visit) 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.. 
12.11. 
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 subject 
records supporting the eCRFs, and other study-related documents. 
12.12. 
Regulatory Agency Inspections  
The Investigator may undergo a Regulatory Agency/IEC/IRB 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 subject records 
supporting the eCRFs and other study-related documents. If given advance notice of this inspection, the 
Investigator must contact the Sponsor immediately. 
12.13. 
Disclosure of Results and Publication Policy 
Results of this Phase II study will not be publicly disseminated or published until the study data are mature 
for the final analysis of the primary study endpoint (as defined by the protocol). The publications must be 
conform to the CONSORT guidelines.49 
However, for the purpose of submission of abstracts to congresses, a draft version of the analysis report 
may be generated if the Sponsor's Statistician determines prior to abstract submission that the 
inconsistencies remaining in the database will not affect the conclusions of the study, and that the database 
can be cleaned and locked in sufficient time to enable the preparation of the final statistical report by the 
time of presentation. In this case, the abstract should clearly stipulate that the results are not definitive.  


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The publication of the results of ancillary studies (e.g., translational research) is authorized at any time 
provided they do not mention the primary and secondary study endpoints. 
All publications reporting results of this Phase II study must be reviewed and approved by the Sponsor's 
Statistician and Medical Monitor in charge of the study. All publications reporting results of this study must 
be reviewed and approved by the first author and the Study's Steering Committee. The first author is 
responsible for ensuring that all co-authors have seen and approved the final version of the publication prior 
to submission. A written agreement with the intent to submit a publication must be reached between the 
Sponsor, the first author and the Steering Committee. 
In accordance with the International Committee of Medical Journal Editors,50 each author of the publication 
should have participated sufficiently in the work to take public responsibility for the content. All other 
contributors (clinicians, pathologists, …) who do not meet sufficient criteria for authorship will be 
acknowledged in the publication. 
For the primary publication, the first author will be the Steering Committee member who will be the primary 
responsible for generating the first manuscript draft, followed by the other Steering Committee members. 
In principle, the last author will be a Steering Committee Chairman (if different from the first author). The 
Investigators who enrolled evaluable subjects in the trial will be included as co-authors up to the total 
number of co-authors allowed by the journal, according to their contribution to subject enrollment. 
Coordinators of integrated translational research components of the study or pathologists responsible for 
the central pathology review that is part of the study also qualify as co-authors. Two Sponsor representatives 
will be co-authors. These two co-authors are usually the Statistician and the Medical Monitor who were in 
charge of and contributed to the study. 
All Investigators who enrolled evaluable subjects into the study (i.e., clinicians) or contributed scientifically 
to the study (i.e., pathologists, collaborators from the same institutions, ...) will be acknowledged in the 
publication. The acknowledgement list should include the name of all participating institutions and the 
name of the clinicians and other scientists involved with the study at that institution. Whenever a study 
participant has moved from one institution to another in the course of the study, that participant is listed 
with the institution to which s/he was affiliated at the time of starting his/her participation to the study, with 
the mention “(now at new affiliation)”  
Sponsor staff that made a substantial scientific contribution to the study but are not co-authors should be 
mentioned in the acknowledgement section (i.e., data managers, clinical scientists, clinical trial managers).  
The person who took the lead in conducting an ancillary study is the first author of the relevant publication. 
The Sponsor representatives who contributed to the analysis and publication, if any, will also be co-authors. 
The list of co-authors must be approved by the Study's Steering Committee and Sponsor. 
12.14. 
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 IEC/IRB if required. 
12.15. 
Premature Study Discontinuation 
The trial may be prematurely terminated by the Sponsor, the Investigator or the IEC/IRB at any time. If the 
study is prematurely terminated, the Investigator must promptly inform the study subjects 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, s/he should promptly inform the Sponsor and the IEC/IRB and 
provide a detailed written explanation of the termination. If the Sponsor terminates the trial, the Investigator 
should promptly inform the IEC/IRB and provide a detailed written explanation of the termination. If the 


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IEC/IRB 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. 
REFERENCES 
1. Eswarakumar, V.P., Lax, I., and Schlessinger, J., Cellular signaling by fibroblast growth factor 
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2. Wang, Y. and Becker, D., Antisense targeting of basic fibroblast growth factor and fibroblast 
growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and 
tumor growth. Nat Med, 1997. 3(8): p. 887-93. 
3. Singh, D., et al., Transforming fusions of FGFR and TACC genes in human glioblastoma. 
Science, 2012. 337(6099): p. 1231-5. 
4. Williams, S.V., Hurst, C.D., and Knowles, M.A., Oncogenic FGFR3 gene fusions in bladder 
cancer. Hum Mol Genet, 2013. 22(4): p. 795-803. 
5. Nakanishi, Y., et al., Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase 
FGFR3-BAIAP2L1. Mol Cancer Ther, 2015. 14(3): p. 704-12. 
6. Seo, J.S., et al., The transcriptional landscape and mutational profile of lung adenocarcinoma. 
Genome Res, 2012. 22(11): p. 2109-19. 
7. Arai, Y., et al., Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique 
molecular subtype of cholangiocarcinoma. Hepatology, 2014. 59(4): p. 1427-34. 
8. Wu, Y.M., et al., Identification of targetable FGFR gene fusions in diverse cancers. Cancer 
Discov, 2013. 3(6): p. 636-47. 
9. Parker, B.C., et al., Emergence of FGFR family gene fusions as therapeutic targets in a wide 
spectrum of solid tumours. J Pathol, 2014. 232(1): p. 4-15. 
10. Ang, C., Role of the fibroblast growth factor receptor axis in cholangiocarcinoma. J 
Gastroenterol Hepatol, 2015. 30(7): p. 1116-22. 
11. Borad, M.J., et al., Integrated genomic characterization reveals novel, therapeutically relevant 
drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. 
PLoS Genet, 2014. 10(2): p. e1004135. 
12. Zehir, A., et al., Mutational landscape of metastatic cancer revealed from prospective clinical 
sequencing of 10,000 patients. Nat Med, 2017. 23(6): p. 703-713. 
13. Babina, I.S. and Turner, N.C., Advances and challenges in targeting FGFR signalling in 
cancer. Nat Rev Cancer, 2017. 17(5): p. 318-332. 
14. Helsten, T., et al., The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-
Generation Sequencing. Clin Cancer Res, 2016. 22(1): p. 259-67. 
15. Stransky, N., et al., The landscape of kinase fusions in cancer. Nat Commun, 2014. 5: p. 4846. 
16. Xiang, L., et al., Comprehensive analysis of targetable oncogenic mutations in chinese cervical 
cancers. Oncotarget, 2015. 6(7): p. 4968-75. 
17. Graham, R.P., et al., Fibroblast growth factor receptor 2 translocations in intrahepatic 
cholangiocarcinoma. Human pathology, 2014. 45(8): p. 1630-1638. 
18. Nakamura, H., et al., Genomic spectra of biliary tract cancer. Nat Genet, 2015. 47(9): p. 1003-
10. 
19. Gallo, L.H., et al., Functions of Fibroblast Growth Factor Receptors in cancer defined by novel 
translocations and mutations. Cytokine Growth Factor Rev, 2015. 26(4): p. 425-49. 
20. Yaeger, R., et al., Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct 
From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory 
Bowel Disease. Gastroenterology, 2016. 151(2): p. 278-287 e6. 
21. Kim, S.Y., et al., Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer 
through an emergence of novel FGFR2-ACSL5 fusion. Oncotarget, 2017. 8(9): p. 15014. 
22. Bao, Z.S., et al., RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion 
transcript in secondary glioblastomas. Genome Res, 2014. 24(11): p. 1765-73. 
23. Costa, R., et al., FGFR3-TACC3 fusion in solid tumors: mini review. Oncotarget, 2016. 7(34): 
p. 55924-55938. 


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Lausanne, Switzerland  
 
24. Di Stefano, A.L., et al., Detection, Characterization, and Inhibition of FGFR-TACC Fusions 
in IDH Wild-type Glioma. Clin Cancer Res, 2015. 21(14): p. 3307-17. 
25. Parker, B.C., et al., The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation 
in glioblastoma. J Clin Invest, 2013. 123(2): p. 855-65. 
26. Yoshihara, K., et al., The landscape and therapeutic relevance of cancer-associated transcript 
fusions. Oncogene, 2015. 34(37): p. 4845-54. 
27. Capelletti, M., et al., Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung 
adenocarcinoma. Clin Cancer Res, 2014. 20(24): p. 6551-8. 
28. Theelen, W.S., et al., FGFR1, 2 and 3 protein overexpression and molecular aberrations of 
FGFR3 in early stage non-small cell lung cancer. J Pathol Clin Res, 2016. 2(4): p. 223-
233. 
29. Wang, R., et al., FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-
small cell lung cancer. Clin Cancer Res, 2014. 20(15): p. 4107-14. 
30. The Cancer Genome Atlas Research Network, Comprehensive molecular characterization of 
urothelial bladder carcinoma. Nature, 2014. 507(7492): p. 315-22. 
31. Majewski, I.J., et al., Identification of recurrent FGFR3 fusion genes in lung cancer through 
kinome-centred RNA sequencing. J Pathol, 2013. 230(3): p. 270-6. 
32. Zheng, S., et al., SOX2 expression is associated with FGFR fusion genes and predicts favorable 
outcome in lung squamous cell carcinomas. Onco Targets Ther, 2015. 8: p. 3009-16. 
33. Lee, J.C., et al., Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in 
phosphaturic mesenchymal tumour. J Pathol, 2015. 235(4): p. 539-45. 
34. Kurobe, M., et al., Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-
TACC3 Fusion Genes in FFPE Samples. PLoS One, 2016. 11(12): p. e0165109. 
35. Necchi, A., et al., Comparison of Fibroblast Growth-factor Receptor Gene Alterations at the 
DNA versus Messenger RNA Level in Advanced Urothelial Cancer: Insights for Clinical 
Research. Eur Urol Focus, 2017. 
36. Ross, J.S., et al., Comprehensive genomic profiling of 295 cases of clinically advanced 
urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant 
genomic alterations. Cancer, 2016. 122(5): p. 702-11. 
37. Nakanishi, Y., et al., The fibroblast growth factor receptor genetic status as a potential 
predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. 
Mol Cancer Ther, 2014. 13(11): p. 2547-58. 
38. Vaslin, A., et al., Characterization of two novel oncogenic FGFR2 fusions sensitive to the 
FGFR-selective inhibitor Debio 1347 in cholangiocarcinoma, in AACR Annual Meeting 
2015. 2015: Philadelphia, USA  
39. Voss, M.H., et al., Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase 
I dose-escalation study in patients with FGFR genomically activated advanced solid 
tumors. J Clin Oncol, 2017  35 (15 suppl): p. 2500. 
40. Turner, N. and Grose, R., Fibroblast growth factor signalling: from development to cancer. 
Nat Rev Cancer, 2010. 10(2): p. 116-29. 
41. Brooks, A.N., Kilgour, E., and Smith, P.D., Molecular pathways: fibroblast growth factor 
signaling: a new therapeutic opportunity in cancer. Clin Cancer Res, 2012. 18(7): p. 1855-
62. 
42. Cunanan, K.M., et al., An efficient basket trial design. Stat Med, 2017. 36(10): p. 1568-1579. 
43. Mermel, L.A., et al., Clinical practice guidelines for the diagnosis and management of 
intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society 
of America. Clin Infect Dis, 2009. 49(1): p. 1-45. 
44. de Naurois, J., et al., Management of febrile neutropenia: ESMO Clinical Practice Guidelines. 
Ann Oncol, 2010. 21 Suppl 5: p. v252-6. 


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Lausanne, Switzerland  
 
45. Flowers, C.R., et al., Antimicrobial prophylaxis and outpatient management of fever and 
neutropenia in adults treated for malignancy: American Society of Clinical Oncology 
clinical practice guideline. J Clin Oncol, 2013. 31(6): p. 794-810. 
46. Liu, C., et al., Clinical practice guidelines by the Infectious Diseases Society of America for 
the treatment of methicillin-resistant Staphylococcus aureus infections in adults and 
children: Executive summary. Clin Infect Dis, 2011. 52(3): p. 285-92. 
47. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
48. Ramanathan, R.K., et al., Phase I and pharmacokinetic study of imatinib mesylate in patients 
with advanced malignancies and varying degrees of liver dysfunction: a study by the 
National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol, 2008. 26(4): 
p. 563-9. 
49. Schulz, K.F., et al., CONSORT 2010 statement: updated guidelines for reporting parallel 
group randomised trials. BMJ, 2010. 340: p. c332. 
50. Uniform requirements for manuscripts submitted to biomedical journals: Writing and editing 
for biomedical publication. J Pharmacol Pharmacother, 2010. 1(1): p. 42-58. 
 


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Lausanne, Switzerland  
14. 
APPENDICES 
Appendix A 
ECOG Performance Status 
Appendix B 
RECIST criteria 
Appendix C 
NCI-CTCAE v5.0 criteria 
Appendix D 
World Medical Association Declaration of Helsinki 
Appendix E 
Hyperphosphatemia management guidelines 
Appendix F 
Dermatological toxicity prophylaxis and management guidelines  
Appendix G 
Hypercalcemia treatment guidelines 
 
 
 


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Lausanne, Switzerland  
Appendix A: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 
 
 


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Lausanne, Switzerland  
Appendix B: RECIST Criteria 
Please refer to RECIST guidelines version 1.1 (Eur J cancer. 2009; 45(2):228-247) by using the link below: 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf 
 


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Appendix C: NCI-CTCAE v5.0 criteria 
The NCI-CTCAE v5.0 criteria can be consulted at:  
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTCAE v5 Quick Reference
8.5x11.pdf  
 
 
 


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Lausanne, Switzerland  
Appendix D: World Medical Association Declaration of Helsinki  
The declaration of Helsinki can be consulted at:  
https://www.wma.net/wp-content/uploads/2016/11/DoH-Oct2013-JAMA.pdf  
 
 


















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hypercalcemia (such as thiazide diuretics, volume depletion, prolonged bed rest or inactivity, and a high 
calcium diet [> 1000 mg/day]).  
Adequate hydration (at least 6 glasses of water per day) is recommended to minimise the risk of 
nephrolithiasis.  
• 
Moderate asymptomatic hypercalcemia (calcium between 12 and 14 mg/dL [3 to 3.5 mmol/L]): 
The decision to treat with saline hydration and bisphosphonates is at the Investigator's discretion. 
• 
Higher concentrations of calcium > 14 mg/dL (3.5 mmol/L) or the presence of symptoms requiring 
more aggressive therapy. In this case, it is suggested to treat with a three-pronged approach of 
isotonic saline (at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine 
output at 100 to 150 mL/hour), salmon calcitonin (4 IU units/kg) and concurrent administration of 
zoledronic acid (4 mg IV over 15 minutes) or pamidronate (60 to 90 mg over two hours). 
 
 
  

SAP_001.pdf: 
 
Official Title: A Phase II Basket Study of the Oral Selective Pan-FGFR Inhibitor 
Debio 1347 in Subjects With Solid Tumors Harboring a Fusion of 
FGFR1, FGFR2 or FGFR3 
NCT Number: NCT03834220 
Document Date: SAP Version 2.0: 09 April 2021 
 
 


 
 
 
Clinical study Debio 1347-201 
 
Page 1 of 66 
Statistical Analysis Plan 
Version Final 2.0 09Apr2021, Debiopharm International S.A. 
 
 
 
 
Statistical Analysis Plan 
 
A Phase II basket study of the oral selective pan-FGFR inhibitor Debio 1347 in subjects with 
solid tumors harboring a fusion of FGFR1, FGFR2 or FGFR3 
Investigational Medicinal Product: Debio 1347 
 
 
Debiopharm Study Number: Debio 1347-201 
 
 
 
SPONSOR: 
Debiopharm International SA 
5-7 chemin Messidor, P.O. Box 5911 
CH-1002 Lausanne, Switzerland 
 
Version Final 2.0 dated on 09 April 2021  
The information in this statistical analysis plan is confidential. It is provided to personnel directly involved in 
the trial. No information can be provided to a third party without written authorization from Debiopharm 
International S.A. Further reproduction of this document, in whole or in part, is not permitted. 
 
 


 
 
 
Clinical study Debio 1347-201 
 
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Statistical Analysis Plan 
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Relevant Study Information 
 
Study number: 
Debio 1347-201 
Study title: 
A Phase II basket study of the oral selective pan-FGFR inhibitor 
Debio 1347 in subjects with solid tumors harboring a fusion of 
FGFR1, FGFR2 or FGFR3. 
Study phase: 
II 
Protocol version and date: 
Version 3 dated 2020-07-16 
Sponsor 
Debiopharm International S.A., Ch. Messidor 5-7, P.O. Box 5911, 
CH-1002 Lausanne, Switzerland 
 
 MD,
 
Study biostatistician: 
 
 
 


 
 
 
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TABLE OF CONTENTS 
RELEVANT STUDY INFORMATION ............................................................................................................. 2 
TABLE OF CONTENTS ..................................................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITIONS ......................................................................................... 6 
1 
INTRODUCTION ....................................................................................................................................... 8 
2 
STUDY OBJECTIVES ................................................................................................................................ 8 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................. 8 
2.2 
SECONDARY OBJECTIVES ....................................................................................................................... 8 
 
 8 
3 
STUDY ENDPOINTS .................................................................................................................................. 9 
3.1 
PRIMARY ENDPOINT .............................................................................................................................. 9 
3.2 
SECONDARY ENDPOINTS ........................................................................................................................ 9 
 
 9 
4 
STUDY DESIGN AND TREATMENT ................................................................................................... 10 
4.1 
STUDY DESIGN .................................................................................................................................... 10 
4.2 
STUDY TREATMENTS ........................................................................................................................... 12 
5 
RANDOMISATION AND BLINDING.................................................................................................... 12 
6 
SAMPLE SIZE ........................................................................................................................................... 12 
7 
ANALYSIS POPULATIONS.................................................................................................................... 13 
7.1 
SCREENED POPULATION ...................................................................................................................... 13 
7.2 
INTENT-TO-TREAT POPULATION .......................................................................................................... 13 
7.3 
MODIFIED INTENT-TO-TREAT POPULATION ......................................................................................... 13 
7.4 
PER PROTOCOL POPULATION ............................................................................................................... 13 
7.5 
SAFETY POPULATION ........................................................................................................................... 13 
7.6 
PK POPULATION .................................................................................................................................. 14 
7.7 
C-QT POPULATION .............................................................................................................................. 14 
8 
DATA HANDLING ................................................................................................................................... 14 
8.1 
MISSING DATA..................................................................................................................................... 14 
8.1.1 
Adverse Event ................................................................................................................................. 14 
8.1.2 
Concomitant Medications ............................................................................................................... 15 
8.2 
CODING ................................................................................................................................................ 15 
8.3 
HANDLING OF VALUES BELOW (OR ABOVE) A THRESHOLD ................................................................ 15 
8.4 
HANDLING OF UNSCHEDULED ASSESSMENTS OR RETESTS .................................................................. 16 
9 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................. 16 
9.1 
GENERAL CONVENTIONS ..................................................................................................................... 16 
9.2 
DATES, TIMES AND DAYS .................................................................................................................... 16 
9.3 
TIMING OF ANALYSES .......................................................................................................................... 17 
10 
STATISTICAL ANALYSIS METHODS ................................................................................................ 17 


 
 
 
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10.1 
DISPOSITION OF SUBJECTS, DEMOGRAPHIC AND BASELINE DATA ....................................................... 17 
10.1.1 
Subject Disposition ..................................................................................................................... 17 
10.1.2 
Protocol Deviations .................................................................................................................... 18 
10.1.3 
Demographic and Baseline Characteristics ................................................................................ 18 
10.1.4 
Medical History .......................................................................................................................... 18 
10.1.5 
Disease Characteristics ............................................................................................................... 19 
10.1.6 
Prior anti-cancer treatments ........................................................................................................ 19 
10.2 
EFFICACY ANALYSES ........................................................................................................................... 19 
10.2.1 
Objective Response Rate ............................................................................................................ 20 
10.2.1.1 
Primary Analysis .................................................................................................................................... 21 
10.2.1.2 
Supportive Analysis ............................................................................................................................... 22 
10.2.2 
Duration of Response ................................................................................................................. 22 
10.2.3 
Disease Control Rate .................................................................................................................. 23 
10.2.4 
Tumor Size ................................................................................................................................. 23 
10.2.5 
Progression-Free Survival .......................................................................................................... 23 
10.2.6 
Overall Survival ......................................................................................................................... 24 
10.2.7 
Subgroup Analysis ..................................................................................................................... 24 
10.3 
SAFETY ANALYSES .............................................................................................................................. 24 
10.3.1 
Extent of Exposure ..................................................................................................................... 24 
10.3.2 
Adverse Events ........................................................................................................................... 25 
10.3.3 
Clinical Laboratory Evaluations ................................................................................................. 27 
10.3.4 
Vital Signs .................................................................................................................................. 37 
10.3.5 
12-lead ECG ............................................................................................................................... 37 
10.3.5.1 
Central Tendency Analysis .................................................................................................................... 37 
10.3.5.2 
Categorical Analysis .............................................................................................................................. 37 
10.3.5.3 
Morphological Analysis ......................................................................................................................... 38 
10.3.6 
Other Safety Analysis ................................................................................................................. 38 
10.3.7 
Medications and procedures ....................................................................................................... 39 
 
 
 
39 
10.5 
PHARMACOKINETICS ............................................................................................................................ 40 
10.5.1 
Debio 1347 Plasma concentration .............................................................................................. 40 
10.5.2 
Debio 1347 Pharmacokinetics parameters .................................................................................. 40 
 
 41 
10.6 
C-QTCF ANALYSIS .............................................................................................................................. 41 
10.6.1 
Graphical Exploration: ............................................................................................................... 41 
10.6.2 
Model Development ................................................................................................................... 41 
10.6.3 
Model Evaluation ....................................................................................................................... 42 
10.6.4 
Display of Results and Decision Rules ....................................................................................... 42 


 
 
 
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42 
10.8 
INTERIM ANALYSES ............................................................................................................................. 42 
11 
MODIFICATION HISTORY ................................................................................................................... 44 
12 
REFERENCES ........................................................................................................................................... 46 
13 
APPENDICES ............................................................................................................................................ 47 
13.1 
REPORTING CONVENTIONS .................................................................................................................. 47 
13.2 
LISTING OF TABLES, FIGURES AND LISTINGS ....................................................................................... 47 
 
48 
13.4 
OPERATION CHARACTERISTICS OF ADDITIONAL DECISION CRITERIA .................................................... 50 
13.4.1 
Study design ............................................................................................................................... 50 
13.4.1.1 
Study design overview ........................................................................................................................... 50 
13.4.1.2 
Interim Decision criteria ........................................................................................................................ 50 
13.4.1.3 
Operation characteristics ........................................................................................................................ 51 
13.4.2 
Simulation study ......................................................................................................................... 52 
13.4.2.1 
Simulate a study ..................................................................................................................................... 52 
13.4.3 
Estimation of FWER and Marginal Power ................................................................................. 52 
13.5 
OPERATION CHARACTERISTICS ............................................................................................................ 52 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation 
Definition 
AE
Adverse event
AESI
Adverse event of special interest
ATC
Anatomical therapeutic chemical
AUC
Area under the concentration versus time curve
BLOQ
Below limit of quantification
BOR
Best overall response
 
 
CI
Confidence interval
Cmax
Maximum serum concentration
CR
Complete response
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of variation
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern cooperative oncology group
eCRF
Electronic case report form
FGFR
Fibroblast growth factor receptor
FWER
Family-Wise error rate
H0
Null hypothesis
H1
Alternative hypothesis
HR
Heart rate
IMP
Investigational medicinal product
IRC
Independent review committee
ITT
Intent-to-treat
K-M
Kaplan-Meier
LOQ
Limit of quantification
MedDRA
Medical dictionary for regulatory activities
mITT
Modified ITT
NCI
National cancer institute
NE
Not evaluable
ORR
Objective response rate


 
 
 
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Abbreviation 
Definition 
OS
Overall survival
PA2
Protocol amendment 2
PD
Progressive disease
PFS
Progression-free survival
 
 
PK
Pharmacokinetics
PP
Per protocol
PR
Partial response
P-R
Interval between the P and R waves
PS
Performance status
PT
Preferred term
Q1
25th percentile
Q3
75th percentile
QD
Once daily
 
QRS
Distance between the Q and S waves
QT
Interval between the Q and T waves
QTcF
QT interval corrected for heart rate using Fridericia 's formula
QTcSS
Study specific QT correction
RECIST
Response evaluation criteria in solid tumors
RR
Interval between 2 consecutive Rwaves
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SDlog
Standard deviation of the log-transformed values
SE
Standard error
SOC
System organ class
TEAE
Treatment-emergent adverse event
TNM
Tumor-Node-Metastasis
 
 
WHO-DD
World health organization drug dictionary
 
 
 


 
 
 
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1 INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analyses planned to be performed for the 
study Debio 1347-201 entitled “A Phase II basket study of the oral selective pan-FGFR inhibitor 
Debio 1347 in subjects with solid tumors harboring a fusion of FGFR1, FGFR2 or FGFR3”. The SAP 
is compliant with the study protocol version 3, dated of July 16th 2020.The SAP will be finalized prior 
to the database lock for the main analysis. 
The rationale for Protocol Amendment 2 (PA2) was  
 
The results of data monitoring reviews of pooled data (Section Error! Reference source not 
found.) showed that the antitumor activity of Debio 1347 was lower than initially assumed at 
the time the protocol was developed. Considering that further enrolment is unlikely to 
substantially change the magnitude of the efficacy observed up to now, Debiopharm decided 
to permanently halt the enrolment in the study after consultation with the IDMC on June 10th, 
2020.   
After implementation of PA2: 
 
After consenting to PA2, on-treatment subjects will no longer be assessed for efficacy in the 
study, but only for safety. 
 
Off-treatment subjects will not be followed for disease status or survival in the study, but only 
for safety up to 30 days post last dose of Debio 1347.  
 
Subjects will complete study participation at 30 days after the last dose of Debio 1347. In the 
case of off-treatment subjects with >30 days and <2 years follow-up at the time of PA2 
implementation, then these subjects can complete study participation immediately. 
The SAP will pre-specify the statistical consideration for the analysis of study data to ensure validity 
of study findings and conclusions regarding study objectives. 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to assess the efficacy of Debio 1347 in terms of objective response rate 
(ORR) in subjects with solid tumors harboring fibroblast growth factor receptor (FGFR) 1-3 gene 
fusion/rearrangement. 
2.2 
Secondary Objectives 
The secondary objectives are: 
1. To evaluate the efficacy of Debio 1347 in terms of duration of response (DOR), disease 
control rate (DCR), progression free survival (PFS) and overall survival (OS). 
2. To assess the safety of Debio 1347. 
3. To assess exposure-response relationships versus efficacy and safety (notably QTcF). 
 
 
 
   
 
 
 


 
 
 
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3 STUDY ENDPOINTS 
In subjects enrolled late in the study, PA2 shortens the data collection period for efficacy data. After 
PA2 is in force, efficacy assessments and central radiological review will no longer be performed in 
on-treatment subjects, and off-treatment followed up for disease status and survival will no longer be 
performed in off-treatment subjects.  
After PA2 is in force, onl for on-treatment and off-treatment subjects will be collected using standard 
institutional practice and local laboratory testing in accordance with the protocol study plan to support 
the ongoing safety assessments.  
3.1 
Primary Endpoint 
The primary endpoint is ORR, defined as the proportion of subjects with a best overall response 
(BOR) of partial or complete response as centrally measured by RECIST 1.1 criteria.) 
3.2 
Secondary Endpoints 
The secondary endpoints are: 
1. DOR, defined as the time from the date of the initial partial response (PR) or complete 
response (CR) to date of the first documented progressive disease (PD) or death due to any 
cause. 
2. DCR, defined as the proportion of subjects with a BOR of CR, PR or SD . 
3. PFS, defined as the time from the start date of treatment to date of the first documented PD or 
death due to any cause. 
4. OS, defined as the time from the start date of treatment to date of death due to any cause. 
5. Proportion of subjects with treatment-emergent adverse events (TEAEs) assessed by the 
National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v5.0 and proportion of subjects with serious adverse events (SAEs). 
6. Debio 1347 plasma exposure (Ctrough, area under the curve [AUC] and any other PK 
parameters as deemed appropriate) and relationships with efficacy and safety endpoints; 
Debio 1347 plasma concentration (C)-QTcF relationship based on electrocardiogram (ECG) 
and PK matching time-points. These relationships will be derived only if deemed appropriate, 
depending on the safety and efficacy outcomes and data availability. 
 
 
 
 
 
 
 


 
 
 
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4 STUDY DESIGN AND TREATMENT 
4.1 
Study Design  
4.1.1 
Study design before protocol amendment 2 
This is a multicenter, basket, two stage, adaptive single arm Phase II study to examine the efficacy of 
Debio 1347 administered at the recommended Phase II daily dose of 80 mg in subjects with solid 
tumors harboring FGFR1-3 gene fusion/rearrangement. The study will include 3 cohorts of subjects 
comprising biliary tract cancer (Cohort 1), urothelial cancer (Cohort 2) and, in Cohort 3, all other 
solid tumor histologies not included in cohort 1 or cohort 2, such as non-small cell lung cancer 
(NSCLC), head and neck cancer, thyroid cancer, oral cancer, breast cancer, prostate cancer and others 
but excluding primary brain tumors. 
Stage 1 will require 27 evaluable subjects across the three cohorts assuming an equal accrual rate per 
cohort. Stage 2 will require 86 evaluable subjects across all cohorts or per individual cohort 
depending on results of assessments scheduled at the end of Stage 1 (see Figure 1).  


 
 
 
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Figure 1 - Graphical algorithm representing study design (extracted from Cunanan et al. (2017)) 
 
Subjects will be treated with Debio 1347 once daily (QD) in 28-day cycles until the occurrence of 
disease progression (clinical or radiologic) or unacceptable toxicity. Subject safety (AEs) and survival 
will be followed-up respectively for 30 days after the last Debio 1347 dose and every 12 weeks from 
treatment end until death or loss to follow-up but no longer than for a total of 2 years after the last 
subject has discontinued treatment. Disease status will be followed-up every 12 weeks only in 
subjects without PD from treatment end until PD, death or loss to follow-up but no longer than for a 
total of 2 years after the last subject has discontinued treatment. 
An Independent Data Monitoring Committee (IDMC) will be established to review safety, tolerability 
and efficacy data, as well as to monitor the overall conduct of the study at regular intervals. Interim 
analysis will also be discussed by IDMC. 
The IDMC meeting schedule, purpose, roles and responsibilities will be outlined in a separate 
document, the IDMC Charter. 
4.1.2 
Study design after protocol amendment 2 
The interim analysis was not conducted as planned (as detailed in section 10.8.2). Based on an initial 
statistical review of pooled data, the antitumor activity for Debio 1347 is lower than initially assumed 
at the time the protocol was developed. Debiopharm decided to permanently halt the enrollment in 
stage 1 of the study after consultation with the IDMC on June 10th, 2020. 
The subsequent protocol amendment 2 (PA2) was implemented to modify the study design in the 
following ways:  
 
All ongoing patients (on-treatment subjects and off-treatment subjects still under follow-up) 
will be re-consented to PA2.  
 
Subjects showing clinical benefit may remain on-treatment with Debio 1347 until a condition 
to stop treatment is met.  


 
 
 
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 
After consenting to PA2, on-treatment subjects will no longer be assessed for efficacy in the 
study, but only for AE, SAE and AESI as described in the pared down study plan of PA2 
(Error! Reference source not found.).  
 
Off-treatment subjects will not be followed for disease status or survival in the study, but only 
for AE, SAE and AESI up to 30 days after the last dose of Debio 1347.  
 
Subjects will complete study participation at 30 days after the last dose of Debio 1347. In the 
case of off-treatment subjects with >30 days and <2 years follow-up at the time of PA2 
implementation, then these subjects can end (i.e. complete) study participation immediately.   
 
Subsequent efficacy data collected through standard institutional care practice in on-treatment 
and off-treatment subjects will not be collected in the eCRF. 
 
No further IDMC meetings will be required. 
4.2 
Study Treatments 
Subjects will receive Debio 1347 tablets at the dose of 80 mg QD from Day 1 to Day 28 in 28-day 
cycles until occurrence of any of the criteria described in the protocol requiring treatment 
discontinuation. 
5 RANDOMISATION AND BLINDING 
Not applicable. 
6 SAMPLE SIZE  
A basket two stage adaptive design will be used to assess the efficacy of Debio 1347 in terms of ORR, 
(Cunanan et al. 2017). 
With 27 evaluable subjects in Stage 1 and 86 evaluable subjects in Stage 2, the study will have 
approximately 90% power to reject the null hypothesis that ORR ≤ 15% when the true ORR is 30% in 
at least one of the baskets, using a one-sided exact binomial test at an overall significance level of 5%. 
The sample size for Stage 2 is for a pooled sample across baskets in case homogeneity is shown at end 
of Stage 1, or for one active basket taken into Stage 2 in case of heterogeneity. Sample size and design 
operating characteristics were determined using simulations, see Table 1. 
Assuming homogeneity across baskets and a 10% drop out, the study would enroll approximately 125 
subjects.  
If homogeneity is declared at the interim analysis, 86 participants across three cohorts will be enrolled 
in stage 2. Otherwise, 86 participants will be enrolled in stage 2 in each of the cohorts continuing into 
stage 2. 
Table 1 - Power and expected sample size based on 1000 simulations using Cunanan et al. (2017) 
algorithm 
Assumed ORR of 15% for inactive 
cohorts and 30% for active cohorts 
Number of truly active cohorts 
0 Active 
1 Active 
2 Active 
3 Active 
Marginal Power
     FWER
5%
16%
39%
NA
     Power 1 active cohort
3%
64%
88%
92%
     Power 2 active cohorts
3%
15%
87%
93%


 
 
 
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Nt period      Power 3 active cohorts
4%
15%
39%
93%
Expected sample size
111
148
165
161
% Homogeneity rejected at end of stage 1
38%
54%
57%
46%
     Cohort 1 continuing to stage 2
25%
52%
54%
42%
     Cohort 2 continuing to stage 2
26%
36%
53%
42%
     Cohort 3 continuing to stage 2
24%
35%
35%
42%
Homogeneity accepted at end of stage 1
62%
46%
43%
54%
     Continuing to stage 2 
47%
41%
42%
54%
7 ANALYSIS POPULATIONS 
7.1 
Screened Population 
The Screened population consists of all subjects who have signed the informed consent. 
7.2 
Intent-to-Treat Population (ITT) 
The intent-to-treat (ITT) population consists of all subjects who received study drug.  
Receiving study drug is considered to have taken at least 1 full dose (80 mg Debio 1347) of study 
drug. Subjects will be analyzed according to their assigned cohort. 
7.3 
Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat (mITT) population consists of all subjects in the ITT population whose 
gene fusion/rearrangement has been confirmed by central testing.  
A patient has gene fusion/rearrangement confirmed by central testing if the patient appears in the 
Caris central lab external dataset and has a result of gene fusion/rearrangement being present. Subjects 
will be analyzed according to their assigned cohort. 
7.4 
Per Protocol Population (PP) 
The per protocol (PP) population consists of all subjects in the ITT population who have undergone 
radiographic assessment at baseline (i.e., tumor assessment screening visit), received at least one dose 
of study drug, had both baseline and post-baseline disease and had no critical protocol deviation that 
may have an impact on efficacy endpoints. 
Having radiographic assessment at baseline and baseline disease is considered met if inclusion 
criterion 7 (having measurable disease according to RECIST 1.1 at baseline) is Yes.  
Having post-baseline disease is clarified as requiring at least 1 post-baseline disease assessment.  
Critical protocol deviations that may have an impact on efficacy endpoints are defined as (also see 
Section 13.6): 
 
Violation of any inclusion/exclusion criteria at entry. 
 
Actual cumulative dose below 75% of planned cumulative dose from date of first dose to date 
of end of cycle 4 or date of treatment discontinuation, whichever occurs first. 
 
Subject data indicate a major protocol deviation other than the criteria defined above, that 
potentially affects efficacy assessment and is identified prior to database lock.   
7.5 
Safety Population (SAF) 


 
 
 
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The Safety population consists of all subjects who received study drug. 
Receiving study drug is considered to have taken at least 1 full dose or partial dose of study drug. 
7.6 
PK Population (PKP) 
The PK population (PKP) will include subjects who received one or more doses of Debio 1347 and 
have at least one PK concentration result available.   
Receiving one or more doses of Debio 1347 is considered to have taken at least 1 full dose of study 
drug. 
7.7 
C-QT Population (CQP) 
The C-QT population (CQP) will include subjects in PK population who has at least one matching 
ECG evaluation and PK sampling. 
The C-QT population will be used for exposure-response (C-QTcF) analysis. However, whether the 
exposure-response analysis is performed will depend on the outcome of safety and efficacy analyses 
and data availability.  
A matching ECG evaluation and PK sampling pair is defined as follows: measurements for which the 
elapsed time between the two is within a time window of +/- 30 minutes (for pre-dose and 7h post-
dosing time points) and +/- 20 minutes (for 1h and 3h post-dosing time points). Pairs for which the 
elapsed time between the two assessments is outside these windows will be excluded from the 
analysis. If more than 30% of pairs are excluded at 1h and 3h time points because of deviations from 
the protocol-defined window for ECG measurement (within 20 min of PK samplings), the analysis 
will be repeated using a time window of +/-30 min for 1h and 3h post-dose time points. 
8 DATA HANDLING 
8.1 
Missing Data 
In subject listings, incomplete dates will be presented as collected in the electronic case report form 
(eCRF). In order to identify whether an AE is treatment-emergent or whether a medication is prior or 
concomitant, partial dates missing the day, or both the day and month of the year will be considered 
as outlined below. 
8.1.1 
Adverse Event 
When the day of onset of an AE is missing: 
 
If month and year of onset of an AE is the same as the month and year of date of first 
administration of the study drug: 
o If AE end date contains a full date and end date is earlier than study treatment start 
date, then the missing onset day is entered as the 1st of the month. 
o Otherwise, the missing onset day is entered as the day of date of first administration 
of the study drug. 
 
If month and year of onset of an AE is not the same as the month and year of date of first 
administration of the study drug, the missing onset day is entered as 1st of the month. 
When the day and month of onset of an AE are missing: 
 
If year of onset of an AE is the same as the year of date of first administration of the study 
drug:  


 
 
 
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o If AE end date contains a full date and end date is earlier than study treatment start 
date, then the missing onset day and month are imputed as January 1st. 
o Otherwise, the missing onset day and month are imputed as the day and month of 
date of first administration of the study drug 
 
If year of onset of an AE is not the same as the year of date of first administration of the study 
drug, the missing onset day and month are imputed as January 1st. 
If AE onset date is completely missing: 
 
If AE end date is on or after the date of first administration of the study drug, then onset date 
is set to date of first administration of the study drug. 
 
If AE end date is prior to the date of first administration of the study drug, then onset date is 
not imputed, and AE is not considered as treatment-emergent. 
If AE end date is prior to the date of first administration of the study drug, then onset date is not 
imputed, and AE is not considered as treatment-emergent. 
 
If AE end day is missing, then end day will be imputed as last day of the month, or end date of the on-
treatment period, whichever is earlier 
If AE end day or month are missing, then end day will be imputed as last day of the month and end 
month will be imputed as December, or end date of the on-treatment period, whichever is earlier.  
If AE end date is completely missing, then imputed as end date of the on-treatment period. 
8.1.2 
Concomitant Medications 
End date: Missing day will be imputed as the last day of the month, and missing month will be 
imputed as December. 
Start date: Missing day will be imputed as the first day of the month, and missing month will be 
imputed by January. If the start date is completely missing, then: 
 
If the end date is prior to the date of first administration of the study drug, then the medication 
is considered as prior 
 
If the end date is prior to or on the date of last administration of the study drug, then the 
medication is considered as prior and concomitant 
 
If the end date is completely missing or after the date of last administration of the study drug, 
then the medication is considered as prior, concomitant and post. 
8.2 
Coding 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) v23.0 (March 2020). Prior and concomitant medications will be coded using the last 
available World Health Organization Drug Dictionary (WHO-DD) Global B3 March 2020. 
8.3 
Handling of Values Below (or Above) a Threshold 
For statistical and graphical summaries of the safety laboratory tests, values below or above the limit 
of detection (e.g. ‘< 3’ or ‘>500’) are substituted with the lower/upper limit of detection (e.g. ‘< 3’ is 
substituted by ‘3’, ‘> 500’ is substituted by ‘500’). In data listings, the values will be shown as 
collected, e.g. including the < or > sign. 
In the PK analysis, Debio 1347 plasma concentrations below the limit of quantification (BLOQ) will 
be set to ½ LOQ for calculation of all summary statistics. 


 
 
 
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Handling of BLOQ values for deriving PK parameters will be described in the dedicated Data 
Analysis Plan for population PK analysis (cf. study Debio 1347-507). 
8.4 
Handling of Unscheduled Assessments or Retests 
In case of pre-dose retests, the latest value will be used in the analysis. The post-dose retests and the 
unscheduled assessments will not be used in the summary statistics but will be used in the derivation 
of endpoints that are not related to a specific timepoint (i.e. worst-case assessment, BOR, time to 
event endpoints, etc.). They will also be displayed in listings. 
9 GENERAL STATISTICAL CONSIDERATIONS 
9.1 
General Conventions 
The statistical analysis described below corresponds to analysis planned for the study. Any deviation 
from the planned analysis will be documented in clinical study report. 
Continuous data will be presented in the form of descriptive statistics, as the number of observations, 
mean, standard deviation, minimum, 25th percentile (Q1), median, 75th percentile (Q3) and 
maximum. 
Categorical data, including ordinal data, will be presented using contingency tables with absolute and 
relative frequencies. Missing will be considered as a category and included in the calculation of 
percentages, unless otherwise stated. 
For time-to-event endpoints, Kaplan Meier (K-M) estimates will be provided and include number and 
percentage of events/censored, 25th (Q1), median and 75th (Q3) survival time and associated 95% 
confidence interval (CI, if applicable), survival rate and 95% CI at pre-specified time points. For the 
CIs, these will be Brookmeyer-Crowley for the survival time quartiles and Greenwood for the survival 
rate. 
For PK parameters and concentrations, summary statistics in the tabulation will include number of 
non-missing value, number below the LOQ, mean, standard deviation, Q1, Q3, 90% CI of the 
arithmetic mean, coefficient of variation (CV%), median, minimum, maximum, geometric mean, 90% 
CI of the geometric mean, geometric standard deviation [calculated as: geo standard deviation = exp 
(SDlog)] and geometric CV% [calculated as: geo CV% =SQRT(exp(SDlog2)-1)*100%; where SDlog 
is the standard deviation of the log-transformed values]. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean, median, confidence intervals, Q1 and Q3 will be reported to one 
more decimal place than the raw data recorded in the database. The standard deviation will be 
reported to two more decimal places than the raw data recorded in the database. Percentages will be 
reported with one decimal place. The CV% is reported as a percentage with 1 decimal place. 
Baseline measurement is the latest value collected prior to the administration of study drug.  
All data analyses will be performed using SAS® statistical software version 9.4 or higher, R software 
version 3.3 or higher and NONMEM.  
9.2 
Dates, Times and Days 
Study day is defined as: 
 
(Date of event) – (Date of first dose of study drug) + 1, if the event is on or after the date of 
first dose; 
 
(Date of event) – (Date of first dose of study drug), if the event is before the date of first dose. 


 
 
 
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9.3 
Timing of Analyses 
The timing of the first IDMC meeting was as planned: 
 
The first IDMC meeting will take place after 15 subjects have either been on treatment for at 
least 8 weeks or discontinued the study treatment. 
The timing of the second IDMC meeting was planned to be conducted at same time as the interim 
analysis: 
 
The second IDMC meeting will be convened to review the Interim Analysis results. An 
interim analysis will be conducted at end of Stage 1 to assess ORR homogeneity across 
baskets as well as futility. A minimum of 4 subjects per cohort and a maximum of 13 subjects 
per cohort will be required for the end of Stage 1 analysis (see Section 10.8 for full details of 
the planned interim analysis).  
 
However, the second IDMC meeting took place with 63 evaluable subjects (30, 4, and 29 in 
cohorts 1, 2 and 3, respectively). 
The timing of the main analysis will be modified by Protocol Amendment 2 as follows: 
 
The main analysis will be conducted with all the safety and efficacy data after the last subject 
has consented to Protocol Amendment Nº 2. The data from this analysis will be used to write 
an abbreviated clinical study report (CSR). 
The final descriptive analysis will be conducted as planned: 
 
A final descriptive analysis focused on safety will be conducted after the last subject has 
completed the EOS visit. 
 
As the study ended earlier than expected, it is decided to conduct the main analysis and the 
final descriptive analysis at the same time after the last subject has completed the EOS visit. 
9.4 
Treatment Period 
The treatment period (or on-treatment period) is defined as from date of first administration of study 
treatment until 30 days after the last dose of study treatment or date of death, whichever is earlier. 
10 STATISTICAL ANALYSIS METHODS 
All tables and figures will be presented by cohort and overall. Since the interim analysis did not 
perform a homogeneity assessment of the primary endpoint, then the by-cohort and total groups will 
be presented for the efficacy endpoints. 
10.1 Disposition of Subjects, Demographic and Baseline Data 
10.1.1 Subject Disposition 
Number (%) of patients will be presented by total patients only for All Screened Subjects, in the 
following: 
 
Screened (patients with informed consent) (number only) 
 
Screened but not enrolled and by reason for not enrolling 
Number of patients will be presented for: 
 
Enrolled but not treated 
 
Treated  


 
 
 
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Number (%, calculated using denominator of treated patients) will be presented for 
 
End of treatment status (ongoing at data cut-off, discontinued) and by reason for treatment 
discontinuation 
 
End of study status (ongoing at data cut-off, discontinued) with reason for study 
discontinuation 
 
Subject in ITT, mITT, Safety, PP, PK population. 
Number (%) of patients will be summarized in each analysis population (ITT, mITT, PP, SAF and 
PKP). Reasons for exclusion from PP will be provided:  
 
No measurable disease at baseline (inclusion criterion 7) 
 
No post-baseline disease assessment 
 
Violation of eligibility criteria at entry 
 
Treatment compliance <75% 
 
Other major protocol deviation that potentially affects efficacy assessment 
Subjects per country and sites will be tabulated for the ITT, mITT and PP. 
All subject disposition data will be presented in data-listings. Screening failure and reasons will be 
listed separately. Reason of exclusion from each analysis population will be listed. 
10.1.2 Protocol Deviations 
All deviations from the protocol will be reviewed and classified as minor, major or critical prior to the 
database lock for the main analysis. The full list of possible protocol deviations will be included in the 
study protocol deviation log which will include the classification. 
Major (combined categories of major and critical) protocol deviations will be summarized by type of 
deviation, cohort and total in the ITT population. A by-subject listing of all protocol deviations will be 
presented and will include the type of deviation and description. 
10.1.3 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT, mITT and PP.  
Demographic and baseline characteristics include: 
 
Age (years) at the time of consent, defined as (Informed consent date – date of birth+1) / 
365.25. In case, the date of birth is not allowed to be collected due to local constraints, age 
entered in the eCRF will be used. Missing day of date of birth will be imputed as the 15th and 
missing month will be imputed as June. 
 
Gender, race, ethnicity and child-bearing potential (for females only). 
 
Height (cm), weight (kg), body mass index (kg/m2) = weight / height2. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status at baseline. 
A by-subject listing showing the demographic characteristics will be provided. 
10.1.4 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
medical dictionary version 22.0 or later. Number (%) of subjects with medical history classified by 
system organ class (SOC) and preferred term (PT) will be summarized for the  ITT, mITT and PP. 


 
 
 
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Medical history will be provided in a data-listing including the information on: SOC, PT, reported 
term, start and end date. 
10.1.5 Disease Characteristics 
Baseline disease characteristics will be summarized on ITT population. The analysis will be repeated 
on mITT and PP population. 
Baseline disease characteristics include: 
 
Primary location of tumor. 
 
Histopathologic Grade 
 
Stage at initial diagnosis  
 
Initial Tumor-Node-Metastasis (TNM) stage. 
 
Time since initial diagnosis (years), defined as (treatment start date – initial diagnosis 
date)/365.25. 
o Missing day of initial diagnosis will be imputed at the 15th and missing month will be 
imputed as June. If the entire date is missing, date of initial diagnosis will be imputed 
as the earliest start date of prior anti-cancer therapy 
 
Site of local/metastatic disease  
 
Time since diagnosis of locally advance/metastatic disease (years), defined as (treatment start 
date – date of diagnosis of locally advance/metastatic disease) / 365.25. 
o Missing day of initial diagnosis will be imputed at the 15th and missing month will be 
imputed as June.  
 
FGFR fusion/alteration at screening (whether central lab or local lab) . 
10.1.6 Prior anti-cancer treatments 
Prior anti-cancer treatments will be summarized for the ITT, mITT and PP. 
Number (%) of patients with prior anti-cancer treatments will be summarized for: 
 
Any prior treatment with radiotherapy. 
 
Any prior systemic therapy.  
 
Any prior surgery. 
 
Number of previous lines of anti-cancer systemic therapy as continuous and categorical (1, 2, 
3, >3). 
Prior anti-cancer treatments will be summarized by ATC level 2, 4 and WHO preferred name. Best 
response to last prior cancer systemic therapy will also be reported. 
Additionally, prior anti-cancer treatments will be listed and will include: 
 
Prior radiotherapy: location, dose, start and end date, number of fraction days. 
 
Prior anti-cancer therapy: therapy agent, therapy class, intent of therapy, line number, start 
and end date, reason for therapy, best overall response reached. 
 
Prior surgery. 
10.2 Efficacy Analyses 


 
 
 
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The efficacy analysis will be performed on the ITT population as the primary analysis. All efficacy 
analyses will be repeated on the mITT and PP population as supportive analysis, unless otherwise 
stated. 
PA2 shortens the data collection period for efficacy data. Compared to early enrolled subjects, the 
later enrolled subjects will systematically have less tumor response assessments  at PA2 
implementation and time to event variables censored at date of last dose. There will be no additional 
statistical considerations to specifically address these systematic differences between earlier and later 
enrolled patients, and therefore, the planned statistical methods remain same as before PA2 was 
implemented. 
Also, since the homogeneity assessment at interim analysis was not conducted, the efficacy endpoints 
will be analyzed and reported by cohort and pooled total subjects. 
10.2.1 Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of subjects with a best overall response  of 
confirmed PR or confirmed CR based on RECIST 1.1 criteria. 
Best overall response (BOR) is defined as the best response designation for each subject that is 
recorded between the date of first administration of the study drug and the date of first documented 
disease progression per RECIST 1.1, the date of non-permitted concomitant treatment, date of a new 
systemic therapy or the date of study withdrawal for other reason, whichever occurs first. 
Stable Disease (SD) will be considered as BOR only if the assessment is performed at least 6 weeks 
(i.e. 42 days) after the date of first dose of the study drug. If the minimum time from first dose of the 
study drug is not met when SD is observed, then subject's BOR depends on the subsequent 
assessments. A subject lost to follow-up after the first SD assessment will be considered not evaluable 
(NE). Subjects without any radiologic tumor assessment will be considered as NE. Patients who die 
with no evaluable RECIST assessments will be assigned to the NE category. 
Per RECIST 1.1 criteria, CR and PR needs to be confirmed at a subsequent assessment, at least 4 
weeks (i.e. 28 days) after initial overall response assessment of CR/PR. Confirmed BOR will be 
derived as described in RECIST 1.1 guidance summarized in Table 2. 
Table 2 - Confirmation of BOR based on RECIST 1.1 
Overall 
response first 
time point 
Overall response 
subsequent time 
point* 
Confirmed BOR 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD, if minimum criteria for SD duration met at first time point. 
Otherwise PD 
CR 
PD 
SD, if minimum criteria for SD duration met at first time point. 
Otherwise PD 
CR 
NE 
SD, if minimum criteria for SD duration met at first time point. 
Otherwise NE 
PR 
CR 
PR 


 
 
 
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Overall 
response first 
time point 
Overall response 
subsequent time 
point* 
Confirmed BOR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, if minimum criteria for SD duration met. Otherwise PD 
PR 
NE 
SD, if minimum criteria for SD duration met. Otherwise NE 
NE 
NE 
NE 
*After the first post-baseline assessment of CR/PR, a subject may have fluctuations in target lesion assessment, but as long 
as they have a subsequent assessment showing response at least 4 weeks after the initial assessment without an assessment of 
progressive disease, this would qualify as an objective response. For instance, if a subject has PR-SD-PR or PR-NE-PR at 
consecutive tumour assessments, the objective response would qualify for PR. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the subject had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
Subjects with a clinical progression determined by investigator will be scheduled to have a radiologic 
tumor assessment as per protocol. The response designation determined per RECIST 1.1 criteria using 
this scan will be included in the derivation of BOR. In case the planned scan is not performed, then 
the clinical progression will be used in the BOR derivation. 
10.2.1.1 Primary Analysis 
The primary analysis will be performed at the time of the main analysis for ORR as centrally 
measured by an Independent Review Committee (IRC) based on RECIST 1.1 criteria. 
IRC tumor response variables will be measured by 2 independent assessors. A patient will have the 
same 2 assessors through out the trial. There are in total 4 assessor, named in numerical sequence: 
‘Independent Assessor 1’, ‘Independent Assessor 2’, ‘Independent Assessor 5’, ‘Independent 
Assessor 6’. The Banook Imaging Review Charter ensures categorical tumor response variables will 
agree between the independent assessors. The continuous tumor size variables can differ between 
independent assessors. An overall independent assessor analysis value will be derived for use in the 
primary analysis. The overall independent assessor analysis value for tumor size will be the value 
from the first alphabetically sorted assessor (e.g. if ‘Independent Assessor 2’ and ‘Independent 
Assessor 5’, the overall tumor size will be assigned as from ‘Independent Assessor 2’). 
The hypothesis tested will be according to the decision taken at the interim analysis: 
 
Scenario 1: If the ORR homogeneity assumption is met at the end of Stage 1 and futility is not 
met, then the hypothesis will be: 
H0: ORR ≤ 15% against H1: ORR > 15 % 
The statistical comparison will be conducted on the combined Stage 1 and Stage 2 pooled 
sample of data across cohorts using a one sided binomial exact test at an alpha level of 5%. 
 
Scenario 2: If the ORR homogeneity assumption is not met at the end of Stage 1, then a 
decision will be made at the time of interim analysis to further continue the study with only 1 
cohort or multiple cohorts. Then the hypothesis tested at the final stage will be: 
H0: ORR ≤ 15% against H1: ORR > 15 % in each continuing cohort 


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The statistical comparison will be conducted within each continuing cohort on the combined 
Stage 1 and Stage 2 pooled sample using a one sided binomial exact test at an alpha level of 
5% divided by the number of non-futile cohorts. 
As such, the overall family wise error rate (FWER) for the study is controlled under 5%. 
However, the interim analysis to examine homogeneity of ORR across cohorts was not conducted 
after data monitoring review observed a lower than expected antitumor activity in the pooled group. 
Therefore, the main analysis will present the analysis of ORR (and other efficacy endpoints) by cohort 
and pooled total subjects. 
Objective response rate will be summarized using frequencies and percentages. The Clopper-Pearson 
CI will be calculated using a one-sided binomial exact test at an alpha level as described in the 
hypothesis testing will be presented for all stage combined. 
The best overall response (CR, PR, SD, PD and NE) will be summarized descriptively to show the 
number and percentage of subjects in each response category. The PD category will be further split 
into radiological progression (RECIST) and clinical progression. (Note: In case a patient has both 
radiological and clinical progression, the patient will be summarized under radiological progression.) 
The NE category will be further split into SD observed before 6 weeks , incomplete post baseline 
assessment and death without post-baseline assessment. 
10.2.1.2 Supportive Analysis 
The analysis on ORR will be repeated on mITT and PP population as supportive analysis. 
A sensitivity analysis will also be performed on the ORR based on local investigator assessment of 
response using RECIST 1.1 criteria. This analysis will be performed using the ITT population and 
repeated using the mITT and PP populations. 
10.2.2 Duration of Response 
Duration of response (months) is defined as (date of the first documented disease progression or death 
due to any cause, whichever occurs first - date of the initial response (PR or CR) + 1)/30.4375. It will 
be calculated only for subjects with a confirmed BOR of CR or PR.  
The following censoring rules will be applied: 
Median, 25th and 75th percentile of duration of response with corresponding 95% CI (using log-log 
transform, Brookmeyer and Crowley 1982) will be provided. Duration of response rate with 
corresponding 95% CIs (using Greenwood’s formula and log-log transform, Kalbfleisch and Prentice 
2002) at every 6 months will be presented. A K-M plot for DOR will be presented. 
Swimmer plots will be used to graphically present the DOR for each subject with a documented 
response of CR or PR. 
The analysis on DOR will be based on the IRC evaluation on using the ITT population as the main 
analysis. Supportive analyses will be performed using: 

Subjects who do not experience death or PD, nor initiate a new anti-cancer therapy will be
right-censored at the date of their last adequate tumor assessment (i.e. a tumor assessment not
showing NE).

Subjects having initiated a new anti-cancer therapy before experiencing death or PD will be
right-censored at the date of their last adequate tumor assessment prior to initiation of a new
anti-cancer therapy.

Subjects who experienced death or PD after two or more consecutive missing or inadequate
tumor assessments will be right-censored at their latest adequate assessment before death or
PD.


 
 
 
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 
IRC evaluation of response on mITT and PP populations. 
 
Investigator assessed response on ITT, mITT and PP populations. 
10.2.3 Disease Control Rate 
Disease control rate is defined as number of subjects with a BOR of confirmed CR, confirmed PR or 
SD at least 6 weeks after the date of first dose of the study drug. 
Disease control rate will be summarized using frequencies and percentages. In addition, 95% Clopper-
Pearson CI will be provided. 
The analysis of DCR will be performed based on the independent review committee (IRC) evaluation 
on the ITT population as the main analysis. Supportive analyses will be performed using: 
 
IRC evaluation of response on mITT and PP populations. 
 
Investigator assessed responses on ITT, mITT and PP populations. 
10.2.4 Tumor Size 
The change in tumor size will be calculated for each subject in the ITT population as the percentage 
change from baseline in the sum of longest diameters of target tumor lesions at each assessment time 
point. The percentage change from baseline in the sum of longest diameters will be summarized for 
each scheduled assessment. In addition, the largest decrease in tumor size or the minimum increase 
from baseline in the absence of a reduction from baseline based on all post baseline assessments will 
be summarized descriptively. Waterfall plots will be used to present graphically the largest decrease 
for each subject by BOR. Reference lines will be drawn at +20% and -30% change from baseline. A 
waterfall plot will be presented for each cohort and overall. 
10.2.5 Progression-Free Survival 
Progression-free survival (months) is defined as (date of the first documented disease progression or 
death due to any cause, whichever occurs first - start date of treatment + 1)/30.4375.   
The following censoring rule will be applied: 
 
Subjects who do not experience death or PD, nor initiate anti-cancer therapy will be right-
censored at the date of their last adequate tumor assessment (i.e. a tumor assessment not 
showing NE). 
 
Subjects having initiated a new anti-cancer therapy before experiencing death or PD will be 
right-censored at the date of their last adequate tumor assessment prior to initiation of a new 
systemic therapy. 
 
Subjects who experienced death or PD after two or more consecutive missing or inadequate 
tumor assessments will be right-censored at their latest adequate assessment before death or 
PD. 
 
Subjects without a baseline or post-baseline assessment will be right-censored at the date of 
first administration of the study drug. 
Progression-free survival rate at every 6 months will be presented with the corresponding 95% CIs 
will be estimated using the K-M method. A K-M plot for PFS will be presented. 
The analysis will be performed on PFS calculated based on IRC assessment of response on the ITT 
population as the main analysis. Supportive analyses will be performed using: 
 
IRC evaluation of response on mITT and PP populations. 
 
Investigator assessed response on ITT, mITT and PP populations. 


 
 
 
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10.2.6 Overall Survival 
Overall survival (months) is defined as (date of death due to any cause - the start date of treatment 
+1)/30.4375. Subjects with no documented death will be censored at the last date known to be alive 
(i.e. latest date collected in the eCRF). 
Survival rate at every 6 months will be presented with the corresponding 95% CIs will be estimated 
using the K-M method. A K-M plot for OS will be presented. 
10.2.7 Subgroup Analysis 
ORR and DOR analysis will be repeated, whenever appropriate, on the following subgroups: 
 
By gender (Male, Female) 
 
By Region: North America, Europe, Rest of the world 
 
Subjects with a dose-reduction (as per investigator’s decision) 
 
Subjects with no dose-reduction (as per investigator’s decision) 
However, given the early stopping and reduced data collection after PA2, it is deemed not appropriate 
to perform the subgroup analysis.  
10.3 Safety Analyses 
The safety analysis will be conducted in the Safety Population.  
After PA2 is in force, safety assessments for on-treatment and off-treatment subjects will be 
performed using standard institutional practice and using local laboratory testing.  Generally, safety 
data collected by the local investigator at all clinic visits but only AEs, SAE and AESI will be 
recorded in the eCRF to support the ongoing safety assessments up to 30 days after last administration 
of study treatment. The changes in study design relating to safety data include: 
 
Central clinical laboratory will no longer be performed but will use the local laboratory. 
Central and local laboratory data will be analyzed together, i.e. not separate analysis for each 
data source. Shifts in central and local laboratory values will be determined based on the 
central or local reference range, respectively.   
 
ECGs will not necessarily be collected in triplicate and central reading will not be performed. 
Local reading of ECGs will be used. Central and local ECG readings will be analyzed 
together.  
10.3.1 Extent of Exposure 
Extent of exposure and compliance derived from the subject diary eCRF and “Date of last study drug 
intake” in the End Of Treatment CRF form will be summarized as continuous for the following: 
 
Date of last dose of study drug, defined as the “Date of last study drug intake” in the End Of 
Treatment CRF form, or if missing will be replaced with the date of last non-zero drug intake 
in the subject diary. 
 
Treatment duration (weeks), defined as (date of last dose of study drug – date of first dose + 
1)/7. 
 
Number of completed 28-day cycles, defined as the integer value of floor(treatment duration 
in days/28). (Note: Report only the median, quartiles, min and max.) 
 
Cumulative dose (mg), defined as (total number of tablets taken during the study)*20 mg.  
Note: In the case of incomplete diary data over the treatment duration of the subject, the days 


 
 
 
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with missing tablet counts will be assumed to have a zero tablet count in the calculation of 
cumulative dose over the treatment duration. 
 
Planned cumulative dose (mg), defined as (treatment duration in days)*80 mg. For any period 
where there is a dose reduction this will be multiplied by 60 mg. Note: This quantity is not 
summarized, but only used in calculation of treatment compliance. 
 
Dose intensity (mg/day), defined as  
Cumulative dose (mg) / Treatment duration (days) 
 
Treatment compliance (a k.a. relative dose intensity) (%), defined as 
(Cumulative dose (mg) / Planned cumulative dose (mg))*100 
 
Treatment compliance for first 4 cycles (%), defined as  
(Cumulative dose (mg) for the period where dose date – treatment start date ≤ 112 / 
planned cumulative dose for first 4 cycles (112 multiplied by 80 mg. For any period 
where there is a dose reduction this will be multiplied by 60 mg.) 
Number (%) of patients will be presented for: 
 
Treatment compliance (>=75, <75%) 
 
Treatment compliance for first 4 cycles (>=75, <75%) 
 
Number of dose reductions: 0 or 1 dose reduction. (Note: Patients will be permanently 
discontinued if a second reduction is necessary and thus having >1 dose reduction should not 
occur according to protocol procedures. If the >1 dose reduction category occurs it will 
additionally be displayed). 
A study day between study drug first dose day and last dose day (or last dose at data cut off) is 
considered a temporary interruption if the number of tablets taken is 0 or missing as recorded in the 
subject diary eCRF. An episode of temporary interruption is defined as a run of consecutive days with 
temporary interruption that are flanked before and after by a day with >0 number of tablets taken. 
Patients can have multiple episodes of temporary interruption. Temporary interruptions based on the 
subject diary eCRF will be summarized as follows: 
 
Number (%) of patients with at least one interruption. 
 
Number of episodes of interruption per patient presented as continuous and as categories (0, 
1, 2, >2). 
 
Maximum duration of an interruption episode (days) presented as continuous and as 
categories (0, >=1 to <5, >=5 to <7, >=7 to <14, >=14 days). This is a summary of the 
episode with the maximum number of consecutive days with interruption. 
 
Cumulative duration of interruption days presented as continuous and as categories (0, >=1 to 
<5, >=5 to <7, >=7 to <14, >=14 days). This is the total interruption days summed over all 
episodes.  
Temporary interruptions due to AE will be defined using the AE CRF data: 
 
Number (%) of patients with at least one interruption due to AE, defined as having at least 1 
TEAE with “Action taken with Study Drug” = Temporarily Interrupted. 
 
Number of interruptions due to AE per patient presented as continuous and as categories (0, 1, 
2, >2), defined as counting unique start dates of TEAEs with “Action taken with Study Drug” 
= Temporarily Interrupted. (Note: Counting only unique start dates ensures we do not double-
count AEs that are part of the same interruption episode.) 
Subject diary information will be presented in a data listing. 
10.3.2 Adverse Events 


 
 
 
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Treatment-emergent AE (TEAE) is defined as any AE that either starts or worsens in severity on or 
after the first administration of the study drug and within 30 days of the last administration of the 
study drug. Details for handling of completely/partially missing dates are described in Section 8.1.1. 
Related TEAE will be defined as any TEAE with “reasonable causal relationship” relationship to 
study treatment as assessed by the investigator or with missing assessment of the causal relationship. 
When assessing investigator reported relationship to study drug of the AEs, if an AE reported multiple 
times changes in causal relationship during an analysis period for a subject, the event is considered 
related. 
When summarizing severity of the AEs, if there are multiple AEs of the same preferred term but 
different grade, the AE with the maximum CTCAE grade will be reported. If the AE term (SOC and 
PT) is reported more than once, one of them with missing grade, and at least another with non-missing 
grade, the maximum CTCAE grade will be chosen from the non-missing grade values and the missing 
grade can be ignored.  If all are of missing grade, then summary of the AE term will include a 
“missing” category of CTCAE grade. 
 
An overview of adverse events table will be presented for the following AEs overall and includes the 
number and percentage of subjects and the number of events: 
 
All TEAE 
 
TEAE related to study drug 
 
TEAE with grade 3 or higher 
 
TEAE with grade 3 or higher related to study drug 
 
TEAE by worst severity grade according to the NCI-CTCAE v5.0 criteria  
 
Serious TEAE 
 
Serious TEAE related to study drug 
 
TEAE leading to fatal outcome 
 
TEAE leading to dose reduction 
 
TEAE leading to temporary treatment interruption 
 
TEAE leading to permanent treatment discontinuation 
 
TEAE leading to any dose modification (discontinuation, dose reduction, interruption) 
 
Treatment emergent adverse event of special interest (AESI – as defined in protocol) 
 
AESI with grade 3 or higher 
 
AESI related to the study drug 
 
AESI with grade 3 or higher related to study drug  
The number and percentage of subjects with the following AEs will be summarized using descriptive 
statistics by SOC and PT. SOCs and PTs within each SOC will be displayed in decreasing order of 
frequency. Subjects who have multiple events in the same PT within a SOC or the same SOC will be 
counted only once by worst grade (if applicable). 
The following by-subject listings will be provided.  
 
Adverse events 
 
Serious adverse event 


 
 
 
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 
Adverse events leading to treatment discontinuation 
 
Adverse events leading to fatal outcome 
 
AESI 
 
All deaths and reasons. 
These listings will include at least: SOC, PT and reported term, treatment-emergent flag, AE start 
date/time, AE end date/time, action taken with study medication, relationship, seriousness, CTCAE 
grade and outcome. 
10.3.3 Clinical Laboratory Evaluations 
Laboratory parameters include: 
 
Hematology: Complete blood count with differential, hemoglobin and platelet count. 
 
Chemistry: Total protein, albumin, indirect and total bilirubin, aspartate aminotransferase, 
alanine aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, calcium, and 
magnesium), serum phosphate, serum creatinine, creatinine clearance, uric acid, bile salts. 
 
Urinalysis: Red blood cells/hpf, white blood cells/hpf, casts/hpf, protein dipstick test. 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
presented in SI units. Both local and central laboratory values will be included in the analysis. 
Hematology and chemistry parameters and corresponding changes from baseline will be presented as 
descriptive statistics by visit. 
Shift tables based on the NCI-CTCAE v5.0 toxicity grading (and ad hoc grading criteria for 
hyperphosphatemia) will be presented for each hematology and chemistry parameter between baseline 
and the highest post-baseline NCI-CTCAE v5.0 toxicity grade or the highest post-baseline ad hoc 
grading criteria for hyperphosphatemia (including unscheduled assessment). The highest toxicity 
grade can either be above or below the laboratory standard normal range. 
For hematology and chemistry parameters without a toxicity grading scale, the shift table will present 
directional shifts from baseline to above or below the laboratory standard normal range using the 
maximum increase and/or decrease observed post-baseline. Subjects who experienced both low and 
high laboratory test results will be reported in a separate “Low and High” column. “Low” and “High” 
column will represent the subjects having only low/high values respectively. 
Boxplots of actual values and change from baseline will be presented by visit for selected hematology 
and chemistry parameters as relevant. Log transformation will be applied if necessary. 
Urinalysis parameters will be summarized by visit using descriptive statistics. For categorical 
urinalysis parameters, missing data will not be considered as a category and the calculation of 
frequencies will use the number of non-missing observations. Results from the urinary pregnancy test 
will be listed. 
 
Summary statistics will be presented for subjects with at least one post-baseline phosphate 
(phosphorus) level above 5.5: 
 
Time from start of treatment to Phosphate level of 5.5mg/dL or higher, defined as [earliest 
date where phosphate ≥ 5.5mg/dL] – [date of first administration of the study drug] +1 
 




















 
 
 
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10.3.4 Vital Signs 
Vital signs parameters include: 
 
weight (kg) 
 
systolic blood pressure (mmHg) 
 
diastolic blood pressure (mmHg) 
 
heart rate (beats/min) 
Actual values and corresponding changes from baseline will be summarized by visit as descriptive 
statistics. 
All vital signs data will be presented in a by-subject listing. 
10.3.5 12-lead ECG 
All ECGs will be sent to a local and central cardiology laboratory for reading and analysis. ECG 
measurement will include: 
 
RR, defined as the interval between 2 consecutive R waves (ms); 
 
Heart rate (HR, in beat per minute [bpm]), calculated as 60000 / RR (ms); 
 
P-R, defined as the interval between P and R waves (ms); 
 
QRS, defined as the distance between the Q and the S waves (ms); 
 
QT, defined as the interval between Q and T waves (ms); 
 
QTcF (ms) = QT (ms) / RR (s)1/3. 
The triplicate values will be averaged in order to obtain one single value per subject and time point. 
As per Protocol Amendment Nº 2, central ECG reading will not be performed.  
10.3.5.1 Central Tendency Analysis 
Actual values for central assessment ECG parameters and their changes from baseline will be 
summarized using the descriptive statistics by time point. Ninety percent CIs of the mean will be 
presented as well. Standard deviation will be computed only if at least 3 records are available and 
90% CIs only for cohorts in which at least 6 subjects are available.  
Graphical representation of mean changes from baseline (with their 90% CIs upper bound when 
applicable) over time will be provided. 
10.3.5.2 Categorical Analysis 
The number and percentage of subjects presenting at least one value above the thresholds 
(irrespectively of the cycle or time point) as defined in Table 3 will be computed per cohort and 
overall. All ECG collected (including unscheduled assessments) will be used for this analysis. 
Table 3 - Thresholds for categorical analysis and corresponding flags for listings 
Criteria 
Flag 
Actual values
     P-R > 220 ms
H
     QRS > 120 ms
H
     QTcF interval > 450 ms 
B


 
 
 
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     QTcF interval > 480 ms 
H
     QTcF interval > 500 ms
P
Changes from baseline
     P-R relative change > 25%
I
     QRS relative changes > 25%
I
     QTcF interval increase from baseline > 30 ms
I
     QTcF interval increase from baseline > 60 ms
I+
Flagging system will be used in listings to identify values above thresholds, also not necessarily 
related to clinically significant events, the flags can be interpreted as follows: 
 
B: Borderline value; 
 
H: High value; 
 
P: Prolonged value; 
 
I: Noticeable absolute increase from baseline; 
 
I+: Marked absolute increase from baseline. 
10.3.5.3 Morphological Analysis 
A qualitative interpretation of the ECG will be performed by the cardiologist. This qualitative 
interpretation will provide a codification of the abnormalities detected on the recordings according to 
a code list grouping the abnormalities as: 
 
Q or Qs pattern; 
 
Axis and Voltage; 
 
Hypertrophy; 
 
ST depression and elevation; 
 
T/U wave abnormalities; 
 
AV conduction; 
 
Intraventricular conduction defects; 
 
Rhythm; 
 
Technical issue; 
 
Overall conclusion. 
Number and percentage of subjects presenting at least one treatment emergent abnormality as defined 
by the code list will be computed per cohort and overall. 
Treatment-emergent abnormality will be defined as any abnormality not already reported on the 
baseline ECG. 
All treatment emergent abnormalities will be listed. Individual data listings will be displayed sorted 
by cohort, subject, and time-point, a flag will be added to identify values above thresholds as 
presented in Table 3. 
10.3.6 Other Safety Analysis 


 
 
 
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ECOG PS will be presented as contingency tables by time point. Missing data will not be considered 
as a category and the calculation of frequencies will use the number of non-missing observations. 
Any abnormal finding in ophthalmologic examination will be listed for each subject including the 
following: date of assessment, type of abnormality, whether the patient wears contact lenses, visual 
acuity and the results from left and right eye if available.  
All safety data collected will be provided in by-subject listings. 
10.3.7 Medications and procedures 
Medications/Procedures will be classified into three categories: 
 
Prior: defined as medications/procedures with start date before the date of first administration 
of study drug. 
 
Concomitant: defined as medications/procedures administered during treatment period, 
between first and last administration of study drug. 
 
Post: defined as medications/procedures started after the date of last administration of study 
drug. 
Details for handling of completely/partially missing dates are described in Section 8.1.2. 
Prior and concomitant medications will be summarized by anatomical therapeutic chemical (ATC) 
levels 2, 4 and WHO drug preferred name. In case multiple ATC codes are assigned to a drug, all 
ATC-2nd level terms will be used for reporting. 
In addition, a summary table will be provided describing: 
 
The number and percentage of subject with Sevelamer  
 
Time from treatment start to first administration of Sevelamer defined as date of start of 
Sevelamer use - date of first administration of the study drug +1. Missing day will be imputed 
as first day of month and missing month will be imputed as January. Completely missing date 
will not be imputed. 
 
Maximal dose of Sevelamer per subject 
 
The number and percentage of subject with Sevelamer, lanthanum carbonate and 
acetazolamide (Standardized term) 
All medications and procedures date will also be listed.  
Post-withdrawal anti-cancer treatments and any procedures will be listed and will include: 
 
Post-withdrawal radiotherapy: location, dose, start and end date, number of fraction days. 
 
Post-withdrawal anti-cancer therapy: therapy agent, therapy class, intent of therapy, line 
number, start and end date, reason for therapy. 
 
Procedures: procedure name/description, reason for procedure, if hospitalization was 
required, date of procedure. 
 
 
 
 
 
 
 
 


 
 
 
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10.5 Pharmacokinetics 
10.5.1 Debio 1347 Plasma concentration 
Individual Debio 1347 plasma concentrations will be listed by cohort, gender, subject, and relative 
time from dosing on PK population, values will be presented as collected. 
Concentrations will be summarized by timepoint according to time window specified in Table 4. 
Concentrations derived from samples taken outside of this time window will be considered as 
unscheduled, hence excluded from descriptive analysis. However, the derivation of PK parameters 
will not exclude those unscheduled samples since the actual time of sampling will be used instead of 
the nominal time. Invalid PK measurements (e.g. due to subject vomiting on the same date after 
dosing, or to sample collected after treatment interruption or dosing reduction and therefore not 
reflecting steady-state) will be excluded from analyses and flagged in the data listing. 
Table 4 - Protocol specified time window for PK plasma sampling 
Cycle 
1 
2 
Time point/Day 
14 
28 
14 
28 
Pre-dose 
● - 2 h 
● -2 h 
● -2 h 
● -2 h 
1 h post-dose 
 
● ± 20 min 
 
 
3 h post-dose
● ± 30 min
● ± 30 min
7 h post-dose 
 
● ± 30 min 
 
 
The following plots will be presented by time point for trough levels (i.e. pre-dose on Cycle 1 Day 14 
and Day 28, Cycle 2 Day 14 and Day 28), concentrations at Cycle 1 Day 28 and Cycle 2 Day 28 
separately. Unscheduled samples will not be presented in the figures: 
 
Arithmetic means ± arithmetic standard deviations using linear/linear scales 
 
Geometric means and 68% prediction interval using log10/linear scales, where the 68% 
prediction interval is calculated as exp(meanlog +/- SDlog) where meanlog and SDlog are 
mean and standard deviation of log-transformed concentration values. 
10.5.2 Debio 1347 Pharmacokinetics parameters 
Based on sparse sample plasma concentrations, PK parameters (Ctrough, AUC and any other PK 
parameters as deemed appropriate) will be derived by population PK data analysis using a nonlinear 
mixed-effects modelling approach. A Data Analysis Plan will be prepared for the dedicated 
population PK analysis and will be presented separately. 
Individual plasma PK parameters will be presented in a by-subject listing, and summarized by cohort 
and overall using descriptive statistics.  
If deemed appropriate depending on the safety and efficacy outcomes, covariate and exposure-
response analyses may be conducted. 
 


 
 
 
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10.6 C-QTcF analysis 
If deemed appropriate depending on the safety and efficacy outcomes and data availability, an 
exposure-response (C-QTcF) analysis may be performed as described below. 
Concentration-response relationship will be investigated for change from baseline in QTcF from 
central reading and Debio 1347 plasma concentrations. 
This study did not include a placebo control and no run-in period with ECG recording before dosing 
with study drug. Therefore, placebo effects on QTcF could not be evaluated and accounted for. 
10.6.1 Graphical Exploration: 
In order to assess quality of QTcF correction before and after dosing the following figures will be 
provided: 
 
Scatter plot of QTcF versus RR at baseline with a regression line. 
 
Scatter plot of change from baseline for QTcF versus change from baseline in RR for values 
collected during Debio 1347 treatment periods with a regression line. 
In both cases, the regression lines should tend toward a horizontal line, otherwise, a dependency still 
exists between QTcF and RR and a study specific QT correction (QTcSS) may be considered as the 
preferred dependent variable. 
The following exploratory plots will also be performed before starting the modelling: 
 
Scatterplot of individual change from baseline for QTc values vs. time-matched 
concentrations including a nonparametric trend curve will be provided to assess the pattern of 
the relationship. 
 
Scatterplot of individual change from baseline for HR values vs. time-matched concentrations 
including a nonparametric trend curve will be provided to detect impact of the treatment on 
HR. 
10.6.2 Model Development 
The model development will start with the pre-specified mixed linear model as detailed in Garnett et 
al. (2017) considering the change from baseline in QTcF as dependent variable. In case of the 
graphical exploration suggests that Fridericia correction does not account for all RR variation, change 
from baseline in QTcSS will be used as a sensitivity analysis. 
The fixed effect parameters of the pre-specified model will be the intercept, slope for Debio 1347 
concentrations, influence of baseline (centered on mean) on the intercept. Subject specific random 
effects will be added on the intercept and slope parameters with an unstructured covariance matrix. In 
the case that the unstructured covariance matrix is not supported by the data, other simplified or 
reduced structures will be investigated (ex. variance components). As no placebo group is included in 
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Additive effects on the intercept may be investigated, e.g. the effect of intrinsic factors (such as 
demographic, pathophysiological, or PGx characteristics if deemed appropriate) or extrinsic factors 
(such as concomitant medications). 
10.6.3 Model Evaluation 
Goodness of fit plots will be provided, consisting of: 
 
Quantile-quantile plots of residuals; 
 
Concentrations versus residuals; 
 
Time and baseline versus residuals; 
 
Any marked bias in residual plots may suggest model misspecification. In addition, structural 
model hypothesis will be checked from graphical exploratory plots; 
 
The absence of effect on HR will be investigated from time course of change from baseline 
for HR; 
 
The hypothesis of direct relationship will be evaluated from the time course of change from 
baseline for QTcF by cohort. If the central tendency analysis allows to reject the hypothesis of 
QT/QTcF prolongation, hysteresis phenomenon will not be considered, otherwise, hysteresis 
will be investigated by visual inspection comparing time of peaks in change from baseline for 
QTcF and concentrations; 
 
The hypothesis of linear relationship between change from baseline for QTcF and 
concentrations will be evaluated from exploratory scatter plots, the goodness of fit plots and 
will be supported by testing a quadratic concentration term in the model. 
In case of the linear relationship between change from baseline for QTcF and Debio 1347 
concentrations cannot be accepted, an alternative model such as saturable model will be considered. 
10.6.4 Display of Results and Decision Rules 
Parameters estimated from the selected model will be presented with their standard error and 95% CI. 
Predicted change from baseline for QTcF at Cmax geometric mean will be presented with their 2-sided 
90% CI and a graphical display of predicted change from baseline for QTcF over the concentration 
range collected during the study will be provided. 
The impact of Debio 1347 on QT/QTc prolongation will be considered as below the threshold of 
regulatory concern if the upper bound of the 90% CI of predicted change from baseline for QTcF at 
Cmax is below the regulatory limit of 20 milliseconds, which is generally applied for oncology 
compounds (Maison-Blanche et al. (2013), Sarapa and Britto (2008)). 
 
 
 
 
10.8 Interim Analyses  
10.8.1 Planned interim analysis 
This study will have IDMC analyses as described in IDMC Charter with focus on study safety, drug 
tolerability as well as efficacy. 
As a part of IDMCs, an interim analysis will be conducted at end of Stage 1 to assess ORR 
homogeneity across baskets as well as futility. The testing will be conducted as per the schema 
provided in Figure 1. 


 
 
 
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The interim analysis will be performed at end of Stage 1 on the first 27 evaluable subjects i.e. subjects 
in the ITT who have at least 1 post-baseline tumor assessments or progressed. 
Every effort will be made to ensure equal accrual rates between cohorts during Stage 1. In case of 
unequal accrual rates during stage 1, the interim analysis will be conducted when the slowest 
enrolling cohort will have a minimum of 4 evaluable subjects and the study has a minimum of 27 
evaluable subjects with a maximum of 13 evaluable subjects in any of the other cohorts.  
A feasibility assessment will be evaluated prior to assessment of homogeneity to ensure the 
recruitment feasibility in the targeted population. One or more cohorts may be stopped prematurely as 
a result of the feasibility assessment. The homogeneity will be assessed by comparing, across cohort, 
the ORR as assessed locally by investigator at the time of the data cut-off. ORR to be used in the 
homogeneity assessment will be defined as the proportion of subject with a BOR of confirmed or 
unconfirmed CR or PR as locally assessed by the investigator. The BOR will be derived using all 
disease assessments performed locally by investigator prior to the data cut-off. The homogeneity 
assessment will be performed by comparing the observed p-value for the Fisher’s exact test for 3x2 
contingency tables to the pre-defined cut off value of 0.5.  Homogeneity assumption will be rejected if 
the p-value generated is below 0.5. The cut-off value was determined as part of the simulations for 
sample size determination (see Section 6). 
A futility assessment will be performed after the homogeneity assessment. Futility stopping rules are 
described in Table 5. 
Table 5 - Futility stopping rules 
Homogeneity 
assessment 
Futility assessment sample 
Futility stopping rule 
Homogeneity 
met 
All cohorts combined on first 27 
evaluable subjects across cohorts 
Stop study for futility if less than 3 
responders 
If 3 or more responders, continue to 
Stage 2 and enroll the remaining 
subjects across all cohorts.
Homogeneity 
not met 
First 9 evaluable subjects OR all 
evaluable subjects if cohort enrolled 
less than 9 subjects 
Stop individual cohort for futility if 0 
responder 
If 1 or more responders, cohort is 
eligible to continue into Stage 2.
Note: For homogeneity and futility assessment at the interim analysis, responder is defined as a subject with a BOR of 
confirmed or unconfirmed PR or CR based on investigator assessment.  
In addition to the homogeneity and futility assessment procedure described above, the posterior 
probability of ORR≥15% in any of the cohorts will be provided to IDMC members as supportive 
information for their recommendation. Based on simulations, a cutoff of a  posterior probability (of 
ORR≥15%) less than 65% ( < 65%) in any of the cohorts, when used as a secondary assessment 
criteria for heterogeneity,  provided improved operating characteristics (see Appendix in section 
13.4). Posterior probability will be calculated using a uniform prior beta distribution with parameters 
1 and 1.  
If homogeneity is concluded at end of Stage 1, every effort will be made to ensure comparable 
enrolment rates between the three cohorts during Stage 2. 
10.8.2 Data monitoring at the second IDMC meeting 
Due to the slow accrual in cohort 2 (urothelial cancer), the above sample size criteria on timing of the 
interim analysis was not achieved and the planned interim analysis was not performed as planned. 


 
 
 
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The second IDMC meeting convened when the sample size in cohorts 1, 2, 3 were n=30, n=4, n=29, 
respectively and pooled total n=63. The homogeneity assessment (Fisher’s exact test) was not 
performed. The estimated ORR unconfirmed by cohort and total subjects and by local and central 
reading is summarized in Table 6. 
The results of this data monitoring review of pooled data showed that the antitumor activity of Debio 
1347 was lower than initially assumed at the time the protocol was developed. Considering that 
further enrolment is unlikely to substantially change the magnitude of the efficacy observed up to 
now, Debiopharm decided to permanently halt the enrolment in the study after consultation with the 
IDMC on June 10th, 2020.   
Table 6 - Objective Response Rate Unconfirmed (uORR) results observed at second IDMC  
Cohort 1 
(Biliary Tract 
Cancer) 
(N=30)
Cohort 2 
(Urothelial 
Cancer) 
(N=4)
Cohort 3 
(All Other Solid 
Tumor 
Histologies) 
(N=29)
Total 
(N=63)
 
Local reading uORR 
n(%)
4 (13.3)
0
0
4 (6.3)
 
Central reading uORR 
n(%)
2 (6.7)
0
1 (3.4)
3 (4.8)
 
 
11 MODIFICATION HISTORY  
 
Version 
Major changes from previous version 
0.1 
Not applicable, first draft version 
1.0 
- 
Subgroup analysis on subjects with and without dose-reduction. The aim is 
to explore the efficacy information while dose reduced. 
- 
Clarification and more detailed description of the analysis on section 10.1 
and 10.3. 
- 
A supportive analysis with a censoring rule for PFS and DOR is added. 
This new censoring rule will assess the impact of censoring the subjects 
who initiate a new systemic therapy prior to progression. The aim is to add 
this analysis to cover the rare case where potentially one subject may 
initiate a new therapy prior to progression. Since the protocol require a 
follow-up until progression regardless of treatment status, a radiological 
assessment following a clinical progression to confirm the progression, this 
may limit the cases of drop-outs prior to progression.     
- 
The sentence “Subjects with a clinical progression determined by 
investigator will be scheduled to have a radiologic tumor assessment as per 
protocol. The response designation determined per RECIST criteria 1.1 
using this scan will be included in the derivation of BOR. In case the 
planned scan is not performed, then the clinical progression will be used in 
the BOR derivation.” is updated to remove the use of clinical progression 
as it is removed from protocol version 2. Indeed, the use of clinical 
progression does not impact any efficacy endpoint since PFS considers 


 
 
 
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only documented progression. Therefore, clinical progression will be 
shown separately.  
- 
ECG population removed, as it is also removed in the protocol version 2. 
ECG analysis will be performed on Safety population rather than a 
dedicated ECG population. 
- 
Posterior probability added in Interim Analysis in order to provide to 
IDMC as additional information that could support their recommendation.  
2.0 
- 
Study design has been changed: No interim analysis performed during the 
2nd IDMC meeting,….. 
 
 
 


 
 
 
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12 REFERENCES 
 
Cunanan K. M., Iasonos A., Shen R., Begg C. B., Gönen M. (2017) An efficient basket trial design. 
Statististics in Medicine, 36(10):1568-1579. doi: 10.1002/sim.7227 
Fridericia L.S. (1920) Die systolendauer im elektrokardiogramm bei normalen menschen und bei 
herzkranken. Acta Medica Scandinavica, 54(1):17-50. doi: 10.1111/j.0954-6820.1921.tb15167.x 
Garnett C., Bonate P. L., Dang Q., Ferber G., Huang D., Liu J., Mehrotra D., Riley S., Sager P., 
Tornoe C., Wang Y. (2018) Scientific white paper on concentration-QTc modelling. Journal of 
Pharmacokinetics and Pharmacodynamics, 45(3):383-397. doi: 10.1007/s10928-017-9558-5 
Maison-Blanche P., Vermorken J.B., Goksel T., Machiels J.P., Agarwala S., Rottey S., Daugaard G., 
Volovat C., Scheulen M., Sengeløv L., Grecea D., Eniu A., Jäger E., Meiri E., Cascinu S., Strumberg 
D., Demir G., Clemens M., Pinotti G., Nardi M., Guthrie T., Boelle E., Magherini E. (2013) A 
randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard 
dose aflibercept in cancer patients treated with docetaxel. Journal of Cardiovascular Pharmacology, 
61(6):495-504. doi: 10.1097/FJC.0b013e31828b73ff 
Sarapa N., Britto M.R. (2008) Challenges of characterizing proarrhythmic risk due to QTc 
prolongation induced by nonadjuvant anticancer agents. Expert Opinion on Drug Safety, 7(3):305-
318. doi: 10.1517/14740338.7.3.305 
The EuroQol Group. EQ-5D: A measure of health-related quality of life developed by the EuroQol 
Group: User Guide. V 2.0. 2009. The EuroQol Group, Rotterdam.  
Eq-5D Scoring algorithm and dictionary. EuroQol, EQ-5D. 4th March 2007. 
 
 
 


 
 
 
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13 APPENDICES 
13.1 Reporting Conventions 
The TLFs shells template will be provided in a separate document. 
13.2 Listing of Tables, Figures and Listings 
The TLFs shells template will be provided in a separate document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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13.4 Operation characteristics of additional decision criteria 
13.4.1 Study design  
13.4.1.1 Study design overview 
A basket two stage adaptive design will be used to assess the efficacy of Debio 1347 in terms of ORR. 
The study will include 3 cohorts of subjects comprising biliary tract cancer (Cohort 1), urothelial 
cancer (Cohort 2) and, in Cohort 3, all other solid tumor histologies not included in cohort 1 or cohort 
2, such as non-small cell lung cancer (NSCLC), head and neck cancer, thyroid cancer, oral cancer, 
breast cancer, prostate cancer and others but excluding primary brain tumors. 
An interim analysis will be conducted at end of Stage 1 to assess futility for agnostic approach and 
then a futility for each cohort if agnostic approach is not selected. The testing will be conducted as per 
the schema provided in Figure 2. This interim analysis will be performed at end of Stage 1 on the first 
27 evaluable subjects, with a minimum 4 and a maximum of 13 evaluable subjects per cohort, i.e. 
subjects who have at least 1 post-baseline tumor assessments or progressed. In the case if for the first 
27 evaluable subjects, the minimal number of subjects required is not reached in a cohort, then 
additional subjects will be included in this cohort to reach at least 4 subjects per cohort.  
If overall futility for agnostic approach is not met, the next analysis steps will be conducted using 
combined data from all cohorts. If overall futility for agnostic approach is met, data will be analysed 
separately for each individual cohort and an additional futility will be conducted on each cohort. 
Table 7 shows the futility criteria in term of responders in each cohort.  
Stage 1 will require 27 evaluable subjects across the three cohorts assuming an equal accrual rate per 
cohort. Stage 2 will require 86 evaluable subjects across all cohorts or per individual cohort 
depending on results of assessments scheduled at the end of Stage 1 (see Figure 2). The study design 
is an updated version of the Cunanan et al. (2017)). 
Figure 2 - Graphical algorithm representing study design  
 
13.4.1.2 Interim Decision criteria  


 
 
 
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At interim analysis, overall futility of agnostic approach will be first assessed in terms of ORR in all 
cohorts, defined as the proportion of subject with a BOR of confirmed or unconfirmed CR or PR as 
locally assessed by the investigator. The BOR will be derived using all disease assessments performed 
locally by investigator prior to the data cut-off. The overall futility for agnostic approach will be 
evaluated determined using two decision criteria (See Table 7).  
Table 7 - Decision criteria for Overall futility for agnostic approach 
Decision 
Criteria 1 
(Fisher & Posterior probability) 
Criteria 2 
(Posterior probability) 
Overall 
futility for 
agnostic 
approach 
Met 
(Do NOT continue 
with agnostic approach 
in stage2)  
P-value of Fisher exact test ≤ 0.5  
or  
P[ORR≥15%] < 65% in at least 
one cohort 
P[ORR≥15%] < 65% 
in at least one cohort 
Not Met 
Continue with agnostic 
approach in stage 2 
p-value of Fisher exact test > 0.5  
and  
P[ORR≥15%] ≥ 65% in any of the 
cohorts 
P[ORR≥15%] ≥ 65% 
in any of the cohorts 
The posterior probability (denoted P) calculated using a uniform prior beta distribution Beta (1, 1) and 
with fisher exact test (for criteria 2).  The fisher exact test consists of comparing the observed p-value 
for the Fisher’s exact test for 3x2 contingency tables to the pre-defined cut off value of 0.5.  
If overall futility for agnostic approach is not met, the next analysis steps will be conducted using 
combined data from all cohorts. If overall futility for agnostic approach is met, data will be analyzed 
separately for each individual cohort and an additional futility will be conducted on each cohort. An 
individual futility analysis will be conducted using the following stopping rule: 
 
Stop individual cohort for futility if 0 responder; 
 
If 1 or more responders, cohort is eligible to continue into Stage 2. 
13.4.1.3 Operation characteristics  
In the setting of multiple cohorts, there is no clear analog of the conventional type 1 and type 2 error 
rates. The null scenario is considered as the case when the drug does not work in any of the cohorts. 
However, there is a composite of alternative scenarios that are considered simultaneously, such as that 
the drug may only work in one cohorts, or that it works in two cohorts, and so on.  
The following three metrics are used to construct our proposed design and evaluate its performance 
under various scenarios: FWER, Marginal power, and expected trial sample size (EN).  
The FWER is defined as the probability of incorrectly declaring activity in one or more baskets when 
in fact the drug does not work in any cohort.  
The marginal power for a cohort is defined as the probability of correctly declaring activity in cohort 
k when in fact the drug works in cohort k. The marginal power differs depending on the true 
alternative, that is, the number of cohorts in which the drug actually works.  
The selection an optimal design involves first electing all candidate designs for which both the FWER 
and the marginal power for a specific alternative conform to desired levels, then choosing from these 
candidates the design that optimizes a utility function that trades off power and expected sample size 
across all alternative hypotheses. If no candidate designs satisfy the condition on both FWER and 
marginal power, then the candidate designs will be determined using FWER. 


 
 
 
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13.4.2 Simulation study 
Data for multiple studies will be generated using simulations to derive the operation characteristics of 
the proposed design. The simulation will be performed for various numbers of active cohorts (i.e. 0, 1, 
2 and 3 active cohorts). A total of 100000 simulated studies were used to generate the proposed study 
design and the operation characteristics under the assumption of 0, 1, 2 and 3 active cohorts. The 
detail of the simulation are described below. 
13.4.2.1 Simulate a study 
For each simulated study, the sample size at stage 1 is set to 27 subjects with 4 to 13 per cohort. An 
inactive ORR is set at 15% and an active ORR is set at 30%. The subjects and time of enrolment are 
simulated using exponential distribution. The first 27 subjects in any cohort with the smallest time of 
enrolment will be selected. If among the first 27 subjects, the minimum number of subjects per cohort 
is not met in one cohort, then additional subjects will be enrolled in this cohort to reach this 
requirement.  
The interim decision criteria will be evaluated on the number of subjects included in interim analysis 
and the simulated number of responders and the corresponding posterior distribution. The number of 
responders are simulated using binomial distribution and the pre-specified ORR in each cohort. With 
a prior beta distribution Beta(1,1), the conjugate posterior distribution of ORR in each cohort is 
defined as a beta distribution  
Beta(1 + number of responders, 1+ number of non-responders). 
If the agnostic approach is not rejected, the subjects will be enrolled into 3 cohorts in the stage 2 with 
a minimal of 1 and up to 45 subjects per cohorts, there will be on average 30 subjects per cohort under 
an equal accrual rate. A maximum of 90 subjects will be enrolled in stage 2. Combining the 
responders observed in the study, an exact binomial test comparing the observed ORR against the 
inactive ORR will be performed at a one-sided alpha level of 5%.  
If the agnostic approach is rejected, then the futility in each cohort will be evaluated on the numbers 
of responders. For any cohort where futility criteria is not met, a number of subjects N21, which is the 
parameter in the simulation, will be enrolled in stage 2. Combining the responders observed in stage 1 
and in stage 2 in each non-futile cohort, an exact binomial test comparing the observed ORR against 
the inactive ORR will be performed in each basket separately at a one-sided alpha level of 5%/ 
number of non-futile basket.  
13.4.3 Estimation of FWER and Marginal Power 
The trial design will be simulated 100000 times in order to gain sufficient data to calculate the 
measures below:  
 
Power: Probability of rejecting 15% in each cohort or in all cohorts combined.  
 
FWER: Probability of H0 in any inactive cohort or in all cohorts combined. 
 
% of heterogeneity: Probability of heterogeneity case  
 
Non-Futility: Probability of stopping in each cohort or stop the study  
 
Expected Sample Size:  
 
13.5 Operation characteristics  
The operation characteristics are calculated using simulations with 27 evaluable subjects in Stage 1 
and 86 evaluable subjects in Stage 2 in each cohort  


 
 
 
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Sample size and design operating characteristics are presented in Table 8 for criteria 1 using fisher 
exact test and posterior probability and in Table 9 for criteria 2 using posterior probability only. 
Table 8 - Power and expected sample size based on 100000 simulations using criteria 1 (Fisher & 
Posterior probability) 
Assumed ORR of 15% for inactive cohorts 
and 30% for active cohorts 
Number of truly active cohorts 
0 Active 
1 Active
2 Active 
3 Active 
Marginal Power 
 
 
 
 
      FWER 
5.0% 
10.0% 
21.6% 
NA 
      Power 1 active cohort 
2.4% 
84.0% 
87.8% 
90.5% 
      Power 2 active cohorts 
2.4% 
9.0% 
88.0% 
90.5% 
      Power 3 active cohorts 
2.3% 
9.0% 
21.6% 
90.7% 
Expected sample size 
202 
207 
202 
181 
% Futility for agnostic met at end of stage 1 
91.3% 
86.3% 
77.1% 
58.3% 
      Cohort 1 continuing to stage 2 
67.6% 
81.8% 
72.5% 
53.6% 
      Cohort 2 continuing to stage 2 
67.8% 
62.9% 
72.5% 
53.6% 
      Cohort 3 continuing to stage 2 
67.5% 
62.6% 
53.2% 
53.8% 
% Futility for agnostic not met at end of stage 1 
8.7% 
13.7% 
22.9% 
41.7% 
      Continuing to stage 2  
8.7% 
13.7% 
22.9% 
41.7% 
 
Table 9 - Power and expected sample size based on 100000 simulations using criteria 2 (Posterior 
probability only) 
Assumed ORR of 15% for inactive cohorts 
and 30% for active cohorts 
Number of truly active cohorts 
0 Active 
1 Active
2 Active 
3 Active 
Marginal Power 
 
 
 
 
      FWER 
5.0% 
12.2% 
29.3% 
NA 
      Power 1 active cohort 
2.4% 
83.1% 
88.3% 
91.5% 
      Power 2 active cohorts 
2.5% 
11.2% 
88.2% 
91.5% 
      Power 3 active cohorts 
2.5% 
11.2% 
29.3% 
91.6% 
Expected sample size 
201 
199 
186 
156 
% Futility for agnostic met at end of stage 1 
90.8% 
83.2% 
69.2% 
43.3% 
      Cohort 1 continuing to stage 2 
67.2% 
78.6% 
64.7% 
38.8% 
      Cohort 2 continuing to stage 2 
67.0% 
59.5% 
64.6% 
38.7% 


 
 
 
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      Cohort 3 continuing to stage 2 
67.0% 
59.5% 
45.5% 
38.7% 
% Futility for agnostic not met at end of stage 1 
9.2% 
16.8% 
30.8% 
56.7% 
      Continuing to stage 2  
9.2% 
16.8% 
30.8% 
56.7% 
 


 
 
 
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13.6 Criteria of protocol violation that can lead to exclusion from the Per Protocol populations 
Criteria of protocol violation that can lead to exclusion from MTD or Efficacy populations 
Per 
Protocol
Exception 
listing #
Inclusion Criteria 
 
1.      Written informed consent given according to International Conference on Harmonisation (ICH)/Good Clinical Practice 
(GCP) guidelines and local regulations. 
  
  
2.     Cytologically or histologically confirmed advanced solid tumor.
3.      Radiographic progression on prior systemic therapy; prior localized therapy (i.e., radiation, ablation, embolization) is 
allowed provided radiographic progression out-of-field or in the treatment field is shown. 
  
  
4.     Male or female ≥18 years of age.
5.      Locally-advanced (unresectable) or metastatic disease harboring an FGFR1-3 gene fusion/rearrangement potentially leading 
to a functional FGFR aberrant protein, identified through local and/or central molecular assay. 
  
  


 
 
 
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a) The subject must have received at least one prior line of standard therapy appropriate for their tumor type and stage of 
disease (if available), and, in the opinion of the Investigator, s/he would have been unlikely to tolerate or derive clinically 
meaningful benefit from further appropriate standard of care therapy. In particular: 
 
a. Biliary tract cancer subjects must have progressed on/after gemcitabine-based chemotherapy (including subjects who 
progressed within 6 months of gemtabicine-based adjuvant chemotherapy). Subjects can have received additional 
chemotherapy after documented intolerance to gemcitabine. 
 
b. Urothelial cancer subjects must have progressed on/after cisplatin-based or carboplatin based chemotherapy either 
given for advanced disease or within 12 months from completion if given as neoadjuvant or adjuvant therapy and anti-
PD1/PDL1 therapy (unless not available, contraindicated for some reasons or refused by the subject).  
 
c. NSCLC subjects must have progressed on chemotherapy and anti PD1/PDL1 therapy (unless contraindicated for some 
reasons). Subjects with known EGFR mutations, ALK rearrangement or BRAF V600E mutation must have received the 
relevant target therapy (unless not available). 
 
d. For all other tumor types, subjects must have progressed on/after appropriate standard of care (SOC) therapy (evidence-
based level 1). Subjects who harbor genomic aberrations for which approved target therapy is available must have 
received such therapy. HER2+ or ER/PR+ breast cancer subjects should have received at least one line of HER2-targeted 
or ER-targeted, respectively. 
  
  
7.      Measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1. 
  
  
8.      Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. 
  
  


 
 
 
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9. Screening laboratory values as follows: 
 
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3 [1.0 x 109/L]. 
b. Platelet count ≥ 75,000/mm3 [75 x 109/L]. 
c. Hemoglobin ≥ 8.0 g/dL. 
d. Total bilirubin ≤ 2 x upper normal limit (UNL) [biliary stent allowed]. A subject with an isolated elevation of indirect 
bilirubin is eligible. 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x UNL (5 x UNL in the presence of liver 
metastases).  
f. Calculated or measured creatinine clearance ≥ 30 mL/min (creatinine clearance measured based on 24-hour urine 
collection should be considered to help assess eligibility). 
g. Serum phosphate < 1.5 x UNL.
  
  


 
 
 
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10. Female subjects of child-bearing potential must have a negative serum pregnancy test (minimum sensitivity of 25 
mIU/mL) at screening and be willing to practice the highly effective contraception methods listed below from the time of 
study entry up to 6 months after the last day of treatment: 
 
a. Intrauterine device (IUD)  
b. Intrauterine hormone-releasing system (IUS) 
c. Bilateral tubal occlusion 
d. Vasectomized partner 
e. Sexual abstinence if corresponds to usual and preferred lifestyle of subject. 
 
For hormonal contraceptives . 
 
Of note:  
 
- Female subjects of non-childbearing potential are defined as either pre-menopausal with a documented tubal ligation or 
hysterectomy or post-menopausal with 12 months of spontaneous amenorrhea. 
- Female subjects of child-bearing potential must refrain from donating egg(s) during the clinical study and for 6 months after 
Debio 1347 discontinuation. 
- Male subjects must agree to use a condom from study entry and up to 6 months after the last day of treatment. The subject’s 
female partner should use highly effective contraception methods, which may include hormonal contraceptives or any of the 
methods outlined above, during this period. 
- Male subjects must refrain from donating sperm during the clinical study and for 6 months after Debio 1347 discontinuation.
  
  
11.   Available fresh tumor sample (preferably) or, if no fresh sample can be obtained, archived tumor sample (slides or block) for 
central analysis of FGFR status or retrospective central confirmation in case of local screening. 
  
  
12.  Life expectancy ≥ 3 months.
Exclusion Criteria 


 
 
 
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1.      History of hypersensitivity to any of the excipients in the Debio 1347 formulation (lactose hydrate, microcrystalline 
cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate and magnesium stearate). 
 
 
2.     Prior treatment with a FGFR1-3 selective inhibitor.
3.      History and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, 
intestine, myocardia, or lung, excepting calcified lymph nodes, lung nodules and asymptomatic vascular or cartilage/tendon 
calcifications. 
 
 
4.      Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic examination. 
 
 
5.      Chemotherapy, radiotherapy or small molecule anti-cancer agents within 2 weeks prior to initial dosing with Debio 1347 (3 
weeks for immune checkpoint inhibitors). 
 
 
6.      Administration of any investigational agent within 2 weeks prior to initial dosing with Debio 1347 (3 weeks for immune 
checkpoint inhibitors).
 
 
7.      Surgery requiring general anesthesia, except diagnostic biopsy or local procedure, within 3 weeks prior to initial dosing with 
Debio 1347 and/or if the subject has not fully recovered from the surgery. 
 
 
8.      Grade > 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0) AEs or 
toxicities from previous treatments except: 
 
a. Albumin (≥ 2.5 g/dL is allowed). 
b. AST and ALT in subjects with liver metastases (£ 5 × ULN is allowed). 
c. Alkaline phosphatase (ALP) in subjects with bone metastases (£ 5 × ULN is allowed). 
d. Any grade of alopecia is allowed. 
e. Other Grade 1-2 clinically insignificant laboratory abnormalities are allowed. 
 
 


 
 
 
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9.      Symptomatic or unstable brain metastases < 1 month (Of note: Subjects with asymptomatic stable and treated brain 
metastases are eligible).
 
 
10.   Total corrected and/or ionized serum calcium ≥ 1.5 x UNL (corrected calcium = [0.8 x (normal albumin - subject albumin)] 
+ serum calcium level).
 
 
11.   Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, gastric resection, significant bowel 
obstruction, active ulcerative colitis, active Crohn’s disease). 
 
 
12.  Concomitant treatment with a prohibited medication.
13.   Subjects with a known history of uncontrolled or unstable angina or myocardial infarction within the last 6 months, unstable 
cardiac arrhythmias despite treatment (subjects with a history of atrial fibrillation stabilized under treatment are allowed), 
unexplained recurrent syncope, family history of sudden death from cardiac-related causes, congestive heart failure greater than 
New York Heart Association (NYHA) class II, uncontrolled diabetes, uncontrolled psychiatric disorders, severe ongoing 
infections or any other medical condition that might be aggravated by the treatment on evaluation. 
 
 
14.  Prolongation of QTcF interval to greater than 480 msec.
15.  History of congenital long QT syndrome
16.   History of another malignancy other than the primary tumor within the last 2 years, with the exception of completely resected 
basal or squamous cell skin cancer or any successfully treated in-situ carcinoma, or clinically insignificant prostate cancer without 
any treatment intent (either treated or on active surveillance/watchful waiting). Other cancers within the last 2 years that are 
considered clinically insignificant by the treating physician should be discussed with the study Sponsor to assess eligibility. 
 
 
17.   Known infection requiring the systemic use of, for example, an antibiotic or antiviral agent. 
 
 


 
 
 
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18.   Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements. 
 
 
19.  If female, pregnant or breast feeding.
20.  Unable to swallow and retain oral medications.
21.   Known contraindication to enhanced magnetic resonance imaging (MRI) and/or computerised tomography (CT) scan. 
 
 
Additional criteria 
Actual cumulative dose below 75% of planned cumulative dose from date of first dose to date of end of cycle 4 or date of 
treatment discontinuation, whichever occurs first;
 
 
Major protocol deviations that may have an impact on efficacy endpoints. 
 
 
 
 
 
 








 
 
 
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n) After treatment discontinuation (= EOT visit) subjects will be followed-up for: 
1) Safety (AEs/SAEs) for 30 days from the date of the last Debio 1347 dose. After this period, the Investigator should report to the Sponsor any unusual safety information or any safety 
information that appears to be related to the study drug.   
2) Survival every 12 weeks (± 14 days) from the date of the last Debio 1347 dose until death or loss to follow-up but no longer than for a total of 2 years after the last subject discontinued 
treatment.  
3) Disease status only in subjects without PD every 12 weeks (± 14 days) from the date of the last Debio 1347 dose until PD, death or loss to follow-up but no longer than for a total of 2 years 
after the last subject discontinued treatment. 
 
5) Urinary pregnancy test post-EOT: Every 28 days for 6 months (home pregnancy test is acceptable). All pregnancies detected during the 6-month post-EOT follow up period should be 
reported according to the standard process described in Section Error! Reference source not found.   
 
 
 
 


 
 
 
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Table 11 Study Plan (applicable to subjects with Debio 1347 treatment ongoing after the implementation of Protocol Amendment Nº 2) 
 
Ongoing Treatment* 
EOT  
EOS (30 days after last 
study drug intake)  
Cycle 
any 
 
 
Written informed consent (amendment 
N 2) 
● 
 
 
Physical examination 
● 
● 
● 
Vital signs 
● 
● 
● 
ECGa 
● 
● 
 
Hematology, fasting biochemistryb 
● 
● 
● 
Urinary pregnancy test 
● 
● 
● 
Urinalysis 
● 
● 
● 
Adverse eventsc 
● 
● 
● 
*For all subjects with Debio 1347 treatment ongoing and who consented to participate in the study after the date of implementation of Protocol Amendment N  2, the assessments and procedures 
plan defined in the study protocol will no longer be in force and will be replaced by standard institutional care practice (at least every 2 months) 
a) ECG trace (PR, RR, QRS and QTcF intervals) will be recorded after at least 5 minutes of supine rest. 
b) Hematology: Complete blood count with differential (including ANC), hemoglobin, platelet count.  
 
 Chemistry: Total protein, albumin, indirect and total bilirubin, AST, ALT, ALP, electrolytes (sodium, potassium, calcium, magnesium), serum phosphate, serum creatinine, creatinine clearance. 
The assessment will be performed in a local laboratory.  
 
 Note regarding safety laboratory asessments: In case of a significant laboratory abnormality or clinical or laboratory evidence of toxicity, the Investigator will collect additional samples for 
repeat or additional analyses at appropriate intervals. The subject will be closely followed until sufficient information has been obtained to determine the cause of the abnormality or the value 
has returned to an acceptable level. Appropriate remedial measures should be taken, and the response recorded. Any clinically relevant change from baseline onwards must be recorded on the 
AE page of the eCRF. 
c) AEs, AESI, SAEs must be documented in the study eCRF and in the dedicated report forms as specified in section 9.2 of this protocol.