Clinical trial NCT01587040
Conditions: Neoplasm Malignant
Sponsor: Sanofi
Start date: 2012-07-20; Completion date: 2018-05-23
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

The purpose of this study was to determine the long term safety and tolerability of SAR245408 and SAR245409 as a monotherapy or as part of a combination regimen in participants who were benefiting from treatment.

Detailed description:
The duration of the study for an individual participant included:

1. Baseline assessments: within 7 days prior to the first dose of investigational medicinal product (IMP).
2. Study treatment period(s):

   Participants started study treatment at the beginning of the initiation or extension periods based on the length of prior therapy with SAR245408 or SAR245409
   * if \<2 cycles, started with initiation period; Participant must have had completed all the visits in the initiation period before moving to the extension period.
   * if \>=2 cycles, started with extension period; duration of extension period was unlimited.
   * Participants who took a SAR245408 or SAR245409 daily dose higher than their established dose of SAR245408 or SAR245409, respectively, in the parental study entered the study on Day 1 of the initiation period.
   * Participants who had dose interrupted in the parental study but fulfilled parental protocol criteria to restart IMP treatment entered the treatment-extension study on Day 1 of the initiation period.
   * Participants who fulfilled the parental study criteria for IMP treatment continuation but had ongoing Grade 2 adverse events (AEs) entered the treatment-extension study on Day 1 of the initiation period.

   Participants continued to receive study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or until commercial supplies of SAR245408 or SAR245409 were available to them outside of the clinical trial.
3. Follow-up assessments: 23 to 37 days after the last dose of IMP.

Arms: arm 1: Participants received SAR245408 400 milligrams (mg) once daily or at the established dose as monotherapy in the parental study until disease progression, unacceptable toxicity, withdrawal of consent, or until commercial supplies of SAR245408 were available (up to 1959 days). arm 2: Participants received SAR245408 400 mg once daily or at the established dose as combination regimen in the parental study until disease progression, unacceptable toxicity, withdrawal of consent, or until commercial supplies of SAR245408 were available (up to 1959 days). Commercially available drugs were used as combination medications with SAR245408 (depending on the parental study, the following drugs were used in combination with SAR245408: paclitaxel and carboplatin, letrozole, trastuzumab, paclitaxel and trastuzumab). arm 3: Participants received SAR245409 50 mg twice daily or at the established dose as monotherapy in the parental study until disease progression, unacceptable toxicity, withdrawal of consent, or until commercial supplies of SAR245409 were available (up to 1917 days). arm 4: Participants received SAR245409 50 mg twice daily or at the established dose as combination regimen in the parental study until disease progression, unacceptable toxicity, withdrawal of consent, or until commercial supplies of SAR245409 were available (up to 1917 days). Commercially available drugs were used as combination medications with SAR245409 (depending on the parental study, the following drugs were used in combination with SAR245409: letrozole, temozolomide, rituximab, bendamustine and rituximab).
Interventions: intervention 1: SAR245408 intervention 2: SAR245409
Intervention descriptions: intervention 1: Pharmaceutical form: capsule or tablet Route of administration: oral intervention 2: Pharmaceutical form: capsule or tablet Route of administration: oral

Protocol documents:
Prot_001.pdf: 
According to template: QSD-002579 VERSION N°5.0 (04-MAY-2011) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 2 
COMPOUND: SAR245408 - SAR245409 
International, multicenter, open-label, treatment-extension study for subjects who 
completed a Phase 1 or Phase 2 parental study to continue receiving treatment 
with SAR245408 or SAR245409 as a monotherapy or as a combination regimen 
STUDY NUMBER: TED12414 
CLINICAL STUDY DIRECTOR:  
, 
, 
 
Clinical Trial Protocol Amendment 2 
Version no. 1 
Date : 16-Jun-2014 
Clinical Trial Protocol Amendment1 
Version no. 1  
Date : 21-Sep-2012 
Clinical Trial Protocol 
Version no. 1  
Date : 16-Jan-2012 
EudraCT number 
IND number (SAR245408) 
IND number (SAR245409) 
2011-006140-78 
77,339 
77,636 
Total number of pages: 
93 
NCT number: NCT01587040


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
 
 
 
 
 
 
 
 
CLINICAL STUDY 
DIRECTOR 
Name:  
Company: 
Address: 
Tel: 
Fax: 
E-mail: 
 
Sanofi 
 
 
 
 
 
CLINICAL TRIAL 
OPERATIONS MANAGER 
Name:  
Company: 
Address: 
Tel: 
Fax: 
E-mail: 
 
 
 
 
  
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
SPONSOR  
Company: 
Address: 


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OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
Name: 
 
Tel: 
Mobile: 
 
 


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CLINICAL TRIAL SUMMARY 
 
COMPOUNDS: SAR245408 and 
SAR245409  
STUDY No : TED12414 
TITLE 
International, multicenter, open-label, treatment-extension study for 
subjects who completed a Phase 1 or Phase 2 parental study to 
continue receiving treatment with SAR245408 or SAR245409 as a 
monotherapy or as a combination regimen. 
INVESTIGATOR/TRIAL LOCATION 
International. 
STUDY OBJECTIVE(S) 
 
Primary Objective 
To determine the long term safety and tolerability of SAR245408 and 
SAR245409 as a monotherapy or as part of a combination regimen 
in subjects who are benefiting from treatment. 
Secondary Objective(s) 
Not applicable. 
STUDY DESIGN 
This treatment-extension, open-label, international, multicenter, 
nonrandomized study is designed to provide continued access to 
SAR245408 or SAR245409 as a monotherapy or as part of a 
combination regimen.  
All subjects in the study will receive SAR245408 or SAR245409; the 
respective dose will be either the recommended Phase 2 dose 
(400 mg SAR245408 [tablet formulation polymorph A] once daily or 
50 mg SAR245409 [capsule formulation] twice daily) or the subject’s 
established dose either as a monotherapy or in a combination 
regimen in the parental study. 
SAR245408 is administered orally and is supplied as a capsule or a 
tablet formulation polymorph A or E. SAR245409 is administered 
orally and is supplied as a capsule or a tablet formulation. For all 
subjects, the dose, regimen, formulation, and food condition for 
study drug intake of SAR245408 or SAR245409 (and the dose and 
regimen of combination medication(s) for subjects taking 
combination therapy) will be agreed on in writing between the site 
and the Sponsor prior to first dose. 
Subjects who will enter the treatment extension study on Day 1 of 
the Initiation Period are those who: 
• 
Received SAR245408 or SAR245409 for less than 2 cycles in 
the parental study 
• 
Had dose interruption in the parental study but fulfill parental 
protocol criteria to restart IMP 
• 
Fulfill the parental study criteria for IMP treatment continuation 
but have ongoing Grade 2 AE(s) 
• 
Will take a daily dose higher than their established dose in the 
parental study  
Subjects who received SAR245408 or SAR245409 for at least 2 
cycles in the parental study will enter the treatment-extension study 
on Day 1 of the Extension Period.  
 


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Subjects may continue in the study until disease progression, 
unacceptable toxicity, withdrawal of consent, until commercial 
supplies of SAR245408 or SAR245409 are available to them outside 
of the clinical trial, or other reasons detailed in Section 22). 
STUDY POPULATION  
Main selection criteria: 
 
Males or females enrolled in Phase 1 or Phase 2 studies of 
SAR245408 or SAR245409 who have complete data collection for 
the primary endpoint(s) of the parental study or who are being 
treated beyond the parental study cut-off. 
Total expected number of subjects: 
Approximately 100-150. 
Expected number of sites: 
Approximately 28. 
STUDY TREATMENT(s) 
 
Investigational Medicinal Product N° 1 
SAR245408 
Formulation: 
(Form A) hard capsules: 25 and 100 mg. 
(Form A) tablets: 50, 100, 150, and 200 mg; and (form E) film-coated 
tablets 50, and 200 mg . 
Route of administration: 
Oral.  Capsules or tablets should be taken with 8 ounces (240 mL) of 
water, with no food allowed for at least 2 hours before and 1 hour 
after dosing. The administration of polymorph E tablets with food is 
allowed, ie, with the morning meal with a full glass of non-carbonated 
water. 
Dose regimen: 
Recommended Phase 2 dose (400 mg [tablet formulation 
polymorph A] once daily) or established dose and regimen, either as 
a monotherapy or in a combination regimen in the parental study.   
Because of the expiration of (form A) tablet, patients need to be 
transitioned to (form E) film-coated tablet. Patients will continue 
taking the same dose that they were receiving of (form A) tablet. 
Subjects who are receiving in the parental study an established dose 
of SAR245408 different than the suggested dose above, may 
continue on the established dose. 
For subjects taking combination therapy, if in the Investigator’s 
opinion the subject has maximally benefited from the combination 
therapy the subject may continue on SAR245408 only. 
For all subjects, the dose, regimen, and formulation of SAR245408 
(and the dose and regimen of combination medication[s] for subjects 
taking combination therapy) should be agreed on in writing between 
the site and the Sponsor prior to first dose and should not exceed 
the maximum tolerated dose for the parental study. 
Investigational Medicinal Product N° 2 
SAR245409 
Formulation: 
SAR245409A hard capsules: 10, 30, 40, and 50 mg. When the 
sponsor has discontinued manufacture of the SAR245409A 10 mg 
hard capsule strength, ongoing patients who are receiving a dose 
lower than 30 mg will continue treatment at a comparable dose level 
in consultation with the sponsor (see Section 8.1.2).   
Film-coated tablets: 20 and 30 mg. 
 


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Route of administration: 
Oral. Capsules or tablets should be taken with 8 ounces (240 mL) of 
water, with no food allowed for at least 2 hours before and 1 hour 
after dosing. 
Dose regimen: 
Recommended Phase 2 dose (50 mg [capsule formulation] twice 
daily) or established dose and regimen, either as a monotherapy or 
in a combination regimen. 
Subjects who are receiving in the parental study an established dose 
of SAR245409 different than the suggested dose above, including 
once daily dosing of SAR245409, may continue on the established 
dose.  
For subjects taking combination therapy, if in the Investigator’s 
opinion the subject has maximally benefited from the combination 
therapy the subject may continue on SAR245409 only. 
For all subjects, the dose, regimen, and formulation of SAR245409 
(and the dose and regimen of combination medication[s] for subjects 
taking combination therapy) should be agreed on in writing between 
the site and the Sponsor prior to first dose and should not exceed 
the maximum tolerated dose for the parental study. 
Combination medications with 
SAR245408 
Depending on the parental study, the following drugs may be used in 
combination with SAR245408: 
- paclitaxel and carboplatin 
- letrozole 
- trastuzumab 
- paclitaxel and trastuzumab 
Commercially available drugs will be used as combination 
medications with SAR245408. 
Combination medications with 
SAR245409 
Depending on the parental study, the following drugs may be used in 
combination with SAR245409: 
- letrozole 
- temozolomide 
- rituximab 
- bendamustine and rituximab 
Commercially available drugs will be used as combination 
medications with SAR245409. 
PRIMARY AND SECONDARY 
ENDPOINT(S) 
 
Primary Endpoint 
Incidence and frequency of adverse events (AEs) and laboratory 
abnormalities. 
Secondary Endpoint(s) 
Not applicable. 
ASSESSMENT SCHEDULE 
See flow chart in Section 1.2. 
STATISTICAL CONSIDERATIONS 
 
The sample size of this study will depend on the number of subjects 
transferred from the parental studies. 
 


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Safety will be evaluated in safety population that consists of all 
subjects who take at least 1 dose of the study treatment. Adverse 
events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Total incidence (ie, Grade 1 or higher) and 
incidence of Grade ≥3 of each AE will be summarized by system 
organ class and preferred term using frequencies and percentages. 
For subjects with several episodes of the same event during the on-
treatment period, the worst grade will be used. Drug-related 
treatment-emergent AEs, deaths, serious AEs, and AEs leading to 
treatment discontinuation will be summarized similarly by treatment 
group. For each parameter that can be graded with the National 
Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 4.03, number and percentage of subjects with 
laboratory abnormalities (all grades and Grade 3 to 4) using the 
worst grade during the on-treatment period will be provided. For 
other parameters, laboratory values outside of the normal ranges will 
be identified. 
DURATION OF STUDY PERIOD (per 
subject)  
Subjects may continue in the study until disease progression, 
unacceptable toxicity, withdrawal of consent, until commercial 
supplies of SAR245408 or SAR245409 are available to them outside 
of the clinical trial, or other reasons detailed in Section 22). 
 


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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Initiation Period 
Extension Period 
Baseline 
A  
B 
 
A – Subjects who received SAR245408 or SAR245409 for <2 cycles in the parental study, 
subjects who will take a daily dose of SAR245408 or SAR245409 higher than their 
established dose in the parental study, subjects who had dose interrupted in the parental 
study but fulfill parental protocol criteria to restart IMP treatment, and subjects who 
fulfil the parental study criteria for IMP treatment continuation but have ongoing Grade 2 
AE(s) will enter the treatment-extension study on Day 1 of the initiation period. 
 
B – Subjects who received SAR245408 or SAR245409 for ≥ 2 cycles in the parental study 
will enter the treatment-extension study on Day 1 of the extension period. 
Study 
Entrance  
Follow-up 


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1.2 
STUDY FLOWCHART FOR SAR245408 OR SAR245409 TREATMENT 
 
Initiationb 
Extensionb 
Cycle 1  
(Visits 1-4) 
Cycle 2 
(Visits 5-6) 
Visits 7+ 
Assessments 
Baselinea 
D1  
D8  
D15  
D22  
D1  
D15  
Every 4-6 wks 
Follow-up 30±7 
days 
Inclusion/exclusion criteria – Informed consentc 
x 
 
 
 
 
 
 
 
 
Demography, cancer history 
x 
 
 
 
 
 
 
 
 
Documentation of agreed dose and regimend 
x 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
x 
 
 
 
 
 
 
 
x 
ECOG performance status 
x 
 
 
 
 
x 
 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examinatione 
x 
 
 
 
 
x 
 
 
 
Symptom-directed physical examination 
 
x 
x 
x 
x 
 
x 
x 
x 
Ophthalmologic examf 
xg 
 
 
 
 
 
 
every 24 wks ± 4 wks 
xh 
12-lead electrocardiogram 
x 
x 
 
x 
 
x 
x 
xk 
x 
Urinalysis 
x 
x 
 
 
 
x 
 
x 
x 
Hematology  
x 
x 
 
x 
 
x 
x 
x 
x 
Serum chemistry 
x 
x 
 
x 
 
x 
x 
x 
x 
PT (INR)/aPTT 
x 
x 
 
 
 
x 
 
x 
x 
HbA1c   
x 
 
 
 
 
 
 
every 12 wks ± 4 wksi 
x 
Dispense study drug. 
Dispense, review, and/or collect patient diary 
 
x 
 
 
 
x 
 
x 
 
Tumor assessment 
 
per standard of care 
 
Combination medication(s) 
 
per established schedule 
 
Adverse events 
x 
continuous throughout the study 
x 
Concomitant medicationsj 
x 
continuous throughout the study 
x 


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D = day; wks = weeks; INR = international normalized ratio; PT = prothrombin time; PTT = activated partial thromboplastin time; HbA1c: hemoglobin A1c. 
a Baseline assessments should be performed within 7 days prior to the first dose of IMP. End-of-treatment assessment from the parental study may be used as baseline assessments if obtained within 7 days prior 
to the first dose of IMP. 
b All subjects complete baseline visit and then start at the beginning of the initiation or extension period based on the length of prior therapy with IMP. If <2 cycles, start with initiation; if ≥2 cycles, start with 
extension. Subjects who will take a SAR245408 or SAR245409 daily dose higher than their established dose in the parental study, subjects who had dose interrupted in the parental study but fulfill parental 
protocol criteria to restart IMP treatment, and subjects who fulfill the parental study criteria for IMP treatment continuation but have ongoing Grade 2 AE(s) will enter the study on Day 1 of the initiation period. 
Subjects must complete all the visits in the initiation period before moving to the extension period. Subjects who are on 3-week therapy cycles will have assessments only on D1, D8, and D15 when in Cycle 1 and 
on D1 and D15 when in Cycle 2. Assessments for the initial visit do not need to be repeated if baseline assessment was obtained in the previous 72 hours. Baseline visit and initial visit may occur on the same 
day. 
c A signed study informed consent is required prior to site personnel conducting any specific study procedures. 
d Documentation of agreed dose, regimen, and formulation of SAR245408 or SAR245409 (and agreed dose and regimen of combination medication[s] for subjects taking combination therapy and study starting 
point [initiation or extension] must be signed by the Sponsor Medical Monitor and the site Principal Investigator prior to first dose on this protocol. 
e Full physical examination including body weight. 
f 
Ophthalmologic exam at baseline is for subjects on SAR245408 and for subjects on SAR245409; ophthalmologic exam during the extension period is only for subjects on SAR245409. Ophthalmologic exam must 
be conducted by a trained ophthalmologist or optometrist. 
g Ophthalmologic exam from the parental study may be used as baseline assessment if conducted within 12 weeks prior to the first study treatment administration. 
h Ophthalmologic exam at the follow-up visit is done only if any of the previous exams were abnormal. 
i 
Every 24 wks ± 4 wks after 60 wks on treatment. 
j 
Including all chemotherapeutic agents taken since initial diagnosis. 
k During the Extension period, 12-lead electrocardiogram is performed approximately every 12 weeks and as clinically indicated. 


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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 2 ................................................................................................1 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOWCHART FOR SAR245408 OR SAR245409 TREATMENT......................................9 
2 
TABLE OF CONTENTS ................................................................................................................11 
3 
LIST OF ABBREVIATIONS ..........................................................................................................17 
4 
INTRODUCTION AND RATIONALE.............................................................................................19 
4.1 
INTRODUCTION............................................................................................................................19 
4.2 
RATIONALE...................................................................................................................................19 
4.2.1 
Study rationale ...............................................................................................................................19 
4.2.2 
Design rationale and risk assessment ...........................................................................................19 
4.2.3 
Safety parameters rationale...........................................................................................................20 
4.2.3.1 
SAR245408 treatment ...................................................................................................................20 
4.2.3.2 
SAR245409 treatment ...................................................................................................................21 
5 
STUDY OBJECTIVES ...................................................................................................................22 
5.1 
PRIMARY.......................................................................................................................................22 
5.2 
SECONDARY ................................................................................................................................22 
6 
STUDY DESIGN ............................................................................................................................23 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................23 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................24 
6.2.1 
Duration of study participation for each subject.............................................................................24 
6.2.2 
Determination of end of clinical trial (all subjects)..........................................................................24 
6.3 
INTERIM ANALYSIS......................................................................................................................25 
6.4 
STUDY COMMITTEES..................................................................................................................25 
7 
SELECTION OF SUBJECTS ........................................................................................................26 
7.1 
NUMBER OF SUBJECTS PLANNED............................................................................................26 
7.2 
INCLUSION CRITERIA..................................................................................................................26 
 


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7.3 
EXCLUSION CRITERIA ................................................................................................................26 
8 
STUDY TREATMENTS .................................................................................................................28 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................28 
8.1.1 
SAR245408....................................................................................................................................28 
8.1.1.1 
Pharmaceutical form ......................................................................................................................28 
8.1.1.2 
Dose preparation and administration.............................................................................................30 
8.1.1.3 
Duration of treatment .....................................................................................................................31 
8.1.2 
SAR245409....................................................................................................................................32 
8.1.2.1 
Pharmaceutical form ......................................................................................................................32 
8.1.2.2 
Dose preparation and administration.............................................................................................32 
8.1.2.3 
Duration of treatment .....................................................................................................................33 
8.2 
COMBINATION MEDICATIONS....................................................................................................33 
8.3 
TREATMENT DELAY OR DOSE MODIFICATIONS.....................................................................34 
8.3.1 
General guidelines for the management of non-hematologic and hematologic adverse 
events.............................................................................................................................................35 
8.3.2 
Specific guidelines for the management of adverse events ..........................................................37 
8.3.2.1 
Skin disorders ................................................................................................................................37 
8.3.2.2 
Pulmonary symptoms.....................................................................................................................41 
8.3.2.3 
Hepatobiliary disorders ..................................................................................................................41 
8.3.2.4 
Gastrointestinal disorders ..............................................................................................................41 
8.3.2.5 
Hyperglycemia ...............................................................................................................................41 
8.3.2.6 
Corrected QT interval prolongation................................................................................................42 
8.4 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUP.............................................42 
8.5 
PACKAGING AND LABELING ......................................................................................................42 
8.6 
STORAGE CONDITIONS..............................................................................................................42 
8.7 
RESPONSIBILITIES ......................................................................................................................43 
8.8 
CONCOMITANT MEDICATION.....................................................................................................43 
8.9 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ...............................................................44 
8.10 
RETURN AND/OR DESTRUCTION OF TREATMENTS ..............................................................45 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................46 
9.1 
SAFETY .........................................................................................................................................46 
9.2 
PHARMACOKINETICS..................................................................................................................46 
9.3 
PHARMACODYNAMICS ...............................................................................................................46 
9.4 
EFFICACY .....................................................................................................................................46 
 


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10 
PATIENT SAFETY.........................................................................................................................47 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL .....................................................................47 
10.1.1 
Performance status........................................................................................................................47 
10.1.2 
Physical examination .....................................................................................................................47 
10.1.3 
Vital signs measurement................................................................................................................47 
10.1.4 
Laboratory tests .............................................................................................................................48 
10.1.5 
Ophthalmologic examination..........................................................................................................50 
10.1.6 
Electrocardiogram..........................................................................................................................50 
10.1.7 
Pregnancy test ...............................................................................................................................50 
10.1.8 
Adverse event reporting.................................................................................................................50 
10.2 
SAFETY INSTRUCTIONS .............................................................................................................50 
10.3 
ADVERSE EVENTS MONITORING..............................................................................................50 
10.4 
DEFINITIONS OF ADVERSE EVENTS.........................................................................................51 
10.4.1 
Adverse Event................................................................................................................................51 
10.4.2 
Serious Adverse Event ..................................................................................................................51 
10.4.3 
Adverse Event of Special Interest..................................................................................................52 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................52 
10.5.1 
General guidelines for reporting Adverse Events ..........................................................................52 
10.5.2 
Instructions for reporting Serious Adverse Events.........................................................................53 
10.5.3 
Guidelines for reporting Adverse Events of Special Interest .........................................................54 
10.5.3.1 Reporting of AESI with immediate notification...............................................................................54 
10.5.3.2 Reporting of AESI without immediate notification..........................................................................54 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................55 
11 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION......................................57 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S).................................................................................................................................57 
11.2 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S).................................................................................................................................57 
11.2.1 
List of criteria for definitive treatment discontinuation....................................................................57 
11.2.2 
Handling of patients after permanent treatment discontinuation ...................................................58 
11.3 
PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY ..............58 
12 
STUDY PROCEDURES ................................................................................................................59 
12.1 
VISIT SCHEDULE..........................................................................................................................59 
 


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12.1.1 
Pretreatment period .......................................................................................................................60 
12.1.2 
Treatment period............................................................................................................................61 
12.1.2.1 Initiation period (if applicable) ........................................................................................................61 
12.1.2.2 Extension period ............................................................................................................................61 
12.1.3 
Post-treatment period.....................................................................................................................62 
12.2 
DEFINITION OF SOURCE DATA..................................................................................................63 
13 
STATISTICAL CONSIDERATIONS..............................................................................................64 
13.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................64 
13.2 
ANALYSIS ENDPOINTS ...............................................................................................................64 
13.2.1 
Demographic and baseline characteristics ....................................................................................64 
13.2.1.1 Demographic and baseline characteristics ....................................................................................64 
13.2.1.2 Prior or concomitant medications (other than anti-cancer therapies)............................................64 
13.2.2 
Safety endpoints ............................................................................................................................64 
13.2.2.1 Adverse events ..............................................................................................................................65 
13.2.2.2 Deaths............................................................................................................................................65 
13.2.2.3 Laboratory safety variables............................................................................................................65 
13.2.2.4 Vital signs.......................................................................................................................................65 
13.2.2.5 12-lead ECG ..................................................................................................................................66 
13.2.2.6 Other safety endpoints...................................................................................................................66 
13.2.3 
Pharmacokinetic variables .............................................................................................................66 
13.2.4 
Pharmacodynamic variables..........................................................................................................66 
13.3 
DISPOSITION OF PATIENTS .......................................................................................................66 
13.4 
ANALYSIS POPULATIONS...........................................................................................................66 
13.4.1 
Safety population ...........................................................................................................................66 
13.4.2 
Efficacy population.........................................................................................................................66 
13.5 
STATISTICAL METHODS .............................................................................................................66 
13.5.1 
Demographic and baseline characteristics ....................................................................................66 
13.5.2 
Prior or concomitant medications (other than anti-cancer therapies)............................................67 
13.5.3 
Extent of study treatment exposure ...............................................................................................67 
13.5.4 
Analyses of safety data..................................................................................................................67 
13.5.5 
Analyses of efficacy endpoints.......................................................................................................69 
13.5.5.1 Analyses of primary and secondary efficacy endpoints.................................................................69 
13.5.5.2 Analyses of exploratory efficacy endpoints....................................................................................69 
13.5.5.3 Multiplicity Considerations .............................................................................................................69 
13.5.6 
Analyses of pharmacokinetic variables..........................................................................................70 
13.5.7 
Analyses of pharmacodynamic variables.......................................................................................70 
13.6 
DATA HANDLING CONVENTIONS ..............................................................................................70 
 


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13.7 
INTERIM ANALYSIS......................................................................................................................70 
13.8 
DATABASE LOCK .........................................................................................................................70 
14 
ETHICAL AND REGULATORY STANDARDS.............................................................................71 
14.1 
ETHICAL PRINCIPLES .................................................................................................................71 
14.2 
LAWS AND REGULATIONS .........................................................................................................71 
14.3 
INFORMED CONSENT .................................................................................................................71 
14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............72 
15 
STUDY MONITORING...................................................................................................................73 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................73 
15.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................73 
15.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................74 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................74 
15.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................74 
16 
ADMINISTRATIVE RULES ...........................................................................................................75 
16.1 
CURRICULUM VITAE....................................................................................................................75 
16.2 
RECORD RETENTION IN STUDY SITES(S) ...............................................................................75 
17 
CONFIDENTIALITY.......................................................................................................................76 
18 
PROPERTY RIGHTS.....................................................................................................................77 
19 
DATA PROTECTION.....................................................................................................................78 
20 
INSURANCE COMPENSATION ...................................................................................................79 
21 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES................................80 
22 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................81 
22.1 
DECIDED BY THE SPONSOR IN THE FOLLOWING CASES:....................................................81 
22.2 
DECIDED BY THE INVESTIGATOR.............................................................................................81 
23 
CLINICAL TRIAL RESULTS.........................................................................................................82 
24 
PUBLICATIONS AND COMMUNICATIONS ................................................................................83 
 


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25 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................84 
26 
BIBLIOGRAPHIC REFERENCES.................................................................................................85 
27 
APPENDICES................................................................................................................................86 
APPENDIX A 
ECOG PERFORMANCE STATUS SCALE.........................................................................86 
APPENDIX B 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS.......................................................................................................................87 
APPENDIX C MODIFIED LUND-BROWDER CHART...............................................................................88 
APPENDIX D LIST OF DRUGS THAT ARE CYP1A2 OR CYP3A SUBSTRATES, OR CYP2C9 
SUBSTRATES WITH NARROW THERAPEUTIC INDEX.............................................................89 
APPENDIX E 
LIST OF DRUGS THAT ARE STRONG CYP3A INDUCERS.............................................90 
APPENDIX F LIST OF DRUGS THAT ARE CYP1A2 SUBSTRATES, INDUCERS OR 
INHIBITORS...................................................................................................................................91 
APPENDIX G 
LIST OF APPLICABLE PARENTAL PROTOCOLS: SAR245408 (FORMERLY XL-
147) AND SAR245409 (FORMERLY XL-765)...............................................................................92 
 


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3 
LIST OF ABBREVIATIONS 
 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESI: 
adverse event of special interest  
ALT: 
Alanine aminotransferase 
API: 
active product ingredient  
aPTT: 
activated  partial thromboplastin time 
ASCO: 
American Society of Clinical Oncology  
AST: 
aspartate aminotransferase 
BSA: 
body surface area 
CLL: 
chronic lymphocytic leukemia 
CR: 
complete response/remission 
CRF: 
case report form  
CV: 
curriculum vitae 
DR: 
duration of response 
DRESS: 
drug reaction with eosinophilia and systemic symptoms 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram  
ECOG: 
Eastern Cooperative Oncology Group 
GCP: 
Good Clinical Practice  
HLGT: 
high group level term 
HLT: 
high level term 
IB: 
investigator's brochure 
ILD: 
interstitial lung disease 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee 
IV: 
intravenous 
MedDRA: 
Medical Dictionary for Regulatory Activities  
MTD: 
maximum tolerated dose 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR: 
objective response rate 
OS: 
overall survival 
PD: 
progressive disease 
PFS: 
progression free survival 
PR: 
partial response/remission 
PT: 
preferred term  
PT/INR: 
prothrombin time/international normalized ratio  
RDI: 
relative dose intensity 
 


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SAE: 
serious adverse event 
SJS: 
Stevens-Johnson syndrome 
SLL: 
small lymphocytic leukemia 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
TEN: 
toxic epidermal necrolysis  
 
 


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4 
INTRODUCTION AND RATIONALE 
This open-label, international, multicenter, treatment-extension study will enable cancer patients who 
are currently receiving benefit from either SAR245408, formerly known as XL147, or SAR245409, 
formerly known as XL765, as a monotherapy or as part of a combination regimen in a Phase 1 or 
Phase 2 study to continue receiving treatment and further assess safety and tolerability of SAR245408 
and SAR245409. 
4.1 
INTRODUCTION 
SAR245408 is an oral, potent and selective inhibitor of PI3K (phosphatidylinositol 3-kinase). 
SAR245409 is an oral, potent ATP-competitive inhibitor of PI3K which also inhibits mTOR.  
More detailed information is provided in the latest version of the Investigator Brochures (IBs) for 
SAR245408 and SAR245409. 
4.2 
RATIONALE 
4.2.1 Study rationale 
This study is designed to provide continued access to either SAR245408 or SAR245409, as a 
monotherapy, or as part of a combination regimen with a commercially available drug(s), to subjects 
enrolled in a sanofi-aventis sponsored Phase 1 or Phase 2 study of SAR245408 or SAR245409 who 
have complete data collection for the primary endpoint(s) of the parental study or who are being 
treated beyond the parental study cut-off date, and who are receiving benefit from the study 
treatment.  
The primary objective of the study is to collect safety data on subjects who are benefiting from 
continued treatment. Safety assessments and the occurrence of adverse events (AEs) will be evaluated 
according to the study flow chart (see Section 1.2) and per standard of care if the subject is on a 
combination regimen.  
4.2.2 Design rationale and risk assessment 
This is a treatment-extension study which will be conducted as an open label, international, multi-
institutional study. SAR245408 or SAR245409 will be given at a fixed dose as a monotherapy or in 
combination regimen. If in the Investigator’s opinion a subject has maximally benefited from the 
combination regimen the subject may continue on SAR245408 or SAR245409 only. 
 


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The study is designed to collect long-term safety data on subjects who are benefiting from treatment 
with either SAR245408 or SAR245409. 
4.2.3 Safety parameters rationale 
4.2.3.1 SAR245408 treatment 
As of June 2011, for 220 evaluable subjects who took SAR245408 as a single agent or in a 
combination regimen, regardless of relatedness to SAR245408, the most common side effects 
reported in ≥10% of subjects have been gastrointestinal related (such as nausea, diarrhea, vomiting, 
and constipation); constitutional (such as decreased appetite, fatigue, and asthenia); or an increase in 
both aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Transaminase elevations 
have been Grade 1 or Grade 2, with the exception of a Grade 3 transaminase increase, which was not 
accompanied by increase in bilirubin, observed in a subject treated with SAR245408 in combination 
with letrozole. The transaminase elevation resolved after SAR245408 was discontinued. Overall, 
approximately 36% of subjects developed rash (including erythematous, macular, pustular, and 
acneiform), approximately 25% developed dyspnea and cough, approximately 18% reported anemia. 
Neutropenia was noted in approximately 76% of subjects treated in combination with cytotoxic 
chemotherapy. 
Grade 3 or 4 events assessed by Investigators as related to SAR245408 were diarrhea, peripheral 
oedema, rash and hyperglycemia. Three subjects have experienced a Grade 3 hypersensitivity 
reaction; each of which resolved with medical intervention and after holding study drug. In addition, 
1 subject with adenoid cystic carcinoma of the lung who previously had a pneumonectomy enrolled 
on study TED11434 (XL147-002) (erlotinib-SAR245408 combination) and developed rash with 
eosinophilia; edema of the face, shoulders, and legs; and increasing dyspnea. The patient 
subsequently died. An autopsy showed widespread carcinomatosis in the remaining lung. The cause 
of death was considered to be malignant neoplasm progression and drug reaction with eosinophilia 
and systemic symptoms (DRESS). Two serious adverse events (SAEs) of pneumonitis possibly 
related to SAR245408 have been reported, one Grade 2 in combination with trastuzumab and 
paclitaxel and one Grade 4 in combination with letrozole; the second patient subsequently died of 
suspected drug-induced pulmonary toxicity. 
Study subjects receiving SAR245408 should be closely monitored for: 
• presence of skin rash and DRESS syndrome; 
• liver function abnormalities: AST and ALT, bilirubin elevation; 
• signs of pneumonitis, eg, dyspnea, cough. 
 


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4.2.3.2 SAR245409 treatment 
As of June 2011, for 175 evaluable subjects who took SAR245409 as a single agent or in 
combination with other regimens the most common AEs, regardless of relatedness to SAR245409, 
reported in ≥10% of subjects across all SAR245409 studies have been gastrointestinal related (such 
as nausea, diarrhea, vomiting, and constipation); constitutional (such as decreased appetite, fatigue, 
and asthenia); transaminase elevations (elevations in both AST and ALT have been reported); as well 
as rash, headache, cough, and abdominal pain. The majority of transaminase elevations have been 
Grade 1 or Grade 2, asymptomatic, and not accompanied by a significant drug related increase in 
bilirubin of Grade ≥1. All elevations related to SAR245409 resolved with SAR245409 withdrawal or 
interruption. Various kinds of rash have been reported with SAR245409, including 1 subject 
receiving SAR245409 (70 mg once daily) and erlotinib who had a Grade 3 DRESS syndrome, which 
resolved with drug discontinuation and supportive care, including intravenous steroid treatments 
followed by oral and topical steroids. 
Periodic ophthalmologic exams are currently being performed on SAR245409 studies due to the 
preclinical observation of focal cataracts in two rats dosed orally with SAR245409 for 180 
consecutive days (1 male dosed at 3 mg/kg twice daily and 1 female dosed at 10 mg/kg twice daily). 
Study subjects receiving SAR245409 should be closely monitored for: 
• presence of skin rash and DRESS syndrome; 
• liver function abnormalities: AST and ALT, bilirubin elevation. 
 


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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To determine the long-term safety and tolerability of SAR245408 and SAR245409 as a monotherapy 
or as part of a combination regimen in subjects who are benefiting from treatment. 
5.2 
SECONDARY 
Not applicable. 
 


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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This open-label, international, multicenter, nonrandomized study is designed to provide continued 
access to SAR245408 or SAR245409, as a monotherapy or as part of a combination regimen, to 
subjects who are receiving benefit from the study treatment. 
All subjects in the study will continue on the Investigational Medicinal Product (IMP) (SAR245408 
or SAR245409) and combination medication(s) (for subjects taking combination therapy) they 
received during the parental study. The SAR245408 or SAR245409 dose will be either the 
recommended Phase 2 dose (400 mg SAR245408 [tablet formulation polymorph A] once a day every 
day or 50 mg SAR245409 [capsule formulation] twice a day every day) or the subject’s established 
dose and formulation either as a monotherapy or in a combination regimen in the parental study.  
When the supply of SAR245408 (form A) hard capsules and SAR245408 (form A) tablets is 
depleted, ongoing patients will be offered SAR245408 (form E) film-coated tablets in order to 
continue treatment (see Section 8.1.1).    
When the sponsor has discontinued manufacture of the SAR245409A 10 mg hard capsule strength, 
ongoing patients who are receiving a dose lower than 30 mg may continue treatment at a comparable 
dose level in consultation with the sponsor.  Patients receiving dose levels ≥30 to ≤ 100 mg (with 10 
mg dose intervals) are not affected by discontinuation of the 10 mg capsule strength (see Section 
8.1.2).     
If in the Investigator’s opinion, the subject has maximally benefited from the combination therapy in 
the parental study, the subject may continue on SAR245408 or SAR245409 as a monotherapy in this 
study. For all subjects, dose, regimen, formulation, and food condition for study drug intake of 
SAR245408 or SAR245409 (and dose and regimen of combination medication(s) for subjects taking 
combination therapy) will be agreed on in writing between the site and the Sponsor prior to first dose. 
Subjects who received SAR245408 or SAR245409 for less than 2 cycles in the parental study will 
enter the treatment-extension study on Day 1 of the initiation period; subjects who received 
SAR245408 or SAR245409 for at least 2 cycles in the parental study will enter the treatment-
extension study on Day 1 of the extension period. Subjects who will take a SAR245408 or 
SAR245409 daily dose higher than their established dose of SAR245408 or SAR245409, 
respectively, in the parental study will enter the treatment-extension study on Day 1 of the initiation 
period. Subjects who had dose interrupted in the parental study but fulfill parental protocol criteria to 
restart IMP treatment and subjects who fulfill the parental study criteria for IMP treatment 
continuation but  have ongoing Grade 2 AE(s) will start the treatment-extension study on Day 1 of 
the initiation period. 
 


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Subjects may continue in the study until disease progression, unacceptable toxicity, withdrawal of 
consent, until commercial supplies of SAR245408 or SAR245409 are available to them outside of the 
clinical trial, or other reasons detailed in Section 22). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each subject 
The duration of the study for an individual subject will include:  
• Baseline assessments: within 7 days prior to the first dose of IMP. 
• Study treatment period(s): 
Subjects will start study treatment at the beginning of the initiation or extension periods based on 
the length of prior therapy with SAR245408 or SAR245409 (see Section 1.1):  
- 
if <2 cycles, start with initiation period; subjects must complete all the visits in the 
initiation period before moving to the extension period. 
- 
if ≥2 cycles, start with extension period; duration of extension period is unlimited. 
- 
subjects who will take a SAR245408 or SAR245409 daily dose higher than their 
established dose of SAR245408 or SAR245409, respectively, in the parental study will 
enter the study on Day 1 of the initiation period. 
- 
subjects who had dose interrupted in the parental study but fulfill parental protocol criteria 
to restart IMP treatment will enter the treatment-extension study on Day 1 of the initiation 
period. 
- 
subjects who fulfill the parental study criteria for IMP treatment continuation but  have 
ongoing  Grade 2 AE(s) will enter the treatment-extension study on Day 1 of the initiation 
period.   
Subjects may continue to receive study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or until commercial supplies of SAR245408 or SAR245409 are available 
to them outside of the clinical trial (see Section 8.1.2.3). 
• Follow-up assessments: 23 to 37 days after the last dose of IMP. 
6.2.2 Determination of end of clinical trial (all subjects) 
The end of clinical trial will occur when all subjects have completed their last follow up visit as 
defined in Section 12.1.3. 
 


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6.3 
INTERIM ANALYSIS 
Not applicable. 
6.4 
STUDY COMMITTEES 
Safety reviews of the IMPs will be conducted at least quarterly by the designated sanofi-aventis team 
members under the lead of the Global Safety Officer. It is the responsibility of the Sponsor Safety 
Committee to review all available safety data (AEs and SAEs) from ongoing clinical trials in order to 
assess and monitor evolving safety trends, evaluate potential changes to clinical trial protocols based 
on safety analysis, and, ultimately, to safeguard subject safety. Additional ad hoc meetings will 
convene as required to address specific safety concerns. 
 


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7 
SELECTION OF SUBJECTS 
7.1 
NUMBER OF SUBJECTS PLANNED 
The number of subjects in this study will depend on the number of subjects who will continue 
receiving treatment from the parental studies. It is expected that approximately 100 to 150 subjects 
will be treated in this study. 
7.2 
INCLUSION CRITERIA 
I 01. Males or females enrolled in Phase 1 or Phase 2 studies of SAR245408 or SAR245409 as 
monotherapy or in combination with other regimens who have complete data collection for the 
primary endpoint(s) of the parental study or who are being treated beyond the parental study 
cut-off and meet all the criteria to continue to be treated per the parental protocol. 
I 02. All sexually active subjects (male and female) must agree to continue to use accepted methods 
of barrier contraception (ie, condoms) during the course of the study and for 3 months after 
discontinuation of study treatment. For women of childbearing potential and for men who can 
father a child, a second method of contraception in addition to a barrier method is 
recommended. Hormonal contraception should be avoided in subjects taking SAR245408 due 
to possible drug-drug interaction. 
I 03. Female subjects of childbearing potential must have a negative pregnancy test at baseline. 
Females of childbearing potential are defined as sexually mature women without prior 
hysterectomy or who have had any evidence of menses in the past 12 months. However, 
women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to other causes, including prior 
chemotherapy, anti-estrogens, or ovarian suppression. 
I 04. The subject is capable of understanding and complying with the protocol requirements and has 
signed the informed consent document. 
7.3 
EXCLUSION CRITERIA 
E 01. The subject discontinued the parental study due to toxicity.  
E 02. Ongoing Grade 3 or higher AE. 
E 03. Ongoing SAE. 
 


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E 04.  Subject with ongoing dose interruption for any reason unless the subject fulfills the criteria in 
the parental protocol for restarting IMP. In such case subject will start the treatment-extension 
study on Day 1 of the initiation period. 
E 05. The subject has a ≥ Grade 3 of any of the laboratory values: 
- 
Absolute neutrophil count (ANC),  
- 
Platelet count, 
- 
Hemoglobin, Bilirubin,  
- 
Serum creatinine, or calculated creatinine clearance, Alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST),  
- 
Fasting plasma glucose,  
- 
Prothrombin time/international normalized ratio (PT/INR) and activated partial 
thromboplastin time (aPTT). 
E 06. The subject has a baseline corrected QT interval (QTc)  >481 msec or if a subject has had a 
QTc interval increase of ≥60 msec from parental protocol baseline to an absolute value of 
>470 msec. 
E 07. The subject has a known allergy or hypersensitivity to components of the study treatment 
formulation(s). 
E 08. The subject is pregnant or breastfeeding. 
 


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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
8.1.1 SAR245408 
8.1.1.1 Pharmaceutical form 
SAR245408 capsules and tablets are used in parental studies and may be used in this study:  
• SAR245408 (form A) hard capsules: powder-in-capsule formulation supplied at strengths of 
25 and 100 mg of drug substance free base form A in size 0 hard gelatin capsules. The 
formulation contains no excipients other than the hard gelatin capsule. Each strength is 
presented in a different capsule color. 
• SAR245408 (form A) tablets: immediate-release tablet formulation with 50 % w/w API load, 
supplied at strengths of 50, 100, 150, and 200 mg of drug substance SAR245408 (form A)  
free base . Each strength will be presented in a different tablet shape and/or size. 
• SAR245408 (form E) film-coated tablets: Immediate-release film-coated tablet with 50% w/w  
drug substance load, supplied at strength of 50 mg or 200 mg (based on the amount of drug 
substance SAR245408 (form E) free base). 
Rationale to transition from SAR245408 (form A) hard capsules and (form A) tablets to 
SAR245408 (form E) film-coated tablets 
When the supply of SAR245408 (form A) hard capsules and SAR245408 (form A) tablets is 
depleted, ongoing subjects will be offered SAR245408 (form E) film-coated tablets in order to 
continue treatment.    
The SAR245408 drug substance used for initial phase 1 and 2 clinical studies, was a single anhydrous 
polymorph (form A). A new anhydrous polymorph (form E) of SAR245408 drug substance was later 
evidenced in development. The form E is thermodynamically more stable than form A. It was 
therefore decided to pursue the SAR245408 development with the drug substance (form E). The drug 
substance (form E) is additionally micronized in order to reach a similar particle size distribution as 
drug substance (form A) previously used in the first clinical studies. 
In order for subjects to continue treatment, it is necessary to transition from drug substance (form A) 
to drug substance (form E).  Subjects must be informed of this new information, have the opportunity 
to discuss the transition and alternative treatment options with the Investigator, and document their 
consent to transition to a new formulation via an updated IRB/IEC approved informed consent.     
 


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Transition from SAR245408 (form A) hard capsule to SAR245408 (form A tablet)  
Two completed SAR245408 studies provide data to support the transition from SAR245408 (form A) 
hard capsule to (form A) tablet  
1. Study TED11433 (NCT00486135): SAR245408 (form A) hard capsule vs. (form A) tablet  
Study TED11433 (NCT00486135) evaluated the SAR245408 (form A) hard capsule using either an 
intermittent (21 days on, 7 days off) or continuous daily dosing (CDD) treatment schedule.  In 
patients with solid tumors (n=69), dose-limiting toxicities were maculopapular rash and 
hypersensitivity reaction.  Of note, skin reactions are an expected toxicity for SAR245408 and for 
PI3K inhibitors as a class.  The maximum tolerated dose for the SAR245408 (form A) hard capsule 
was 600 mg QD for both schedules.  The recommended phase 2 dose for the SAR245408 (form A) 
hard capsule was 600 mg administered on a CDD schedule(1).    
Study TED11433 also included a cohort of patients with B-cell malignancies (n=25) treated with 600 
mg QD SAR245408 (form A) hard capsules.  One DLT (grade 3 rash) was reported.  The PK profile 
of SAR245408 in this cohort was consistent with the solid tumor cohort who received 600 mg (form 
A) hard capsules once daily. 
An additional 22 patients with advanced solid tumors received SAR245408 (form A) tablets at doses 
ranging from 100 to 600 mg QD.  No dose-limiting toxicities were reported.  The recommended 
phase 2 dose for SAR245408 (form A) tablet administered on the CDD schedule was determined to 
be 400 mg based on the PK exposure at this dose, which was similar to the exposure achieved with 
600 mg (form A) hard capsule.  
1. Study ARD11437 (NCT01082068): SAR245408 (form A) tablet  
Study ARD11437 (NCT01082068), a phase 1/2 trial of patients with hormone receptor positive breast 
cancer, further evaluated the 400 mg (form A) tablet in combination with letrozole with a CDD 
schedule.  Thirty-one (31) of 37 patients enrolled to receive SAR245408 were treated with the 400 
mg (form A) tablet with 2.5 mg letrozole.  In the Phase 1 portion of the study, one DLT, serious grade 
3 drug reaction with eosinophilia and systemic symptoms, was reported among the 6 patients enrolled 
at 400 mg QD.  In the Phase 2 portion (n=25), 1 patient had pneumonitis approximately 1 month after 
the last dose of study drug.  The event was considered possibly related to study drug and resulted in 
the patient’s death approximately 4 months after discontinuing study treatment 
Transition from SAR245408 (form A) tablet to (form E) film-coated tablet  
Two studies (1 completed [BDR12246] and 1 ongoing [TED12863 (NCT01943838)] provide data to 
support the formulation transition from SAR245408 (form A) tablet to (form E) film-coated tablet.    
1. Study BDR12246: Bioavailability of SAR245408 (form A) tablet vs. SAR245408 (form E) 
film-coated tablet  
 


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Results of a single (reduced) dose (50 mg) relative bioavailability study in healthy male patients 
indicate the bioavailability of SAR245408 (form E) film-coated tablets relative to SAR245408 (form 
A) tablets administered as a 50-mg tablet in the fasted state was generally lower based on the point 
estimates for Cmax, AUClast, AUC0-120, and AUC geometric mean ratios, with a decrease in the point 
estimates in the range of 15% to 22%.  A moderate fat meal did not appear to have an appreciable 
impact on the exposure of SAR245408 (form E).    
2. Study TED12863 (NCT01943838): SAR245408 (form E) film-coated tablet  
Sanofi is currently testing the safety, tolerability and pharmacokinetics of SAR245408 (form E) film-
coated tablets in a phase 1 dose escalation study in patients with solid tumors or lymphomas. Among 
the first 6 patients enrolled to receive 400 mg QD SAR245408 (form E) film-coated tablets, no dose 
limiting toxicities were observed.  Two patients experienced grade 2 rash assessed as related to study 
treatment.  In both cases, rash was managed with topical steroid treatment. The exposure of 400 mg 
(form E) film-coated tablets was similar when compared with 400 mg (form A) tablets, as well as 
with 600 mg (form A) hard capsules on C1D1 and C1D28 or C2D1.  High inter-patient variability 
was observed and consistent with data from (form A) hard capsules and (form A) tablets in the above 
mentioned Study TED11433. Based on the absence of DLTs in the 400 mg cohort, patients are now 
being enrolled to receive (form E) film coated tablets at 600 mg QD. Based on these clinical data, the 
SAR245408 400 mg (form E) film-coated tablet is considered as a safe dose with comparable 
exposure to the 400 mg (form A) tablet. 
8.1.1.2 Dose preparation and administration 
Subjects will take 400 mg SAR245408 (tablet formulation polymorph A) once a day every day (ie, 
the recommended SAR245408 Phase 2 dose and regimen). Subjects who are receiving in the parental 
study an established dose of SAR245408 (tablet polymorph A or E) different from 400 mg (tablet 
polymorph A) may continue on the established dose. Subjects who will take a SAR245408 daily dose 
higher than their established dose of SAR245408 in the parental study and subjects who had dose 
interrupted in the parental study but fulfill parental protocol criteria to restart IMP treatment will 
enter the study on Day 1 of the initiation period.  
The recommendations for transition of SAR245408 formulation are (see Table 1): 
• 
Patients taking SAR245408 (form A) hard capsules at a dose level of 400 mg QD transition to 
200 mg (form A) tablets (as supply permits) or 200 mg (form E) film-coated tablets  
• 
Patients taking SAR245408 (form A) hard capsules at a dose level of 600 mg QD transition to 
a dose level of 400 mg using 200 mg (form A) tablets (as supply permits) or 200 mg (form E) 
film-coated tablets 
• 
Patients taking SAR245408 (form A) tablets transition to the same dose with SAR245408 
(form E) film-coated tablets 
 


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Table 1 - Recommendations for Transition of SAR245408 Formulation 
Current 
Formulation 
Current Daily 
Dose 
New Formulation 
New Daily Dose 
Form A hard capsule 
400mg* 
Form E  tablet 
200mg 
Form A hard capsule 
600mg* 
Form E  tablet 
400mg 
Form A tablet 
Any 
Form E  tablet 
Same dose as Form A tablet 
*For patients taking any other dose of the Form A hard capsule, consult sponsor for recommended daily dose 
for the Form E tablet. 
For all subjects, the dose, regimen, and formulation of SAR245408 should be agreed on in writing 
between the site and the Sponsor prior to first dose and should not exceed the maximum tolerated 
dose (MTD) for the parental study. The number of capsules or tablets and strength will vary 
depending on the dose level assignment. SAR245408 dose may be modified for toxicity as described 
in Section 8.3.  
The guidelines for treatment delay or dose modification provided in Section 8.3 are applicable 
regardless of formulation.   SAR245408 doses should be taken at approximately the same time each 
day with a full glass (8 fluid ounces or 240 mL) of water. If a dose is missed, the missed dose can be 
taken up to 12 hours after the normal dosing time, but subjects must be instructed not to make up 
missed doses of SAR245408 outside of the 12 hour allowable time window. Subjects treated with 
SAR245408 (form A) tablets must fast for 2 hours before and for 1 hour after each dose. Extra doses 
should not be taken if the subject vomits after taking SAR245408. For subjects treated with 
SAR245408 (form E) film-coated tablets, the administration of the IMP with food is allowed as per 
their parental protocol, ie, with the morning meal with a full glass of noncarbonated water.  
Doses will be administered at the study site at specific protocol-defined visits. Subjects will be 
provided with a sufficient supply of SAR245408 and instructions for self-administration at home on 
all other study days. For SAR245408 doses taken at home, the subject will record precisely the date 
and time of self-administration on the provided diary. 
8.1.1.3 Duration of treatment 
Subjects may continue to receive study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or until commercial supplies of SAR245408 are available to them outside of 
the clinical trial or other reasons detailed in Section 22).   
Note: subjects who are experiencing tumor shrinkage in response to study treatment but who have 
disease progression limited to the CNS may receive local radiation therapy (if needed) and remain on 
study treatment with the permission of the Sponsor. 
 


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8.1.2 SAR245409 
8.1.2.1 Pharmaceutical form 
SAR245409 capsules and tablets are used in parental studies and may be used in this study: 
• SAR245409A hard capsules: powder-in-capsule formulation supplied at strengths of 10, 30, 
40, and 50 mg of drug substance HCl salt in size 0 hard gelatin capsules. The formulation 
contains no excipients other than the hard gelatin capsule. Each strength will be presented in a 
different capsule color. 
• SAR245409 film-coated tablets: immediate-release film-coated tablet formulation with 20% 
w/w drug substance load, supplied at strengths of 20 and 30 mg of API free base form 1. Each 
strength will be presented in a different size and embossing. 
When the supply of SAR245409A 10 mg hard capsules is depleted, ongoing patients whose dose has 
included the 10 mg capsule strength will be offered continuation of treatment at a comparable dose 
level with a revised schedule in consultation with the sponsor.  For example, patients unable to 
tolerate 30 mg capsules BID may be permitted to take 30 mg capsules QD.  Treatment will be 
discontinued for patients who cannot tolerate 30 mg capsules QD. 
The current supply of strengths covers treatment from 30 mg to 100 mg in 10 mg increments. Only 
patients receiving a capsule dose below 30 mg will be affected.  
8.1.2.2 Dose preparation and administration 
Subjects will take 50 mg SAR245409 (capsule formulation) twice a day every day (ie, the 
recommended SAR245409 Phase 2 dose and regimen). Subjects who are receiving in the parental 
study an established dose of SAR245409 different from 50 mg (capsule formulation), including once 
daily dosing of SAR245409, may continue on the established dose and regimen. Subjects who will 
take a SAR245409 daily dose higher than their established dose of SAR245409 in the parental study 
and subjects who had dose interrupted in the parental study but fulfill parental protocol criteria to 
restart IMP treatment or who have ongoing Grade 2 AE (s) will enter the treatment-extension study 
on Day 1 of the initiation period.   
For all subjects, the dose, regimen, and formulation of SAR245409 should be agreed on in writing 
between the site and the Sponsor prior to first dose and should not exceed the MTD for the parental 
study. The number of capsules or tablets and strength will vary depending on the dose level 
assignment. As indicated above, when the supply of SAR245409A 10mg hard capsules is depleted, 
ongoing patients impacted will be offered continuation of treatment at a comparable dose regimen in 
consultation with the sponsor.  SAR245409 dose may be modified for toxicity as described in Section 
8.3. 
 


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SAR245409 doses should be taken at approximately the same times each day with a full glass (8 fluid 
ounces or 240 mL) of water, allowing a 12-hour (± 2 hours) interval between morning and evening 
doses. If a dose is missed, the missed dose can be taken up to 4 hours after the normal dosing time, 
but subjects must be instructed not to make up missed doses of SAR245409 outside of the 4 hour 
allowable time window. Subjects must fast for 2 hours before and for 1 hour after each dose. Extra 
doses should not be taken if the subject vomits after taking SAR245409. 
Doses will be administered at the study site at specific protocol-defined visits. Subjects will be 
provided with a sufficient supply of SAR245409 and instructions for self-administration at home on 
all other study days. For SAR245409 doses taken at home, the subject will record precisely the date 
and time of self-administration on the provided diary. 
8.1.2.3 Duration of treatment 
Subjects may continue to receive study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or until commercial supplies of SAR245409 are available to them outside of 
the clinical trial or other reasons detailed in Section 22).   
Note: Subjects who are experiencing tumor shrinkage in response to study treatment but who have 
disease progression limited to the CNS may receive local radiation therapy (if needed) and remain on 
study treatment with the permission of the Sponsor.  
8.2 
COMBINATION MEDICATIONS 
This study is designed to provide continued access to either SAR245408 or SAR245409 as a 
monotherapy, or SAR245408 or SAR245409 as part of a combination regimen with a commercially 
available drug(s). Only the combination regimen from the parental study is allowed in this study. The 
dose and regimen of the combination medication(s) should be agreed on in writing between the site 
and the Sponsor prior to first dose. 
Depending on the parental study, the following drugs may be used in combination with SAR245408: 
• paclitaxel and carboplatin  
• letrozole  
• trastuzumab ±  paclitaxel  
Depending on the parental study, the following drugs may be used in combination with SAR245409: 
• letrozole 
• temozolomide 
• rituximab  
 


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• bendamustine and rituximab  
Commercially available drugs will be used as combination medications with SAR245408 or 
SAR245409. For details on description, preparation, administration, and precautions for use for 
combination medications, please refer to package insert or summary of product characteristics. 
8.3 
TREATMENT DELAY OR DOSE MODIFICATIONS 
Subjects will be monitored for AEs while on-study and will be instructed to notify their physician as 
soon as possible at the sign of any new or worsening AEs. As a general approach, it is suggested that 
all AEs be treated with supportive care when possible at the earliest signs of toxicity. 
Subjects experiencing one or more AEs due to the study treatment may require dosing interruptions 
or reductions in their IMP doses in order to continue with study treatment.  
Guidelines for the management of AEs and SAR245408 and SAR245409 dose modifications (ie, 
dose interruptions and dose reductions) are presented in details in Section 8.3.1 and Section 8.3.2. 
Commercially available drug(s) given in combination with SAR245408 or SAR245409 should be 
managed according to the product label and standard of care. 
For SAR245408, each dose reduction should be at least ≥25% of the current dose. For a subject dosed 
at 400 mg, first dose reduction will be 300 mg and second 200 mg. A subject requiring more than 
2 dose reductions of SAR245408 - considering both the parental study and the treatment-extension 
study - (or less than 100 mg SAR245408), or if SAR245408 is held for more than 6 weeks due to an 
AE, should be permanently discontinued from study treatment. 
For SAR245409, each dose reduction should be at least 10 mg below the current dose. For a subject 
dosed at 50 mg twice a day, first dose reduction will be 30 mg twice a day and second 20 mg twice a 
day. When the supply of SAR245409A 10mg hard capsules is depleted, patients requiring dose 
reduction below 30 mg will be offered continuation of treatment at a reduced dose and/or schedule in 
consultation with the sponsor.  A subject requiring more than 2 dose reductions of SAR245409 - 
considering both the parental study and the treatment-extension study - (or less than 20 mg 
SAR245409), or if SAR245409 is held for more than 21 days due to an AE, should be permanently 
discontinued from study treatment. 
All dose reductions should be discussed with the Sponsor.  
Once a subject’s dose has been reduced, the dose may be re-escalated 1 dose level if the toxicity that 
led to the dose reduction was Grade ≤3 and does not reoccur after the subject has been treated at the 
reduced dose level for at least 4 weeks. Additional safety monitoring should be implemented upon 
dose re-escalation. 
 


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However, dose re-escalation is not allowed for subjects remaining on study treatment after 
experiencing a Grade 4 AE, regardless of causality, and is only allowed one time for any specific AE 
(Grade ≤3) that led to a dose reduction. 
No dose re-escalation will be permitted for SAR245409 if the dose was reduced for 
transaminase elevations. 
8.3.1 General guidelines for the management of non-hematologic and hematologic adverse 
events 
General guidelines for the management of non-hematologic and hematologic toxicities are provided 
in Table 2 and Table 3, respectively.  
For more specific guidelines on AEs including skin, pulmonary, hepatobiliary, and gastrointestinal 
disorders, hyperglycemia, and QT interval prolongation, refer to 
Section 8.3.2 . 
Table 2 - Management guidelines for non-hematologic adverse events 
CTCAE v4.03 Grade 
Guidelines / Intervention 
Grade 1: 
No dose adjustments. 
Grade 2: 
 
Grade 2 AEs that are subjectively 
tolerable 
Continue SAR245408/SAR245409 at the current dose levels.  
Grade 2 AEs subjectively 
intolerable, or an AE deemed 
unacceptable in the Investigator’s 
judgment 
Interrupt SAR245408/SAR245409 until the AE resolves to Grade ≤1 or baseline. Upon 
recovery, resume SAR245408/SAR245409 at the same dose or at a reduced dose as 
clinically indicated. If the dose is not reduced after the first occurrence, a dose reduction 
must be implemented after a second recurrence. All SAR245408/SAR245409-related 
transaminase elevations require dose reduction. 
Grade 3: 
 
Grade 3 AEs without optimal 
prophylaxis or are easily managed 
with or without medical 
intervention 
Interrupt SAR245408/SAR245409 until the AE resolves to Grade ≤1 or baseline. Upon 
recovery, resume SAR245408/SAR245409 at the same dose or at a reduced dose as 
clinically indicated. If the dose is not reduced after the first occurrence, a dose reduction 
must be implemented after a second recurrence. 
Grade 3 AEs despite optimal 
prophylaxis or are not easily 
managed  
Interrupt SAR245408/SAR245409 until recovery to Grade ≤1 or baseline, and resume 
SAR245408/SAR245409 with 1 dose reduction  
Grade 4: 
Discontinue SAR245408/SAR245409 permanently unless determined by the Investigator 
and agreed to by the Sponsor that the subject is deriving clinical benefit. In this case, 
the subject may be re-treated at a reduced dose that is agreed upon by the Investigator 
and the Sponsor once the AE resolves to Grade ≤1. 
AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events. 
 


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The following guidelines for hematologic AEs apply for subjects with solid tumors and subjects with 
lymphoma (except chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL)) without 
bone marrow involvement who are not receiving concurrent cytotoxic chemotherapy in combination 
and who had baseline blood count values for neutrophils and platelets of Grade ≤1 (Table 3).  
Table 3 - Management guidelines for hematologic adverse events 
Adverse event (CTCAE v4.03 grading) 
Guidance 
Grade ≥3 neutropenia or 
Grade 3 thrombocytopenia associated with clinically 
significant bleeding or 
Grade 4 thrombocytopenia 
Interrupt SAR245408/SAR245409 until resolution to Grade ≤2, and 
resume SAR245408/SAR245409 at 1 dose level lower. 
Grade 3 febrile neutropenia 
Interrupt SAR245408/SAR245409 until recovery of ANC to Grade ≤1 
and temperature to ≤38°C, and resume SAR245408/SAR245409 at 1 
dose level lower. 
Grade 4 febrile neutropenia  
Discontinue SAR245408/SAR245409. 
All other clinically significant Grade 4 hematologic AEs 
Interrupt SAR245408/SAR245409 until resolution to Grade ≤2, and 
resume SAR245408/SAR245409 at 1 dose level lower, as agreed to by 
the Investigator and the Sponsor. 
AE(s) = adverse event(s); ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events. 
The following guidelines for hematologic AEs apply for subjects who are receiving concurrent 
cytotoxic chemotherapy in combination: 
• Treatment with SAR245408/SAR245409 may continue.  
• Chemotherapy agents should be delayed, interrupted or reduced and supportive care should be 
provided according to product label and standard of care. 
The following guidelines for hematologic AEs apply for subjects with CLL/SLL, and subjects with 
compromised bone marrow function (baseline blood count values for neutrophils and platelets of 
Grade ≥2): 
• 
Interrupt SAR245408/SAR245409 as clinically indicated. The Sponsor must be notified of the 
dose interruption.  
- 
If the subject does not recover from the hematologic AEs to baseline values within 6 
weeks for SAR245408 treatment and within 21 days for SAR245409 treatment, the 
subject should be discontinued from SAR245408/SAR245409.  
- 
If the subject recovers from the hematologic AEs to baseline values, 
SAR245408/SAR245409 can be resumed with or without a dose reduction, as agreed to 
by the Investigator and the Sponsor. 
 


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8.3.2 Specific guidelines for the management of adverse events 
8.3.2.1 Skin disorders 
Prophylactic skin care recommendations for all subjects include sunscreen with SPF ≥30, 
hypoallergenic moisturizing products for dry skin, and gentle skin care with fragrance-free soaps and 
detergents. 
Subjects must contact the Investigator immediately if they develop a new rash or have worsening of 
an existing rash while on study. A complete blood count with differential and serum chemistry that 
includes liver function tests should be obtained, and subjects should be evaluated for any associated 
systemic involvement (cardiac, hepatic, pulmonary, or renal) at least weekly with either new onset or 
worsening of existing rash.  
It is recommended that a dermatologist be involved in subject management, especially for severe or 
life-threatening rash. A skin biopsy for histopathological diagnosis is strongly encouraged, and serial 
digital photographs are recommended (photography guidelines in the study manual).  Photographs 
and biopsy results should be sent to the Sponsor and/or designee. Biopsy samples should be made 
available to the Sponsor and/or designee for additional evaluation upon request. 
Permanent discontinuation of study treatment (SAR245408 or SAR245409) will be required for 
subjects who develop a Grade 4 skin AE, Stevens-Johnson syndrome (SJS), or toxic epidermal 
necrolysis (TEN). Additionally, permanent discontinuation of study treatment is required for subjects 
with study treatment-related skin rash associated with: 
• Grade 3 systemic organ (cardiac, hepatic, pulmonary, or renal) dysfunction (with or without 
eosinophilia)  
• Any of the following symptoms of an allergic/hypersensitivity reaction:  
- 
Any grade anaphylaxis, angioedema, or bronchospasm; 
- 
Grade 2 or greater urticaria (urticarial lesions covering ≥10% of the body surface area 
(BSA), or oral or intravenous (IV) intervention indicated);  
- 
Grade 3 or greater hypotension (hypotension for which urgent medical intervention or 
hospitalization is indicated, or is life threatening). 
Note: rash with associated eosinophilia but without associated systemic symptoms is not an absolute 
indication to permanently discontinue study treatment. Discussion with the Sponsor is recommended 
in these cases. 
For study treatment-related skin AEs not meeting the above criteria for permanent discontinuation of 
study treatment, the following guidelines must be followed regarding dosing of 
SAR245408/SAR245409): 
 


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• Please refer to Table 4 for management guidelines for macular or papular rash, pruritus, dry 
skin, and palmar-plantar erythrodysesthesia syndrome;  
• The general guidelines for other skin AEs are the following: 
- 
Grade 1 or tolerable Grade 2 events: SAR245408/SAR245409 may be continued at the 
current dose with symptomatic treatment based on the specific type of AE. Reassess at 
least weekly; if skin reactions worsen at any time or do not improve with 2 weeks of 
symptomatic treatment, proceed to the guidelines for the next grade events. 
- 
Intolerable Grade 2 or Grade 3 events: SAR245408/SAR245409 must be held, with 
treatment of symptoms based on the specific type of AE. Reassess at least weekly; if skin 
reactions do not improve with 2 weeks of symptomatic treatment, permanently 
discontinue the subject from study treatment. Resume SAR245408/SAR245409 at a 
reduced dose if the reaction recovers to Grade ≤1. Permanently discontinue the subject 
from study treatment if intolerable Grade 2 or Grade 3 reaction recurs at a reduced dose. 
For any subject with a rash, obtain bacterial and/or viral cultures if infection is suspected. 
 


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Table 4 - Treatment guidelines for specific skin adverse events 
CTCAE 
(v4.03) AEs 
Type of rash 
Intervention 
Rash maculopapular 
Grade 1 (<10% 
of BSA) 
Study druga may be continued at the current dose. Monitor for changes in severity. Start application of topical 
treatments to affected areas: alclometasone 0.05% cream to the face and neck and mometasone 0.05% cream to 
the body. 
Reassess at least weekly. If skin rash worsens at any time or does not improve with 2 weeks of treatment, 
proceed to the management guidelines for Grade 2 maculopapular rash (or Grade 3 if rash covers ≥30% of BSA). 
Grade 2 (≥10% 
but ≤30% of 
BSA) 
Study drug may be continued at the current dose*. Monitor for changes in severity. Start (or continue) application 
of topical treatments to affected areas: alclometasone 0.05% cream to the face and neck and mometasone 0.05% 
cream to the body. Start oral treatment with prednisone 0.5 mg/kg PO or the equivalent amount of 
dexamethasone. Reassess at least weekly. If skin rash worsens at any time or does not improve after 1 week of 
treatment, proceed to the management guidelines for Grade 3 maculopapular rash.  
* Study drug may be held for patients who cannot tolerate Grade 2 rash (see the management guidelines for 
Grade 3 rash for restarting study drug and reducing oral steroids). 
Grade 3 (>30% 
of BSA) 
Study drug must be held. Monitor for changes in severity. Start (or continue) application of topical treatments to 
affected areas: alclometasone 0.05% cream to the face and neck and mometasone 0.05% cream to the body. 
Start (or continue) oral treatment with prednisone 0.5 mg/kg PO or the equivalent amount of dexamethasone for at 
least 7 days. Reassess at least weekly. If skin rash worsens or does not improve with 2 weeks of topical and oral 
treatment, discontinue patient from study drug. Otherwise, resume study drug at a reduced dose if reaction 
recovers to Grade ≤1. Oral corticosteroids should continue for at least 1 week after resumption of reduced dose of 
study drug prior to starting corticosteroid taper. Discontinue patient from study drug if intolerable Grade 2 or 
Grade 3 reaction recurs at a reduced dose.  
Pruritus 
Grade 1 
Study drug may be continued at the current dose. Start application of topical agents such as hypoallergenic 
moisturizing cream, over the counter antipruritic creams or topical triamcinolone 0.1% cream.  
Reassess at least weekly; if skin pruritus worsens at any time or does not improve with 2 weeks of treatment, 
proceed to the management guidelines for Grade 2 pruritus (or Grade 3 pruritus if these criteria are now met). 
Grade 2 
Study drug may be continued at the current dose*. Start (or continue) application of topical agents such as 
hypoallergenic moisturizing cream, over the counter antipruritic creams or topical triamcinolone 0.1% cream. Start 
oral antihistamines (hydroxyzine 25 mg TID or diphenhydramine 25 mg TID) or GABA agonists (eg, gabapentin 
300 mg TID or pregabalin 75 mg TID).  
Reassess at least weekly; if pruritus worsens at any time or does not improve with 2 weeks of treatment, proceed 
to the management guidelines for Grade 3 pruritus. 
* Study drug may be held for intolerable Grade 2 pruritus. 
 


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CTCAE 
(v4.03) AEs 
Type of rash 
Intervention 
Grade 3 
Interrupt study treatment. Start (or continue) application of topical agents such as hypoallergenic moisturizing 
cream, over the counter antipruritic creams or topical triamcinolone 0.1% cream. Start (or continue) oral 
antihistamines (hydroxyzine 25 mg TID or diphenhydramine 25 mg TID) or GABA agonists (eg, gabapentin 
300 mg TID or pregabalin 75 mg TID). Start doxepin 25 mg BID. 
Reassess at least weekly; if skin reactions do not improve with 2 weeks of symptomatic treatment, discontinue 
patient from study drug. Resume study drug at a reduced dose if reaction recovers to Grade ≤1. Discontinue 
patient from study drug if intolerable Grade 2 or Grade 3 reaction recurs at a reduced dose.  
Dry skin 
Grade 1 
Study drug may be continued at the current dose. Start application of over the counter hypoallergenic moisturizing 
cream or ointment to the face BID and ammonium lactate 12% cream to the body BID.  
Reassess at least weekly; if dry skin worsens at any time or does not improve with 2 weeks of treatment, proceed 
to the management guidelines for Grade 2 dry skin (or Grade 3 dry skin if these criteria are now met). 
Grade 2  
Study drug may be continued at the current dose*. Start (or continue) over the counter hypoallergenic moisturizing 
cream or ointment to the face BID and ammonium lactate 12% cream or salicylic acid 6% cream (if lesions are 
hyperkeratotic) to the body BID or equivalent.  
Reassess at least weekly; if dry skin worsens at any time or does not improve with 2 weeks of treatment, proceed 
to the management guidelines for Grade 3 dry skin 
* Study drug may be held for intolerable Grade 2 dry skin. 
Grade 3 
Interrupt study treatment. Start (or continue) over the counter hypoallergenic moisturizing cream or ointment to the 
face BID and ammonium lactate 12% cream or salicylic acid 6% cream (if lesions are hyperkeratotic) to the body 
BID or equivalent. Start triamcinolone 0.25% cream to eczematous areas BID. 
Reassess at least weekly; if dry skin does not improve with 2 weeks of symptomatic treatment, discontinue patient 
from study drug. Resume study drug at a reduced dose if dry skin recovers to Grade ≤1. Discontinue patient from 
study drug if intolerable Grade 2 or Grade 3 dry skin recurs at a reduced dose.  
Palmar-plantar erythrodysesthesia syndrome (PPE) 
Grade 1 or 
tolerable Grade 2  
Study drug may be continued at the current dose. Start urea 20% cream BID and clobetasol 0.05% cream QD.  
Reassess at least weekly; if PPE worsens at any time or does not improve with 2 weeks of treatment, proceed to 
the management guidelines for the next grade event. 
Intolerable 
Grade 2 or 
Grade 3 
Interrupt study treatment. Start (or continue) clobetasol 0.05% cream BID and add analgesics (eg, NSAIDs, GABA 
agonists, and/or narcotics).  
Reassess at least weekly; if PPE does not improve with 2 weeks of symptomatic treatment, discontinue patient 
from study drug. Resume study drug at a reduced dose if reaction recovers to Grade ≤1. Discontinue patient from 
study drug if intolerable Grade 2 or Grade 3 reaction recurs at a reduced dose.  
a "Study drug" refers to SAR245408 or SAR245409. 
BID: twice daily; BSA: body surface area; GABA: gamma-aminobutyric acid; NSAID: nonsteroidal antiinflammation drug; PO: oral; QD: once a day; 
TID: 3 times a day.  
Notes: Please refer to Appendix C for a chart to estimate BSA. For all recommended therapeutic interventions, an equivalent class/ strength of 
medication may be substituted. 
 


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8.3.2.2 Pulmonary symptoms 
In this study, subjects should be instructed to contact the Investigator promptly for new or worsening 
unexplained pulmonary symptoms such as dyspnea or cough. A chest x-ray and/or a high-resolution 
chest CT scan (for higher sensitivity when clinically indicated) should be obtained at the onset of 
clinically significant pulmonary symptoms such as dyspnea and cough to assess for interstitial lung 
disease (ILD). Study treatment (SAR245408 or SAR245409) interruption will be required for 
subjects who develop clinically significant pulmonary symptoms. Subjects with pulmonary AEs 
should be monitored closely as clinically indicated (eg, by chest x-ray, high-resolution CT scan, 
and/or pulmonary function tests (eg, measuring the diffusing capacity of carbon monoxide [DLCO]). 
Permanent discontinuation of the study drug will be required for subjects who have symptomatic and 
radiographic evidence of ILD. 
8.3.2.3 Hepatobiliary disorders 
Study treatment (SAR245408 or SAR245409) must be interrupted for subjects who develop Grade ≥2 
transaminase or bilirubin elevations deemed possibly related to the study drug. Subjects must have at 
least weekly monitoring of liver function tests until the AE has returned to Grade ≤1 or baseline. All 
subjects with Grade ≥2 toxicity must have their dose reduced by 1 dose level, if study treatment is 
resumed; for SAR245409, no dose re-escalation will be permitted after dose reduction. Any subject 
experiencing Grade 4 toxicity should be evaluated by a hepatologist and must be permanently 
discontinued from study treatment. Subjects who develop elevation of ALT ≥3 x ULN in conjunction 
with bilirubin ≥2 x ULN should be evaluated by a hepatologist and must be permanently discontinued 
from study treatment, unless a correctable non-drug related cause of hepatic injury is identified. 
8.3.2.4 Gastrointestinal disorders 
Diarrhea should be treated promptly with supportive care and loperamide at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Nausea and vomiting should be 
treated as indicated with supportive care and anti-emetics. For dose reductions for diarrhea, nausea 
and vomiting, refer to Table 2. 
8.3.2.5 Hyperglycemia 
SAR245408 and SAR245409 may augment food-induced changes in plasma insulin resulting in 
hyperglycemia. Subjects who develop hyperglycemia should have a confirmatory fasting blood sugar 
drawn and should be managed according to standards of care for hyperglycemia. If, in the opinion of 
the Investigator, the hyperglycemia is possibly related to study treatment, and requires treatment with 
oral hypoglycemic agents, metformin is recommended as first-line therapy. Dose modifications are as 
outlined in Table 2. 
 


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8.3.2.6 Corrected QT interval prolongation 
If a subject taking SAR245408 or SAR245409 has a QTc interval increase of ≥60 msec from baseline 
to an absolute value of >470 msec OR increase to an absolute value of >500 msec at any evaluation, 
and if the subject is asymptomatic (ie, does not have palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on electrocardiogram (ECG), or a change in vital 
signs), the following actions should be taken: 
• The study treatment should be halted. 
• Electrolytes, especially magnesium and potassium, should be checked and abnormalities 
should be corrected as clinically indicated. 
• A blood sample for pharmacokinetics should be obtained. 
• ECGs should be repeated hourly until the QTc is <60 msec increased over the baseline value 
and ≤470 msec. 
• The Sponsor should be contacted prior to restarting study treatment. Subjects with a second 
prolongation of the QTc to >500 msec will be permanently discontinued from study treatment. 
8.4 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUP 
The IMP will be administered only to subjects included in this study following the procedures set out 
in this clinical trial protocol. Subjects withdrawn from the study retain their subject number, and new 
subjects must always be allotted a new subject number. Subjects will be assigned a 9 digit subject 
identification number according to the site number and IMP (SAR245408 or SAR245409) and 
corresponding to his/her order of enrollment in the study. This number will differ from the subject 
number on the parental study, but the subject number from the parental study and the parental study 
number will be collected for each subject. 
8.5 
PACKAGING AND LABELING 
The content of the labeling is in accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS 
Storage of IMP should be in a secure area with restricted access in accordance with labeling 
specifications. 
 


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8.7 
RESPONSIBILITIES 
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense IMP will 
be responsible for ensuring that the IMP used in the clinical trial is securely maintained as specified 
by sanofi-aventis and in accordance with the applicable regulatory requirements. 
All IMP shall be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
A potential defect in the quality of IMP may be subject to initiation by sanofi-aventis of a recall 
procedure. In this case, the Investigator will be responsible for promptly addressing any request made 
by sanofi-aventis, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be used 
other than as directed by this Clinical Trial Protocol, or dispose of IMP in any other manner. 
8.8 
CONCOMITANT MEDICATION 
All treatments being taken by the subject 30 days prior to the first study drug administration and at 
any time during the study in addition to the IMP are regarded as concomitant treatments and the type, 
dose, and route of administration must be documented on the appropriate pages of the Case Report 
Form (e-CRF). 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the subject's welfare and are unlikely to interfere with the IMP, they may be 
given at the discretion of the Investigator and recorded in the e-CRF. Concomitant treatments will be 
collected through 30 days after the last dose of IMP. 
• Concurrent systemic anticancer therapy, including investigational or noninvestigational 
cytotoxic agents, small molecules, biologics, immunotherapies, hormones, leukapheresis, and 
therapeutic radiation therapies, is prohibited unless it is part of the combination regimen from 
the parental study and agreed on in writing at the time of study entry. 
•  Radiotherapy may be administered for palliation of symptoms (eg, pain, obstruction) only if 
in the opinion of the Investigator, the symptoms do not represent progressive disease. The 
sanofi-aventis representative should be notified prior to treatment if palliative radiotherapy is 
being considered. 
• The concomitant use with SAR245408 of drugs which are CYP1A2 or CYP3A substrates, or 
CYP2C9 substrates with narrow therapeutic index, or strong inducers of CYP3A, is 
discouraged and should be avoided if possible. For a list of relevant compounds, see 
Appendix D and Appendix E. 
 


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• The concomitant use with SAR245409 of drugs which are CYP1A2 substrates, or strong 
inducers or strong inhibitors of CYP1A2, is discouraged and should be avoided if possible. 
For a list of relevant compounds see Appendix F. 
• Systemic corticosteroids are prohibited unless required for management of hypersensitivity 
reactions or skin disorders. If required for management of drug-related rash, recommendation 
in Table 4 should be followed. Oral prednisone ≤10 mg daily topical or inhalation 
maintenance steroids for comorbidities are permitted but may not be dose escalated. 
• Long-acting antacids, histamine H2-receptor antagonists, and proton pump inhibitors should 
be avoided. Short-acting antacids as well as supplemental calcium carbonate are permitted but 
must not be given either 2 hours before or 2 hours after SAR245408 or SAR245409 dose. In 
the event that antacids are not adequate to control symptoms, the use of short-acting histamine 
H2-receptor antagonists is permitted but must be taken 2 hours after SAR245408 or 
SAR245409 dose. 
• Antiemetics (other than corticosteroids) and antidiarrheals are permitted, if clinically 
indicated (see also Section 8.3.2.4). 
• Use of myeloid hematopoietic growth factors and erythropoetin should be in accordance with 
the American Society of Clinical Oncology (ASCO) treatment guidelines. 
• Transfusions of red blood cells and platelets may be performed according to standard of care. 
• For lymphoma subjects: 
- 
Infectious disease prophylaxis is permitted and recommended for subjects with CD4 
counts <200 cell/mm3. 
- 
Prophylaxis with uricosurics for tumor lysis syndrome is permitted at the discretion of the 
Investigator. 
- 
Subjects with hypogammaglobulinemia may receive intravenous immunoglobulin as 
indicated. 
- 
All live vaccines are prohibited. 
Permitted concomitant medications can be administered with water at the same time as taking 
SAR245408 or SAR245409, except for gastrointestinal pH-altering medications, including histamine 
H2-receptor antagonists, proton pump inhibitors, antacids, and calcium supplements (see above). 
8.9 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
Administration of IMP will be supervised by the Investigator or subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from sanofi-aventis, 
 


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dispensed for subject and destroyed or returned to sanofi-aventis. The packaging batch number must 
be recorded on the drug accountability form. 
The person responsible for study treatment administration to the subject at the study site will record 
precisely the date and the time of the study treatment administration. Subjects will be provided a 
study treatment diary with dosing instructions to record study treatment taken on an outpatient basis 
during the study treatment period. For subjects starting study treatment at the beginning of the 
initiation period (see Section 1.1), the diary will be initially distributed on Cycle 1 Day 1. On Cycle 2 
Day 1 and at each subsequent site visit during the extension period, the diary will be collected from 
the subject and a new diary will be provided. For subjects starting study treatment at the beginning of 
the extension period (see Section 1.1), the diary will be initially distributed on the first site visit of the 
period. At each subsequent site visit, the diary will be collected from the subject and a new diary will 
be provided. The diary will serve as source documentation and be maintained with other subject 
clinical source documents. Study site staff should carefully review the diary with the subject and/or 
caregiver to ensure it is complete and accurate before transcription to the CRFs. 
8.10 
RETURN AND/OR DESTRUCTION OF TREATMENTS 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the Monitoring Team. The Investigator will 
not destroy the unused IMP unless the Sponsor provides written authorization. 
 


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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
SAFETY 
The primary objective of this study is to determine the long-term safety and tolerability of 
SAR245408 and SAR245409 as a monotherapy or as part of a combination regimen in subjects who 
are benefiting from treatment. Safety is thus the primary study endpoint and will be assessed 
continuously. 
The safety profile will be assessed from the findings of physical examination, vital signs 
measurement, laboratory data, ECGs, ophthalmologic assessments, concomitant medications and 
treatments, and date of study treatment withdrawal and cause.  
The safety profile will be based on incidence, severity (as graded by the National Cancer Institute 
Common Terminology Criteria for Adverse Events v4.03 [NCI CTCAE v4.03]) (see Appendix B), 
and cumulative nature of AEs. Adverse event seriousness, severity grade, and relationship to IMP 
will be assessed by the Investigator. 
Serious adverse events, pregnancy and symptomatic overdose must be reported to the Sponsor within 
24 hours (see Section 10.5.2). 
The general and study-specific safety assessments/evaluations are described in details in Section 10.1. 
Additional safety assessments/evaluations for the subjects on a combination regimen will be done per 
standard of care. 
9.2 
PHARMACOKINETICS 
No pharmacokinetic assessment is planned. 
9.3 
PHARMACODYNAMICS 
No pharmacodynamic assessment is planned. 
9.4 
EFFICACY 
Tumor assessment will be performed per standard of care, and tumor response as per Investigator will 
be collected for each tumor assessment. No tumor measurement data will be collected in this study. 
 


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10 
PATIENT SAFETY 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL 
The safety profile will be assessed from the findings of physical examination, vital signs 
measurement, laboratory data, ECGs, ophthalmologic assessments, concomitant medications and 
treatments, and date of study treatment withdrawal and cause. 
The safety profile will be based on incidence, severity (as graded by the NCI CTCAE v4.03; see 
Appendix B), and cumulative nature of AEs. Adverse event seriousness, severity grade, and 
relationship to IMP will be assessed by the Investigator. 
10.1.1 Performance status 
The Eastern Cooperative Oncology Group (ECOG) performance status scale (see Appendix A) will 
be used to assess performance status. 
Please refer to the study flow chart in Section 1.2 for performance status assessment schedule. 
10.1.2 Physical examination 
Full physical examination consists of examination of major body systems (including neurologic, 
gastrointestinal, cardiovascular, respiratory, skin, and lymphatics), body weight, and height (at 
baseline visit only). 
Symptom-directed physical examination is a physical examination relevant to the subject’s 
symptoms.  
If abnormal findings emerge or worsen from baseline assessment, then the AE page of the e-CRF 
should be completed for these findings. If a finding meets the criteria for an SAE, then the 
appropriate procedures for reporting such events should be followed as described in Section 10.5. 
Please refer to the study flow chart in Section 1.2  for physical examination schedule. 
10.1.3 Vital signs measurement 
Vital signs consist of body temperature, blood pressure, and heart rate. Vital signs should be taken 
within 1 hour before dosing. 
Please refer to the study flow chart in Section 1.2  for vital signs measurement schedule. 
 


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10.1.4 Laboratory tests 
Local laboratories will perform all laboratory tests, and results will be provided to the Investigator. 
Blood and urine samples for hematology, serum chemistry, coagulation, and urinalysis will be 
prepared using standard procedures. If the serum chemistry panel is not performed in the fasted state 
and an abnormal glucose result is observed, it should be followed with a fasting plasma glucose 
assessment after an overnight fast. 
Laboratory tests are detailed in Table 5. Please refer to the study flow chart in Section 1.2 for 
laboratory tests schedule. 
All laboratory tests performed as part of standard of care for a combination regimen or for assessment 
of a possible AE outside of the scheduled visits will also be collected as unscheduled assessments. 
 


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Table 5 - Laboratory tests 
Hematology 
Serum chemistry 
Coagulation 
Urinalysis 
Others 
• 
White blood 
cell (WBC) 
count with 
differentiala 
• 
Hemoglobin 
• 
Platelet count 
• 
Albumin 
• 
Alkaline 
phosphatase 
(ALP) 
• 
Amylase 
• 
Alanine 
aminotransfe
rase (ALT) 
• 
 Aspartate 
aminotransfe
rase (AST) 
• 
Blood urea 
nitrogen 
(BUN) 
• 
Calcium 
• 
Carbon 
dioxide 
• 
Chloride 
• 
Creatinine 
• 
γ-
glutamyltran
sferase 
(GGT) 
• 
Glucose 
• 
Lipase 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total 
bilirubin 
 
• 
Prothrombin 
time / 
International 
normalized 
ratio (PT/INR) 
• 
Activated 
partial 
thromboplastin 
time (aPTT) 
• 
Protein 
• 
Glucose 
• 
Bilirubin 
• 
Occult 
bloodb 
 
• 
Hemoglobin 
A1c (HbA1c) 
• 
Serum 
pregnancy 
test (β-HCG) 
 
a Including at minimum: neutrophils, basophils, eosinophils, lymphocytes, and monocytes. 
b Microscopic examination of sediment will be performed only if the results of the urinalysis dipstick evaluation are positive. 
 


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10.1.5 Ophthalmologic examination 
Ophthalmologic examination at baseline is for subjects taking SAR245408 and for subjects taking 
SAR245409; ophthalmologic examination during the extension period is only for subjects taking 
SAR245409. Ophthalmologic examination will be conducted by an ophthalmologist or an optometrist 
and will include a slit lamp examination. New adverse findings should be evaluated more frequently 
as medically indicated and reported in the e-CRF. Investigators have the discretion to request an 
ophthalmology consultation for any emerging ophthalmologic conditions at any time during the 
study. 
10.1.6 Electrocardiogram 
Twelve (12)-lead ECGs will be performed at baseline, during the treatment period and at the follow-
up visit. 
10.1.7 Pregnancy test 
A serum pregnancy test will be performed on women of child bearing potential within 7 days prior to 
first study treatment administration and at the follow-up visit. 
10.1.8 Adverse event reporting 
Adverse events observed by the Investigator or reported by the subject will be graded and 
documented as described in Section 10.4. 
10.2 
SAFETY INSTRUCTIONS 
Please refer to Section 8.3 for dosing interruptions and reductions in the IMP dose due to IMP-related 
toxicity.  
Subjects requiring more than 2 dose reductions of IMP (SAR245408 or SAR245409) - considering 
both the parental study and the treatment-extension study - will be permanently discontinued from 
study treatment. If IMP is held for more than 6 weeks (SAR245408) or more than 21 days 
(SAR245409) due to an AE, subject should be permanently discontinued from study treatment. 
10.3 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and included 
in the final CSR. 
 


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10.4 
DEFINITIONS OF ADVERSE EVENTS  
10.4.1 Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.2 Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
• 
Results in death or; 
• 
Is life-threatening or; 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization or; 
• 
Results in persistent or significant disability/incapacity or; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes 
listed in the definition above. 
Note: The following medically important events intend to serve as a guideline for determining 
which condition has to be considered as a medically important event. It is not intended to be 
exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
allergic bronchospasm,  
- 
blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia…),  
- 
convulsions (seizures, epilepsy, epileptic fit, absence…) 
- 
Development of drug dependency or drug abuse; 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase  >10 x ULN; 
 


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- 
Suicide attempt or any event suggestive of suicidality; 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling); 
- 
Bullous cutaneous eruptions; 
- 
Cancers diagnosed during the study or aggravated during the study (only if judged as 
unusual/significant by the Investigators in oncology studies); 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged as unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
10.4.3 Adverse Event of Special Interest 
An Adverse Event of Special Interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the Investigator to the Sponsor may be appropriate. Such events may require 
further investigation in order to characterize and understand them and may require follow-up beyond 
the planned time of study completion. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.5.1 General guidelines for reporting Adverse Events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the first dose 
of IMP in the study until the end of the study as defined by the protocol for that subject, are to 
be recorded on the corresponding screen(s) of e-CRF. 
• For continuity of evaluation of safety through the parental and treatment-extension studies, for 
each subject that may have an AE or SAE in the treatment-extension study, the parental study 
number, subject ID in the parental study and a specific designation for the parental study will 
be collected as mandatory fields on the corresponding screen(s) of e-CRF of the treatment-
extension study. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
• The Investigator should take appropriate measures to follow all treatment related AEs and 
SAEs until clinical recovery is complete, laboratory results have returned to patient’s baseline 
level or until stabilization or death, in order to ensure the safety of the subjects. This may 
imply that observations will continue beyond the last planned visit per protocol, and that 
 


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additional investigations may be requested by the Monitoring Team up to as noticed by the 
Sponsor. 
• When treatment is prematurely discontinued, the subject’s observations will continue until the 
end of the study as defined by the protocol for that subject. 
• Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic, and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• See Table 6 for a summary of AE reporting guidelines. 
10.5.2 Instructions for reporting Serious Adverse Events 
In the case of occurrence of a SAE, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of the 
e-CRF; the system will automatically send the notification to the Monitoring Team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• 
SEND  (preferably by fax or e-mail) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the Monitoring 
Team whose name, fax number and email address appear on the clinical trial protocol. Care 
should be taken to ensure that the subject's identity is protected and the subject's identifiers in 
the Clinical Trial are properly mentioned on any copy of source document provided to the 
Sponsor. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
subject status ...) should be sent (by fax or e-mail) to the Monitoring Team within 24 hours of 
knowledge. In addition, any effort should be made to further document each Serious AE that 
is fatal or life threatening within the week (7 days) following initial notification. 
• 
A back-up plan is available and should be used (using paper CRF process) when the e-CRF 
system does not work. 
• 
In case of any SAE brought to the attention of the Investigator at any time after the end of the 
study for the subject and considered by him/her to be caused by the IMP with a reasonable 
possibility, this should be reported to the Monitoring team. 
• 
Any SAE occurring within 30 days after last study treatment administration, regardless of 
relationship to the study treatment must be reported within 24 hours. 
 


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• 
All SAEs related to the study drug occurring beyond 30 days must also be reported within 
24 hours. 
• 
All deaths regardless of cause, including progression of disease that occur within 30 days of 
study drug need to be reported as SAE, regardless of relationship to the study drug. 
• 
All SAEs related to study treatment must be followed until resolution, stabilization or death. 
10.5.3 Guidelines for reporting Adverse Events of Special Interest   
Skin toxicities (SAR245408 and SAR245409) and transaminases elevation (for SAR245409) are 
AESIs. Please refer to the specific guidance for management of skin disorders and hepatobiliary 
disorders in Section 8.3.2.1 and Section 8.3.2.3, respectively, for monitoring and management of 
these events and to the latest IB for additional information.  
10.5.3.1 Reporting of AESI with immediate notification 
For AESIs with immediate notification, the Sponsor will be informed immediately (ie, within 
24hours), as per SAEs notification instructions described in Section 10.5.2, even if not fulfilling a 
seriousness criterion, using the corresponding screens in the e-CRF.  
• Grade ≥2 increase in ALT (for SAR245409 only) 
• Pregnancy 
- 
Pregnancy occurring in a female subject included in the clinical trial. Pregnancy will be 
recorded as an AESI with immediate notification in all cases. It will be qualified as an 
SAE only if it fulfills the SAE criteria. 
- 
In the event of pregnancy, IMP should be discontinued.  
- 
The follow-up of the pregnancy will be mandatory until the outcome has been determined. 
• Symptomatic overdose with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is defined as any dose 
exceeding the intended dose in a single day which is suspected by the Investigator or 
reported by the subject (not based on systematic pills count) 
10.5.3.2 Reporting of AESI without immediate notification 
• Asymptomatic overdose with IMP/NIMP   
• Skin toxicities ≥ Grade 2 (SAR245408 and SAR245409)  
- 
The Investigator is required to provide additional information for skin toxicities as per the 
specific supplemental AE form. 
 


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Table 6 - Summary of Adverse Event reporting instructions 
CASE REPORT FORM 
COMPLETION 
EVENT CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS 
IN THIS CATEGORY 
AE 
form 
Safety 
Comple-
mentary Form 
Other 
specific 
forms 
Adverse Event (non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or 
AESI 
Yes 
No 
No 
Serious Adverse Event (non-AESI or 
AESI) 
Expedited (within 
24 hours) 
Any AE meeting 
seriousness criterion per 
Section 10.4.2 
Yes 
Yes 
No 
Asymptomatic overdose 
with IMP/NIMP 
Yes 
No 
No 
Adverse Event of Special Interest 
WITHOUT immediate notification (non-
SAE) 
Routine 
≥ grade 2 Skin toxicities  
(SAR245408 and 
SAR245409) 
Yes 
No 
Yes 
Pregnancy of female 
subject 
Yes 
Yes 
No 
Symptomatic overdose with 
IMP/NIMP 
Yes 
Yes 
No 
Adverse Event of Special Interest 
WITH immediate notification (non-
SAE) 
Expedited (within 
24 hours) 
Grade ≥2 increase in ALT 
(SAR245409) 
Yes 
Yes 
Yes 
Laboratory, vital sign, or ECG 
abnormality (non-SAE, non-AESI) that 
is:  
- 
symptomatic 
- 
requiring corrective 
treatment or consultation 
- 
leading to IMP 
discontinuation or dose 
modification  
Routine 
NA 
Yes 
No 
No 
 
10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• all SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR) to the 
Health Authorities, IECs/IRBs as appropriate and to the Investigators.    
 


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• all SAEs that are expected and at least reasonably related to the IMP to the Health Authorities, 
according to local regulations. 
Any other AE not listed as an expected event in the IB or in this protocol will be considered as 
unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
 
 


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11 
HANDLING OF PATIENT TEMPORARY OR PERMANENT 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be determined 
if the stop can be made temporarily; permanent IMP discontinuation should be a last resort. Any IMP 
discontinuation should be fully documented in the e-CRF. In any case, the subject should remain in 
the study as long as possible. 
Pregnancy will lead to definitive study treatment discontinuation in all cases. 
11.1 
TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
Please refer to Section 8.3. 
All temporary treatment discontinuation, whatever the duration, should be recorded by the 
Investigator on the appropriate screen(s) of the e-CRF. 
11.2 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
Permanent treatment discontinuation is any treatment discontinuation associated with the definitive 
decision from the Investigator or the subject not to re-expose the subject to the IMP at any time. 
11.2.1 List of criteria for definitive treatment discontinuation 
The subjects may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Treatment with IMP should be definitively discontinued in any of the following cases: 
• Unacceptable AE (including AE requiring more than 2 dose reductions of SAR245408 or 
SAR245409 - considering both the parental study and the treatment-extension study - or 
interruption of SAR245408 for more than 6 weeks, or interruption of SAR245409 for more 
than 21 days);   
• Disease progression; 
• Poor compliance to the study protocol; 
• Loss of follow-up; 
 


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11.2.2 Handling of patients after permanent treatment discontinuation 
Subjects will be followed up according to the study procedures as specified in this protocol up to the 
Day 23-37 follow-up visit (see Section 1.2), or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All permanent treatment discontinuation should be recorded by the Investigator on the appropriate 
screens of the e-CRF when considered as confirmed. 
11.3 
PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY  
The subjects may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason: 
• All study withdrawals should be recorded by the Investigator on the appropriate screens of the 
e-CRF and in the subject’s medical records when considered as confirmed (at least date of 
withdrawal and reason for). 
• 
If possible, the subjects are assessed using the procedures normally planned for the Day 23-37 
follow-up visit (see Section 1.2). 
For subjects who fail to return to the site, the Investigator should make the best effort to re-contact 
the subject (eg, contacting subject’s family or private physician, review available registries or health 
care database), and to determine his/her health status, including at least his/her vital status. Attempts 
to contact such subjects must be documented in the subject’s records (eg, times and dates of 
attempted telephone contact, receipt for sending a registered letter). The statistical analysis plan will 
specify how these subjects lost to follow-up for their primary endpoints will be considered. 
Subjects who have withdrawn from the study cannot be re-treated in the study. Their inclusion and 
treatment number must not be reused. 
 


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12 
STUDY PROCEDURES 
12.1 
VISIT SCHEDULE 
During the course of the study, all subjects entering the study must be evaluated according to the 
schedule outlined in the flow chart in Section 1.2 and described below. The results of the evaluation 
will be recorded on the e-CRF screens until the subjects are not followed anymore. Safety 
assessments will be evaluated according to the schedule outlined in the flow chart in Section 1.2 and 
per standard of care if the subject is on a combination regimen. 
This study consists of a 7-day baseline period and treatment cycles. A cycle is 28-days for 
SAR245408 and SAR245409 given as monotherapy; cycle duration may be different for SAR245408 
and SAR245409 given as a combination regimen. After the baseline visit, all the subjects eligible and 
included in the study will continue on the IMP (SAR245408 or SAR245409) and combination 
medication(s) (for subjects taking combination therapy) they received during the parental study and 
will start the study treatment period at the beginning of the initiation or extension period based on the 
length of prior treatment with SAR245408 or SAR245409 in the parental study: 
• if <2 cycles, start with initiation period; 
• if ≥2 cycles, start with extension period; 
• subjects who will take a SAR245408 or SAR245409 daily dose higher than their established 
dose of SAR245408 or SAR245409, respectively, in the parental study will start with 
initiation period;  
• subjects who had dose interrupted in the parental study but fulfill parental protocol criteria to 
restart IMP treatment will start the treatment-extension study on Day 1 of the initiation period; 
• subjects who fulfil the parental study criteria for IMP treatment continuation but  have 
ongoing Grade 2 AE(s) should start the treatment-extension study on Day 1 of the initiation 
period. 
 
Subjects will have a visit on site every week (Cycle 1) or every 2 weeks (Cycle 2) during the 
initiation period (if applicable), and every 4 to 6 weeks during the extension period. Subjects must 
complete all the visits in the initiation period before moving to the extension period.  
Subjects may continue to receive study treatment until disease progression, unacceptable toxicity, 
withdrawal of consent, or until commercial supplies of SAR245408 or SAR245409 are available to 
them outside of the clinical trial. A complete visit will be performed about 30 days after last IMP 
administration, corresponding to the follow-up visit. The subjects will be followed until recovery or 
consolidation of any IMP-related AE or until deemed irreversible by the Investigator. 
 


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12.1.1 Pretreatment period 
Please also refer to flow chart in Section 1.2 and to Section 10.1. 
The baseline evaluations are to be performed within 7 days prior to the first study treatment 
administration. The end-of-treatment assessments from the parental study may be used as baseline 
assessments for this study if obtained within 7 days prior to the first study treatment administration. 
The informed consent will have to be signed by the subject before any procedure specific to the study 
is performed. 
The following evaluations will be performed: 
• Demography and disease history  
• ECOG performance status. 
• Vital signs. 
• Full physical examination and height. 
• Ophthalmologic exam (ophthalmologic exam from the parental study may be used as baseline 
assessment if conducted within 12 weeks prior to the first study treatment administration). 
• 12-lead ECG. 
• Laboratory tests (see Table 5): 
- 
hematology; 
- 
serum chemistry; 
- 
PT/INR, aPTT; 
- 
HbA1c; 
- 
urinalysis. 
• Serum pregnancy test: female subjects of childbearing potential must have a negative serum 
pregnancy test (β-hCG) within 7 days prior to the first study treatment administration. 
Subjects who meet all the inclusion criteria, and none of the exclusion criteria, will be eligible for 
inclusion in the study. Each subject will receive an incremental identification number corresponding 
to his/her order of enrollment in the study. 
Documentation of agreed dose, regimen, and formulation of SAR245408 or SAR245409 (and of 
agreed dose and regimen of combination medication(s) for subjects taking combination therapy) and 
starting point of the study treatment period (initiation or extension) must be signed by the Sponsor 
Medical Monitor and the site Principal Investigator prior to first dose. 
 


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12.1.2 Treatment period 
12.1.2.1 Initiation period (if applicable) 
Please also refer to flow chart in Section 1.2 and to Section 10.1. 
The baseline assessments may be used as Cycle 1 Day 1 assessments if obtained within 72 hours of 
Cycle 1 Day 1. The baseline visit and the initial visit may occur on the same day. All subjects 
receiving monotherapy with SAR245408 or SAR245409 should be followed using 28-day treatment 
cycles during the initiation period. A 21-day treatment cycle should only be used for subjects who are 
receiving a combination regimen based on a 21-day treatment cycle. 
The following evaluations will be performed (subjects on 28-day treatment cycles): 
• ECOG performance status: on Cycle 2 Day 1. 
• Vital signs: on Cycle 1 Day 1, Day 8, Day 15, and Day 22, and on Cycle 2 Day 1 and Day 15. 
• Full physical examination: on Cycle 2 Day 1. 
• Symptom-directed physical examination: on Cycle 1 Day 1, Day 8, Day 15, and Day 22, and 
on Cycle 2 Day 15. 
• 12-lead ECG: on Cycle 1 Day 1 and Day 15, and on Cycle 2 Day 1 and Day 15. 
• Laboratory tests (see Table 5): 
- 
hematology: on Cycle 1 Day 1 and Day 15, and on Cycle 2 Day 1 and Day 15; 
- 
serum chemistry: on Cycle 1 Day 1 and Day 15, and on Cycle 2 Day 1 and Day 15. 
- 
PT/INR, aPTT: on Cycle 1 Day 1 and Cycle 2 Day 1. 
- 
urinalysis: on Cycle 1 Day 1 and Cycle 2 Day 1. 
Subjects on 21-day treatment cycles will have assessments only on Day 1, Day 8, and Day 15 when 
in Cycle 1 and on Day 1 and Day 15 when in Cycle 2. 
Tumor assessment will be performed per standard of care. 
12.1.2.2 Extension period 
Please also refer to flow chart in Section 1.2 and to Section 10.1. 
The following evaluations will be performed every 4 to 6 weeks: 
• Vital signs. 
• Symptom-directed physical examination. 
 


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• 12-lead ECG (approximately every 12 weeks and as clinically indicated) 
• Laboratory tests (see Table 5): 
- 
hematology; 
- 
serum chemistry; 
- 
PT/INR, aPTT; 
- 
HbA1c (every 12 weeks (± 4 weeks) until 60 weeks on treatment and every 24 weeks (± 4 
weeks) after 60 weeks on treatment); 
- 
urinalysis. 
Ophthalmologic examination will be performed (only for subjects taking SAR245409) every 24 
weeks (± 4 weeks)). 
Tumor assessment will be performed per standard of care. 
12.1.3 Post-treatment period 
Please also refer to flow chart in Section 1.2 and to Section 10.1. 
Subjects will return to the study site 23-37 days after the last dose of IMP for a follow-up visit. 
Additional follow up may be required in case of unresolved toxicities. 
The following evaluations will be performed: 
• Vital signs. 
• Symptom-directed physical examination. 
• 12-lead ECG. 
• Laboratory tests (see Table 5): 
- 
hematology; 
- 
serum chemistry; 
- 
PT/INR, aPTT; 
- 
HbA1c; 
- 
urinalysis. 
• Serum pregnancy test (female subjects of childbearing potential). 
Ophthalmologic examination will be performed if any of the previous examinations were abnormal. 
 


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12.2 
DEFINITION OF SOURCE DATA 
Source data includes all information in original records and certified copies of original records of 
clinical findings, observations, or other activities necessary for reconstruction and evaluation of the 
trial. Source data are contained in source documents. 
Source documents are original documents, data, and records (eg, hospital records, clinical and office 
charts, laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcripts certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm, magnetic media, X-
rays, patient files, and records kept at the pharmacy, at the laboratories, and at the medical-technical 
departments) involved in the clinical study.  Source documentation must be maintained to support 
information provided within a CRF. 
 


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13 
STATISTICAL CONSIDERATIONS 
13.1 
DETERMINATION OF SAMPLE SIZE 
The sample size of this study will depend on the number of subjects who will continue receiving 
treatment from the parental studies. It is expected that approximately 100 to 150 subjects will be 
treated in this study. There is no statistical power consideration for this treatment-extension study, as 
the study is for investigating the long term safety and tolerability of SAR245408 and SAR245409 as 
a monotherapy or as part of a combination regimen. 
13.2 
ANALYSIS ENDPOINTS 
13.2.1 Demographic and baseline characteristics 
13.2.1.1 Demographic and baseline characteristics 
Demographic and baseline characteristics are sex (male, female), race (Caucasian/white, Black, 
Asian/Oriental, American Indian or Alaska Native, Native Hawaiian or other Pacific Island, other), 
age in years (quantitative and qualitative variable: <65, 65 – 75, and ≥75 years), weight, ethnicity 
(Hispanic, Non Hispanic). Medical history, cancer diagnosis and prior anti-cancer therapy will be 
collected at baseline. Baseline safety variables include signs and symptoms at baseline, laboratory 
tests and vital signs, and baseline value is defined as the last value or measurement taken before and 
up to the first study dose in this study. 
13.2.1.2 Prior or concomitant medications (other than anti-cancer therapies) 
All medications will be coded by the Medical Dictionary for Regulatory Activities (MedDRA). Prior 
medications will record any medications (except the study medications in the parental study) taken 
within 30 days prior to the first study drug administration. Concomitant medications are any 
treatments received by the subjects concomitantly with the study drugs from the start of the first study 
drug dose to the last study drug dose + 30 days. 
13.2.2 Safety endpoints 
Safety endpoints include AEs (including deaths), vital signs, physical examination, ophthalmologic 
examination, ECG, and laboratory data. 
 


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Observation period  
The observation of safety data will be as follows: 
• Treatment period: the treatment period is defined from the date of the first dose of any study 
drug up to 30 days after the last dose of any study drug.  
• On-study observation period: the on-study period is defined as the time from the first dose of 
any study drug until the end the study (see Section 6.2.1).  
• Post-treatment period: post-treatment period is defined as the time from the day after the end 
of treatment period to the end of the study (see Section 6.2.1). 
13.2.2.1 Adverse events 
AE observation period:  
The AE observations are per the on-study observation periods defined above, and will include all 
treatment-emergent AE (TEAE), serious AE, AESI (AE of special interest), AE leading to death, AE 
that causes dose reduction and/or delay, AE that causes treatment interruption, AE that causes 
treatment discontinuation, and AE related to treatment. AEs which occur after the first dose of any 
study drug in this study will be reported to this study regardless of the timing of the last dose of study 
drug in the parental study. 
TEAE is defined as any AE that is new, worsened in severity or becomes serious from the first dose 
of any study drug up to 30 days after the last dose of any study drug. 
13.2.2.2 Deaths 
Death observation period:  
The death observations are per the observation periods defined above. In addition, post-study death 
includes all deaths reported after the end of study. 
13.2.2.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
PT/INR and aPTT, and HbA1c) and urinalysis. Clinical laboratory values will be analyzed after 
conversion into standard international units. International units will be used in all listings and tables. 
13.2.2.4 Vital signs 
Vital signs include body temperature, blood pressure, and heart rate.  
 


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13.2.2.5 12-lead ECG 
ECG values and abnormalities will be used for the safety analyses. 
13.2.2.6 Other safety endpoints 
Results from physical examination and ophthalmologic examination will be used for the safety 
analyses. 
13.2.3 Pharmacokinetic variables 
Not applicable. 
13.2.4 Pharmacodynamic variables 
Not applicable. 
13.3 
DISPOSITION OF PATIENTS 
All treated subjects (safety population) are those who took at least one dose of the study drug. 
13.4 
ANALYSIS POPULATIONS 
13.4.1 Safety population 
This population includes all subjects who took at least 1 dose of study drug during the study. 
13.4.2 Efficacy population 
Evaluable population: this population includes all subjects who have at least 1 valid post-baseline 
tumor response assessment per Investigator. 
13.5 
STATISTICAL METHODS 
13.5.1 Demographic and baseline characteristics 
Standard demographic and baseline characteristics, medical history, cancer diagnosis and prior anti-
cancer therapy will be collected at baseline. Baseline value is defined as the last value or 
measurement taken up to the first dose in the study. Baseline safety variables include sign and 
 


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symptoms at baseline, laboratory tests and vital signs. Parameters will be summarized on safety 
population by treatment group (SAR245408 and SAR245409). 
13.5.2 Prior or concomitant medications (other than anti-cancer therapies) 
The prior and concomitant medications will be presented on the safety population by treatment group 
(SAR245408 and SAR245409). Medications will be summarized according to the WHO-DD 
dictionary, considering the first digit of the ATC class (anatomic category) and the first 3 digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be summarized; 
subjects will be counted once in each ATC categories (anatomic or therapeutic) linked to the 
medication, therefore subjects may be counted multiple time for the same medication. 
13.5.3 Extent of study treatment exposure 
Extent of study treatment exposure will be assessed on the safety population by treatment group 
(SAR245408 and SAR245409).  
Duration of study drug exposure is defined as: last dose date – first dose date + 1 day regardless of 
unplanned intermittent discontinuations. The first and the last study dose administration is any dose 
of first and last administration of study drug. 
Dose information will be assessed by the following variables: 
• Total number of cycles administered (by formulation) 
• Cumulative dose: sum of all doses administered for all cycles while the subject is on treatment 
• Actual dose intensity (ADI): defined as the cumulative dose divided by duration of study drug 
exposure in terms of the number of weeks on study (by formulation) 
• Relative dose intensity (RDI): defined as the ratio of the actual dose intensity to the planned 
dose intensity. The RDI is an indicator of the feasibility of the chosen schedule of 
administration. 
• Dose reduction and reason for dose reduction. 
• Dose interruption and reason for dose interruption. 
13.5.4 Analyses of safety data 
The summary of safety results will be presented by treatment group (SAR245408 and SAR245409) 
on the safety population. Analyses of AEs and laboratory data will be descriptive and performed on 
the safety population. For each of the safety parameters, a baseline value will be defined as the last 
value or measurement taken up to the first dose in the study. Descriptive analyses will be presented 
for TEAEs, AESIs, SAEs and AEs that cause dose reduction, dose delay and treatment 
discontinuation. 
 


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Treatment-emergent adverse event (TEAE) incidence tables will present by system-organ-class 
(SOC) and preferred term (PT) by treatment group (SAR245408 and SAR245409), using number and 
percentage of subjects experiencing an AE. Multiple occurrences of the same event in the same 
subject will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
The grade will be taken into account in the summary. For subjects with multiple occurrences of the 
same event, the maximum grade is used. 
The following deaths summaries will be generated: 
• Number (%) of subjects who died during on-treatment period and reasons for deaths 
summarized on the safety population by treatment received. 
• TEAEs leading to deaths (death as an outcome on the AE e-CRF page as reported by the 
Investigator) and related TEAEs leading to death by primary SOC, high group level term 
(HLGT), high level term (HLT), and PT, showing number (%) of subjects sorted by 
internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT. 
Adverse events of special interest (AESIs), AEs related to study treatment, AEs leading to study 
treatment discontinuation, AEs leading to dose delay/reduction will be summarized in a similar way. 
Ophthalmologic examination results will be summarized by number and percentage of subjects with 
abnormality by treatment group at respective visits. 
ECG results will be summarized by treatment group at respective visits. Vital signs and change from 
baseline will be summarized by treatment group at respective visits. 
Hematological toxicities will be assessed from laboratory parameters. Worst NCI CTCAE v4.03 
grades will be calculated. Qualitative and quantitative results will be summarized for hematological 
toxicities. 
Serum chemistry will be analyzed in a similar way using the worst NCI CTCAE v 4.03 grade, 
whenever applicable (laboratory normal ranges, otherwise), calculated from laboratory values.  
Prothrombin time/international normalized ratio, HbA1c and their changes from baseline will be 
summarized by treatment group at respective visits. 
Subgroup safety analyses will be performed by parental study, monotherapy and combination 
therapy, when appropriate. In addition, cumulative incidence combining parental and extension 
studies may be provided for TEAEs, SAEs, AESIs, etc., as appropriate. 
 


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13.5.5 Analyses of efficacy endpoints 
13.5.5.1 Analyses of primary and secondary efficacy endpoints 
This treatment-extension study is for investigating the long term safety and tolerability of 
SAR245408 and SAR245409 as a monotherapy or as part of a combination regimen, and thus there is 
no primary or secondary efficacy endpoint. All the efficacy variables and analyses are exploratory. 
13.5.5.2 Analyses of exploratory efficacy endpoints 
Tumor response as per Investigator will be summarized by treatment group (SAR245408 and 
SAR245409) in the evaluable population. Overall Survival (OS), Progression Free Survival (PFS), 
Objective Response Rate (ORR), and Duration of Response (DR) will be summarized and the 
survival curves will be estimated using Kaplan-Meier estimates by treatment group. Tumor response 
will be summarized by number and percentage of subjects in each response category by treatment 
group. 
Overall survival is defined as the time (days) from the study Day 1 of the parental study to the date of 
death (whatever the cause) in the study (treatment-extension study). If death is not observed during 
the study, data on OS will be censored at the last date subject is known to be alive or the cut-off date 
(if defined during the study), whichever occurs first. 
Progression free survival is defined as the time (days) from the study Day 1 of the parental study to 
the date of progressive disease (PD) or death (regardless of cause) in the study (treatment-extension 
study). The actual dates of tumor assessments will be used for this calculation. If death or disease 
progression is not observed, data on PFS will be censored at the earlier of the date of last tumor 
assessment without evidence of progression.  
Objective response rate is defined as the proportion of subjects who experience complete 
response/remission (CR) or partial response/remission (PR) in the study (treatment-extension study). 
Duration of response is defined as the time (days) from the date of first tumor response (CR or PR) in 
the parental study or in the study (treatment-extension study), whichever occurs first, to the time of 
the first tumor assessment of PD or death due to any cause. This endpoint is defined only for those 
subjects with a tumor response. 
Subgroup efficacy analyses will be performed by parental study, monotherapy and combination 
therapy, when appropriate. 
13.5.5.3 Multiplicity Considerations 
Due to the nature of the exploratory analyses, no adjustment for multiple efficacy analyses will be 
made. 
 


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13.5.6 Analyses of pharmacokinetic variables 
Not applicable. 
13.5.7 Analyses of pharmacodynamic variables 
Not applicable. 
13.6 
DATA HANDLING CONVENTIONS 
Missing dates will be handled using conservative approaches, and no imputation will be applied at the 
data level: 
• If the date of the last dose of IMP is missing, the exposition duration should be kept as 
missing. 
• If a medication date is missing or partially missing, it will be considered as a prior, 
concomitant, and a follow-up medication, when no reasonable conclusion can be reached in 
this situation. 
• If onset dates are missing or partially missing, the AE will be classified as treatment-
emergent. 
• If the date of the first study drug dose in the study is missing, all AEs that occurred on or after 
the day the subject entered into the study will be considered as treatment-emergent AEs. 
Handling of missing relationship to IMPs of AEs: if the assessment of the relationship to IMPs is 
missing, then the relationship to IMPs has to be assumed and the AE considered as such in the 
frequency tables of possibly-related AEs. 
Handling of missing severity/grades of AEs: if the severity/grade is missing for 1 of the treatment-
emergent occurrences of an AE, the maximal severity on the remaining occurrences will be 
considered. If the severity is missing for all the occurrences a “missing” category will be added in the 
summary table. 
13.7 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
13.8 
DATABASE LOCK 
The database is planned to be locked within 4 to 8 weeks from the last subject last visit. 
 


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14 
ETHICAL AND REGULATORY STANDARDS 
14.1 
ETHICAL PRINCIPLES 
This clinical trial will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies and the ICH guidelines for Good Clinical Practice (GCP). 
In compliance with sanofi-aventis public disclosure commitments, this clinical trial will be recorded 
in the public registry website clinicaltrials.gov before the enrollment of the first patient. The registry 
will contain basic information about the trial sufficient to inform interested patients (and their 
healthcare practitioners) how to enroll in the trial. 
14.2 
LAWS AND REGULATIONS 
This clinical trial will be conducted in compliance with all international guidelines, and national laws 
and regulations of the country(ies) in which the clinical trial is performed, as well as any applicable 
guidelines. 
14.3 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Institutional Review Board/Independent Ethics Committee (IRB/IEC). All participants 
should be informed to the fullest extent possible about the study, in language and terms they are able 
to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled in 
and personally dated by the patient or by the patient’s legally acceptable representative, and by the 
person who conducted the informed consent discussion. A copy of the signed and dated written ICF 
will be provided to the patient. 
The ICF used by the Investigator for obtaining the patient's informed consent must be reviewed and 
approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for 
approval/favorable opinion.  
 


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14.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial protocol 
to the appropriate Ethics Committee (IRB/IEC), and is required to forward to the respective other 
party a copy of the written and dated approval/favorable opinion signed by the Chairman with Ethics 
Committee (IRB/IEC) composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB, Investigator’s curriculum vitae [CV], etc.) and the date of 
the review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
Investigational medicinal product will not be released at the study site and the Investigator will not 
start the study before the written and dated approval/favorable opinion is received by the Investigator 
and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is necessary 
to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be informed as 
soon as possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the IB will be 
sent to the Ethics Committee (IRB/IEC). 
A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a summary of the 
clinical trial’s outcome at the end of the clinical trial. 
 


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15 
STUDY MONITORING 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator(s) and delegated Investigator staff undertake(s) to perform the clinical trial in 
accordance with this clinical trial protocol, ICH guidelines for GCP and the applicable regulatory 
requirements. 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial protocol 
(with the help of the CRF, discrepancy resolution form [DRF] or other appropriate instrument) in an 
accurate and legible manner according to the instructions provided and to ensure direct access to 
source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of the 
patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
Investigators to assist in the conduct of the clinical trial in accordance with the clinical trial protocol. 
All Sub-Investigators shall be appointed and listed in a timely manner. The Sub- Investigators will be 
supervised by and work under the responsibility of the Investigator. The Investigator will provide 
them with a copy of the clinical trial protocol and all necessary information. 
15.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to Health Authorities for taking all reasonable steps to 
ensure the proper conduct of the clinical trial protocol as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of the 
Monitoring Team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the Monitoring Team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following aspects: 
patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, AESI 
documentation and reporting, AE documentation, IMP allocation, patient compliance with the IMP 
regimen, IMP accountability, concomitant therapy use and quality of data. 
 


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15.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH guidelines for GCP, the Monitoring Team must check the CRF entries against 
the source documents, except for the pre-identified source data directly recorded in the CRF. The ICF 
will include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to original medical 
records which support the data on the CRFs (eg, patient's medical file, appointment books, original 
laboratory records, etc.). These personnel, bound by professional secrecy, must maintain the 
confidentiality of all personal identity or personal medical information (according to confidentiality 
and personal data protection rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to the 
technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting the 
initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor when available in the e-CRF may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or modifying 
the data questioned. The requests with their responses will be managed through the e-CRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS 
Computerized systems used during the different steps of the study are: 
• 
For data management activities: Oracle Clinical; 
• 
For statistical activities: SAS; 
• 
For pharmacovigilance activities: AWARE; 
• 
For monitoring activities: IMPACT and POLARIS; 
• 
For medical writing activities: DOMASYS. 
No external data loading is planned for this clinical trial. 
 


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16 
ADMINISTRATIVE RULES 
16.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of each 
Investigator and Sub-Investigator will be signed, dated and provided to the Sponsor prior to the 
beginning of the clinical trial. 
16.2 
RECORD RETENTION IN STUDY SITES(S) 
The Investigator must maintain confidential all study documentation, and take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a longer 
period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents following 
the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, the 
Investigator shall inform the Sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee. 
 


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17 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial protocol, 
the CRFs, the IB and the results obtained during the course of the clinical trial, is confidential, prior 
to the publication of results. The Investigator and any person under his/her authority agree to 
undertake to keep confidential and not to disclose the information to any third party without the prior 
written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-Investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-Investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
Furthermore, the Investigator and the Sponsor agree to adhere to the principles of personal data 
confidentiality in relation to the patients, Investigator and its collaborators involved in the study. 
 


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PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the sole 
property of the Sponsor. 
The Investigator shall not mention any information or the product in any application for a patent or 
for any other intellectual property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance required 
by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, including signature 
of legal documents. 
 


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19 
DATA PROTECTION 
The patient's personal data, which are included in the Sponsor database shall be treated in compliance 
with all applicable laws and regulations. 
When archiving or processing personal data pertaining to the Investigator and/or to the patients, the 
Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
The Sponsor also collects specific data regarding Investigator as well as personal data from any 
person involved in the study which may be included in the Sponsor’s databases, shall be treated by 
both the Sponsor and the Investigator in compliance with all applicable laws and regulations. 
 


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20 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials under 
its sponsorship.  This insurance policy is in accordance with local laws and requirements. The 
insurance of the Sponsor does not relieve the Investigator and the collaborators from maintaining 
their own liability insurance policy. An insurance certificate will be provided to the Ethics 
committees/IRB or Health Authorities in countries requiring this document. 
 


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21 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY 
AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the Sponsor 
and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records 
for review, being understood that these personnel is bound by professional secrecy, and as such will 
not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform the 
Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected during 
these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective actions 
for all problems found during the audit or inspections. 
 


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22 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE 
CLOSE-OUT OF A SITE 
22.1 
DECIDED BY THE SPONSOR IN THE FOLLOWING CASES: 
• 
If the information on the product leads to doubt as to the benefit/risk ratio. 
• 
If the Investigator has received from the Sponsor all IMP, means and information necessary to 
perform the clinical trial and has not included any patient after a reasonable period of time 
mutually agreed upon. 
• 
In the event of breach by the Investigator of a fundamental obligation under this agreement, 
including but not limited to breach of the clinical trial protocol, breach of the applicable laws 
and regulations or breach of the ICH guidelines for GCP. 
• 
If the total number of patients are included earlier than expected. 
• 
Drug supply or manufacturing issues. 
• 
The Sponsor’s decision to discontinue the development of the IMP. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
22.2 
DECIDED BY THE INVESTIGATOR 
The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the 
reason in writing. 
In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements. 
 


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23 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
 


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24 
PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will not 
unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with scientific 
standards, first presentation or publication of the results of the study shall be made only as part of a 
publication of the results obtained by all sites performing the protocol.  However, if no multicenter 
publication has occurred within 12 months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study to the review 
procedure set forth herein.   The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication derived from the Study for review and comment at least 30 days in 
advance of any presentation or submission for publication.  In addition, if requested by the Sponsor, 
any presentation or submission for publication shall be delayed for a limited time, not to exceed 90 
days, to allow for filing of a patent application or such other measures as the Sponsor deems 
appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
 


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25 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion from 
the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to 
clinical trial patients, or when the change(s) involves only logistical or administrative aspects of the 
trial. Any change agreed upon will be recorded in writing, the written amendment will be signed by 
the Investigator and by the Sponsor and the signed amendment will be filed with this clinical trial 
protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive an 
IRB/IEC approval/favorable opinion concerning the revised Informed Consent Form prior to 
implementation of the change and patient signature should be re-collected if necessary. 
 


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26 
BIBLIOGRAPHIC REFERENCES 
1. Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Brana I, et al. Phase I safety, 
pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K 
inhibitor, in patients with advanced solid tumors.  Clin Cancer Res 2014;20:233-245.Not 
applicable. 
 
 

SAP_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 4.0 (09-APR-2013) 
Page 1
STATISTICAL ANALYSIS PLAN 
An international, multicenter, open-label, treatment-extension study for subjects 
who completed a Phase 1 or Phase 2 parental study to continue receiving 
treatment with SAR245408 or SAR245409 as a monotherapy or as a combination 
regimen 
SAR245408 - SAR245409 - TED12414 
STUDY BIOSTATISTICIAN: 
  
DATE OF ISSUE: 13-Jul-2015 
Total number of pages: 
32 
(electronic 1.0)
NCT number: NCT01587040


Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives .......................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................7 
1.4 
STUDY PLAN...................................................................................................................................8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................10 
2.1 
ANALYSIS ENDPOINTS................................................................................................................10 
2.1.1 
Demographic and baseline characteristics ....................................................................................10 
2.1.2 
Prior or concomitant medications (other than anticancer therapies)..............................................11 
2.1.3 
Efficacy endpoints ..........................................................................................................................11 
2.1.3.1 
Primary efficacy endpoint(s)...........................................................................................................11 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................11 
2.1.4 
Safety endpoints.............................................................................................................................12 
2.1.4.1 
Adverse event (AE) variables.........................................................................................................12 
2.1.4.2 
Deaths............................................................................................................................................13 
2.1.4.3 
Vital signs variables........................................................................................................................14 
2.1.4.4 
Electrocardiogram variables...........................................................................................................14 
2.1.4.5 
Other safety endpoints ...................................................................................................................14 
2.1.5 
Pharmacokinetic variables .............................................................................................................14 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................14 
2.1.7 
Quality-of-life endpoints..................................................................................................................14 
2.1.8 
Health economic endpoints............................................................................................................14 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................14 
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2.2.1 
Randomization and drug dispensing irregularities .........................................................................15 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................15 
2.3.1 
Efficacy populations .......................................................................................................................15 
2.3.1.1 
Intent–to-treat/Modified intent-to-treat population ..........................................................................15 
2.3.2 
Safety population............................................................................................................................15 
2.4 
STATISTICAL METHODS .............................................................................................................16 
2.4.1 
Demographics and baseline characteristics ..................................................................................16 
2.4.2 
Prior or concomitant medications (other than anticancer therapies)..............................................16 
2.4.3 
Extent of study treatment exposure ...............................................................................................16 
2.4.3.1 
Extent of study treatment exposure ...............................................................................................17 
2.4.3.2 
Compliance ....................................................................................................................................17 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................17 
2.4.4.1 
Analysis of primary efficacy endpoint(s).........................................................................................17 
2.4.4.2 
Analyses of secondary efficacy endpoints .....................................................................................17 
2.4.4.3 
Multiplicity issues............................................................................................................................17 
2.4.4.4 
Analyses of exploratory efficacy endpoints ....................................................................................18 
2.4.5 
Analyses of safety data ..................................................................................................................18 
2.4.5.1 
Analyses of adverse events ...........................................................................................................18 
2.4.5.2 
Deaths............................................................................................................................................20 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................20 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................21 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................21 
2.4.5.6 
Other safety analyses.....................................................................................................................21 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................21 
2.4.7 
Analyses of quality of life/health economics variables ...................................................................21 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................22 
2.5.1 
General conventions ......................................................................................................................22 
2.5.2 
Study day calculation......................................................................................................................22 
2.5.3 
Data handling conventions for secondary efficacy variables..........................................................22 
2.5.4 
Missing data ...................................................................................................................................22 
2.5.5 
Windows for time points.................................................................................................................23 
2.5.6 
Unscheduled visits .........................................................................................................................24 
2.5.7 
Pooling of centers for statistical analyses ......................................................................................24 
2.5.8 
Statistical technical issues .............................................................................................................24 
3 
INTERIM ANALYSIS .....................................................................................................................25 
4 
DATABASE LOCK ........................................................................................................................26 
5 
SOFTWARE DOCUMENTATION..................................................................................................27 
(electronic 
 
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6 
REFERENCES...............................................................................................................................28 
7 
LIST OF APPENDICES .................................................................................................................29 
APPENDIX A 
POTENTIALLY AND CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ..............30 
APPENDIX B 
ECOG PERFORMANCE STATUS SCALE .........................................................................32 
(electronic 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADI 
actual dose intensity 
AE
adverse event
AESI 
adverse event of special interest 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
aPTT 
activated partial thromboplastin time 
AST
aspartate aminotransferase
ATC 
anatomical therapeutic chemical 
CTCAE 
common terminology criteria for adverse events 
CR
complete response/remission
DR 
duration of response 
ECG
electrocardiogram
ECOG 
Eastern Cooperative Oncology Group 
GGT
gamma glutamyltransferase
HLGT 
high-level group term 
HLT
high-level term
IMP
investigational medicinal product 
INR 
international normalized ratio 
LLT
lower-level term
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS
overall survival
PCSA
potentially clinically significant abnormalities 
PD
pharmacodynamics, progressive disease 
PFS 
progression free survival 
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PK
pharmacokinetic
PR
partial response
PT 
prothrombin time, preferred term 
QT 
Q wave and T wave in heart’s electric cycle 
QTcF 
QT interval corrected using Fridericia’s formula 
RDI 
relative dose intensity 
RR 
two R waves in ECG 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD
standard deviation
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
WHO-DD 
World Health Organization-Drug Dictionary 
β-HCG 
Beta-subunit of human chorionic gonadotropin 
(electronic 
 
1.0)


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is an open-label, international, multicenter, treatment-extension study, which will enable 
cancer patients who are currently receiving benefit from either SAR245408, formerly known as 
XL147, or SAR245409, formerly known as XL765, as a monotherapy or as part of a combination 
regimen in a Phase 1 or Phase 2 study to continue receiving treatment and further assess safety and 
tolerability of SAR245408 and SAR245409. 
No randomization is implemented in the study. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective is to determine the long-term safety and tolerability of SAR245408 and 
SAR245409 as a monotherapy or as part of a combination regimen in subjects who are benefiting 
from treatment. 
1.2.2 Secondary objectives 
Not applicable. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size of this study will depend on the number of subjects who will continue receiving 
treatment from the parental studies. It is expected that approximately 100 to 150 subjects will be 
treated in this study. There is no statistical power consideration for this treatment-extension study, 
as the study is for investigating the long term safety and tolerability of SAR245408 and 
SAR245409 as a monotherapy or as part of a combination regimen. 
(electronic 1.0)


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1.4 
STUDY PLAN 
This treatment-extension, open-label, international, multicenter, nonrandomized study is designed 
to provide continued access to SAR245408 or SAR245409 as a monotherapy or as part of a 
combination regimen. 
All subjects in the study will receive SAR245408 or SAR245409; the respective dose will be 
either the recommended Phase 2 dose (400 mg SAR245408 [tablet formulation polymorph A] 
once daily or 50 mg SAR245409 [capsule formulation] twice daily) or the subject’s established 
dose either as a monotherapy or in a combination regimen in the parental study. 
As shown in Figure 1, subjects who received SAR245408 or SAR245409 for less than 2 cycles in 
the parental study or who will take a daily dose of SAR245408 or SAR245409 higher than their 
established dose in the parental study will enter the treatment-extension study on Day 1 of the 
initiation period (A); subjects who received SAR245408 or SAR245409 for at least 2 cycles in the 
parental study will enter the treatment-extension study on Day 1 of the extension period (B).  
Subjects may continue in the study until disease progression, unacceptable toxicity, withdrawal of 
consent, or until commercial supplies of SAR245408 or SAR245409 are available to them outside 
of the clinical trial. 
(electronic 
 
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Figure 1 - Graphical study design 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
Initiation Period 
Extension Period 
Baseline 
A   
B 
A – Subjects who received SAR245408 or SAR245409 for <2 cycles in the parental study or 
who will take a daily dose of SAR245408 or SAR245409 higher than their established 
dose in the parental study will enter the treatment-extension study on Day 1 of the 
initiation period. 
B – Subjects who received SAR245408 or SAR245409 for ≥ 2 cycles in the parental study 
will enter the treatment-extension study on Day 1 of the extension period. 
Study 
Entrance  
Follow-up 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last value or measurement taken before and up to the first 
study dose in this study. 
All baseline safety parameters are presented along with the on-treatment summary statistics in the 
safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic variables are sex (Male, Female), race (Caucasian/white, Black, Asian/Oriental, 
American Indian or Alaska Native, Native Hawaiian or other Pacific Island, other), age in years 
(quantitative and qualitative variable : <65, [65 – 75[ and ≥75 years), weight,  ethnicity (Hispanic, 
non-Hispanic). 
Age in years will be calculated as (Date of Informed Consent – Date of Birth + 1)/365.25. 
Cancer diagnosis   
Cancer diagnosis is divided into two categories based on tumor type – solid tumor or lymphoma.  
The following parameters, date of initial diagnosis (years), location of primary tumor and 
histology type, are collected.  
Prior anticancer therapies 
Prior anticancer therapies only include parental study drug (SAR245408 or SAR245409) that was 
administered in the parental study. Any anticancer therapies prior to the parental study drug are 
not collected in this study. Information about drug per regimen and start/end date are collected. 
Vital signs  
Vital signs at baseline are weight in kg, height in cm, blood pressure (systolic and diastolic) in 
mmHg, heart rate, body temperature. 
Other baseline measures 
Other baseline measures include physical examination, ophthalmologic examination, 
electrocardiogram (ECG), tumor assessment and Eastern Cooperative Oncology Group (ECOG) 
performance status. 
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Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken within 30 days before the first investigational medicinal product (IMP) 
administration in the current study and until the end of the study are to be reported in the case 
report form pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
•
Prior medications are any medications (except the study medications in the parental study)
taken by patients within 30 days prior to the first IMP intake.  Prior medications can be
discontinued before first administration or can be ongoing during treatment phase.
•
Concomitant medications are any treatments received by the patient concomitantly with
the IMPs, from the start of the first study drug dose to the last study drug dose + 30 days. A
given medication can be classified both as a prior medication and as a concomitant
medication.  Concomitant medications do not include medications started during the
post-treatment period (as defined in the observation period in Section 2.1.4).
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.  
2.1.3 Efficacy endpoints 
This treatment-extension study is for investigating the long term safety and tolerability of 
SAR245408 and SAR245409 as a monotherapy or as part of a combination regimen, and thus 
there is no primary or secondary efficacy endpoint. All the efficacy variables and analyses are 
exploratory. 
2.1.3.1 Primary efficacy endpoint(s) 
Not applicable. 
2.1.3.2 Secondary efficacy endpoint(s) 
Not applicable. 
(electronic 
 
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2.1.4 Safety endpoints 
Safety endpoints include AEs (including deaths), vital signs, physical examination, 
ophthalmologic examination, ECG, and laboratory data. 
Observation period  
The observation of safety data will be as follows: 
•
Pre-treatment period: the pre-treatment period is defined from the date the subjects give
informed consent to the first study treatment intake in the current study.
•
Treatment period: the treatment period is defined from the date of the first dose of any
study drug up to 30 days after the last dose of any study drug.
•
Post-treatment period: post-treatment period is defined as the time from the day after the
end of treatment period to end of the study (study cut-off date) specified in the protocol.
•
On-study period: the on-study period is defined as the time from the first dose of any
study drug until the end the study.
2.1.4.1 Adverse event (AE) variables 
Adverse event observation period  
The AE observations are per the on-study observation periods defined above, and will include all 
treatment-emergent AE (TEAE), serious AE, AE of special interest (AESI), AE leading to death, 
AE that causes dose reduction and/or delay, AE that causes treatment interruption, AE that causes 
treatment discontinuation, and AE related to treatment. AEs which occur after the first dose of any 
study drug in this study will be reported to this study regardless of the timing of the last dose of 
study drug in the parental study. 
Treatment-emergent AE is defined as any AE that is new, worsened in severity or becomes serious 
during the on treatment period. 
All AEs (including serious AEs  and AESI) will be coded to a lower-level term (LLT), preferred 
term (PT), high-level term (HLT), high-level group term (HLGT), and associated primary system 
organ class (SOC) using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database. All AEs are graded using the NCI CTCAE 
v4.03. 
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Adverse events of special interests (AESI) 
An AESI (serious or non-serious) is one of scientific and medical concern specific to Sanofi 
product or program, for which ongoing monitoring and rapid communication by the Investigator 
to Sanofi may be appropriate. Such events may require further investigation in order to 
characterize and understand them and may require follow-up beyond the planned time of study 
completion.  
•
Grade ≥2 increase in ALT (for SAR245409 only)
•
Pregnancy
•
Symptomatic overdose with IMP/NIMP
•
Asymptomatic overdose with IMP/NIMP
•
Skin toxicities ≥ Grade 2 (SAR245408 and SAR245409).
2.1.4.2 Deaths 
•
The death observations are per the observation periods defined above.
2.1.4.3 Laboratory safety variables 
The laboratory parameters will be classified as follows:   
•
Hematology
WBC (including neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet,
hemoglobin, hematocrit, glycosylated hemoglobin
•
Serum chemistry
Sodium, potassium, calcium, phosphorus, magnesium, glucose, creatinine, chloride,
carbon dioxide, total proteins, albumin, amylase, aspartate aminotransferase (AST),
alkaline phosphatase, alanine aminotransferase (ALT), total bilirubin, blood urea nitrogen,
gamma glutamyltransferase (GGT), lipase
•
Coagulation
Prothrombin time/international normalized ratio (PT/INR), activated partial
thromboplastin time (aPTT)
•
Urinalysis
Proteins, glucose, bilirubin, occult blood
•
Others
hemoglobin A1c (HbA1c), serum pregnancy test (β-HCG)
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2.1.4.4 Vital signs variables 
Vital signs include:  blood pressure (systolic and diastolic; mmHg), heart rate (bpm), temperature 
and weight in kg. 
2.1.4.5 Electrocardiogram variables 
ECG parameters include heart rate, PR, QRS, QT, corrected QTc and RR. QTc will be calculated 
based on Fridericia’s formula (QTcF=QT/RR0.33) if possible. Both reported and calculated QTcF 
will be summarized.  
2.1.4.6 Other safety endpoints 
Results from physical examination and ophthalmologic examination will be used for the safety 
analyses. Ophthalmologic examinations are required at extension visit only for subjects 
administered SAR245409. 
2.1.5 Pharmacokinetic variables  
Not applicable. 
2.1.6 Pharmacodynamic/genomics endpoints  
Not applicable. 
2.1.7 Quality-of-life endpoints  
Not applicable. 
2.1.8 Health economic endpoints  
Not applicable. 
2.2 
DISPOSITION OF PATIENTS 
Safety population is defined to be all treated subjects (safety population) are those who took at 
least one dose of the study drug. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a summary table: 
• 
Treated patients (safety population) 
• 
Patients who discontinued study treatment with reason for treatment discontinuation. 
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For all categories of patients percentages will be calculated. Reasons for treatment discontinuation 
will be supplied in tables giving numbers and percentages by treatment group (SAR245408 and 
SAR 245409). 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable. 
2.2.2 Protocol deviations 
During the blinded review of the database, compliance with the protocol will be examined with 
regard to inclusion and exclusion criteria, treatment, prohibited therapies, and timing and 
availability of planned assessments.  Protocol deviations will be identified by the study team 
before database lock and listed in the Data Review Report, including missing data and study drug 
discontinuations, and classified as minor, major or critical deviations. 
Important protocol deviations will be derived adequately (algorithmically and/or following 
medical review from data listings) and determination of deviations will be finalized prior to 
database lock. 
Following are potentially important protocol deviations to be considered: 
• 
Inclusion/exclusion deviations 
• 
The first dose administration date is before the date of informed consent 
• 
Dose interruption/delay for more than 7 days that is not due to AE 
• 
IMP symptomatic overdose 
• 
Used prohibited medications during the study 
All important deviations will be listed and summarized as appropriate. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 Efficacy populations 
Efficacy population is not defined because efficacy analysis is exploratory. 
2.3.1.1 Intent–to-treat/Modified intent-to-treat population  
Not applicable. 
2.3.2 Safety population 
The safety population is defined as: All treated subjects (safety population) are those who took at 
least one dose of the study drug. 
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2.4 
STATISTICAL METHODS 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
P-values on demographic and baseline characteristic data will not be calculated  
2.4.1 Demographics and baseline characteristics 
Demographic characteristics and other baseline characteristics described in Section 2.1.1 will be 
summarized by treatment groups using descriptive statistics.  
Parameters such as age, height and weight will be summarized as continuous data. Age group, sex, 
race, ethnicity, ECOG performance status and cancer history will be summarized as 
categorical/ordinal data.  
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
The prior and concomitant medications will be presented on the safety population and summarized 
by treatment group (SAR245408 Monotherapy, SAR245408 Combination regimen, SAR245409 
Monotherapy and SAR245409 Combination regimen)according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 
3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication 
will be summarized, and patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication. Therefore patients may be counted several time for the same 
medication.  
The table for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on the overall incidence across treatment groups 
(SAR245408 and SAR245409).  In case of equal frequency regarding ATCs, alphabetical order 
will be used. 
2.4.3 Extent of study treatment exposure  
The extent of study treatment exposure will be assessed and summarized by treatment group 
(SAR245408 Monotherapy, SAR245408 Combination regimen, SAR245409 Monotherapy and 
SAR245409 Combination regimen) within the safety population (Section 2.3.2). 
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2.4.3.1 Extent of study treatment exposure 
The extent of study treatment exposure will be assessed by the duration (in days) of IMP exposure, 
and actual dose information. 
Duration of study drug exposure is defined as last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.4 for calculation in case of missing or 
incomplete data). The first and last study dose administration is any dose of first and last 
administration of study drug recorded on CRF pages.   
Dose information will be assessed by the following variables: 
• 
Total number of cycles administered   
• 
Cumulative dose: sum of all doses administered for all cycles while the subject is on 
treatment 
• 
The actual dose intensity (ADI) is defined as the cumulative dose divided by duration of 
study drug exposure in terms of the number of weeks on study 
• 
The relative dose intensity is (RDI) defined as the ratio of the actual dose intensity to the 
planned dose intensity.   
• 
Dose reduction   
Dose information variables will be summarized descriptively (number, mean, SD, median, 
minimum, and maximum).   
2.4.3.2 Compliance  
Not applicable because no additional analysis is planned for compliance. 
2.4.4 Analyses of efficacy endpoints 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Not applicable. 
2.4.4.2 Analyses of secondary efficacy endpoints 
Not applicable. 
2.4.4.3 Multiplicity issues 
Not applicable since no statistical test will be performed in the study. 
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2.4.4.4 Analyses of exploratory efficacy endpoints 
The efficacy analysis will be exploratory. Listings of tumor response and subgroup efficacy 
analyses may be performed by parental study, monotherapy and combination therapy, when 
appropriate. 
2.4.5 Analyses of safety data 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, by 
treatment group (SAR245408 Monotherapy, SAR245408 Combination regimen, SAR245409 
Monotherapy and SAR245409 Combination regimen) unless otherwise specified, using the 
following common rules: 
• The baseline value is defined as the last available non-missing measurement prior to the 
first dose of study treatment 
• The analysis of the safety variables will be essentially descriptive and systematic testing is 
planned. 
2.4.5.1 Analyses of adverse events 
Generalities  
The primary focus of AE reporting will be on TEAE.  Pretreatment and post-treatment AEs will 
be described separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pretreatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine it is 
pretreatment or post-treatment.  
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an AE.  
Multiple occurrences of the same event in the same patient will be counted only once in the tables 
within a treatment phase.  The denominator for computation of percentages is the safety 
population within each treatment group. 
The grade will be taken into account in the summary.  For patients with multiple occurrences of 
the same event, the maximum grade is used.   
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Analysis of all TEAEs 
The following TEAE summaries will be generated for the safety population. 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
Treatment-emergent AE 
- 
Grade 3-4 TEAE 
- 
Treatment-emergent SAE (TESAE) 
- 
Grade 3-4 TESAE 
- 
Treatment-related TEAE 
- 
Treatment related grade 3-4 TEAE 
- 
Treatment related grade3-4 TESAE 
- 
Treatment-emergent AE leading to death 
- 
Treatment-emergent AE leading to permanent treatment discontinuation 
- 
Treatment-emergent AE leading to dose reduction or interruption 
• 
All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least 1 TEAE sorted by the SOC internationally agreed order.  The other levels (HLGT, 
HLT, PT) will be presented in alphabetical order 
• 
All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 
1 TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of 
PTs within each SOC.   
Analysis of all TESAE(s) 
• 
All TESAEs by primary SOC and PT (all grade, grade 3-4), showing the number (%) of 
patients with at least 1 TESAE, sorted by the internationally agreed SOC order and by 
decreasing incidence of PTs within each SOC.  
• 
Listing of all SAEs with onset date, grade, relationship and outcome. 
Analysis of all TEAE(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation, by primary SOC and PT (all grade, 
grade 3-4), showing the number (%) of patients sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC. 
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Analysis of all TEAE(s) leading to dose modification  
• 
All TEAEs leading to dose reduction, by primary SOC and PT, showing the number (%) of 
patients, sorted by the internationally agreed SOC order and by decreasing incidence of 
PTs within each SOC. 
• 
All TEAEs leading to dose interruption, by primary SOC and PT, showing the number (%) 
of patients, sorted by the internationally agreed SOC order and by decreasing incidence of 
PTs within each SOC. 
Analysis of AESI  
• 
All AESIs, by PT, showing the number (%) of patients, sorted by decreasing incidence of 
PTs.  
Analysis of TEAE(s) based on Sanofi-defined grouping method  
• 
TEAEs based on sanofi-defined grouping method 
Analysis of pretreatment and post-treatment AEs  
• 
All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
• 
Listing of all pre-treatment and post-treatment AEs. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
• 
Number (%) of patients who died by study period (pre-treatment, on study, post-study as 
appropriate)  
• 
Listing of death 
• 
Treatment-emergent AEs leading to death, by primary SOC and PT showing number (%) 
of patients sorted by internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. This table may be replaced by a listing if number of deaths is smaller 
than or equal to 5. 
2.4.5.3 Analyses of laboratory variables  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Hematological and clinical biochemistry 
toxicities will be assessed from selected laboratory test parameters including hematological and 
serum chemistry parameters. Each test results will be graded by the NCI CTCAE v4.03 as 
appropriate. The number of patients with abnormal laboratory tests at baseline will be presented 
by grade. The frequency of patients in each grade of laboratory tests during treatment will be 
summarized. When appropriate, the summary table will present the frequency of patients with any 
grade of abnormal laboratory tests.  
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Possible drug induced liver toxicity will be assessed using AST, ALT, ALP and total bilirubin. 
The frequency and percentage of subjects by worst NCI CTCAE v4.03 post-baseline grade will be 
presented for these parameters. Summarization and listing of possible Hy’s Law cases identified 
with either ALT/AST >3 x ULN and total bilirubin >2 x ULN will display ALT, AST, ALP and 
total bilirubin.  
2.4.5.4 Analyses of vital sign variables 
The incidence of potentially clinically significant abnormalities (PCSA, defined in Appendix A) at 
any time during the TEAE period will be summarized by treatment group. 
2.4.5.5 Analyses of electrocardiogram variables 
The incidence of PCSAs (defined in Appendix A) at any time during the TEAE period will be 
summarized by treatment group irrespective of the baseline level and/or according to the following 
baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
2.4.5.6 Other safety analyses 
Ophthalmologic examination results will be summarized by number and percentage of subjects 
with abnormality by treatment group any time during the treatment-emergent period. 
Abnormalities in prothrombin time/international normalized ratio, HbA1c  will be described in 
data listings as needed. 
Subgroup safety analyses will be performed by parental study, monotherapy and combination 
therapy, when appropriate. In addition, cumulative incidence combining parental and extension 
studies may be provided for TEAEs, SAEs, AESIs, etc., as appropriate. 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
Not applicable as subjects have been exposed to the IMP in parental studies. 
2.4.7 Analyses of quality of life/health economics variables 
Not applicable. 
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2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
Some general rules of data handling conventions and analyses are provided in this section. 
Baseline variables 
The baseline demographics variables were recorded in the demography CRF page. For laboratory 
parameters and vital signs, the baseline values will be based on the last non-missing value prior to 
the first study drug day in the rollover study. 
2.5.2 Study day calculation 
In some cases such as AEs or laboratory safety presentation, days relative to IMP would be 
needed, this will be defined as the date of the event – 1st IMP date in rollover study + 1 if the event 
occurred on or after 1st study drug date. Otherwise, it was defined as the date of event- 1st study 
drug date.  
2.5.3 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.4 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
The analyses and summaries for variables with continuous scales will be based on the observed 
data only. The number of patients with non-missing observations will be provided. 
Handling of computation of treatment duration if IMP end of treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the end-of-treatment case report form page.  If this date is missing, 
the exposure duration should be left as missing.  
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and follow-up medication. 
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Handling of AEs with missing or partial date/time of onset 
Missing or partial AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent.  No imputation of AE end dates/times 
will be performed.  These data imputations are for categorization purpose only and will not be 
used in listings.  No imputation is planned for date/time of AE resolution. 
Handling of AEs when date and time of first investigational medicinal product administration 
is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day the subject entered into the study should be considered as TEAEs.  The exposure 
duration should be kept as missing. 
Handling of missing assessment of relationship of AEs to investigational medicinal product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation should be done at the data level. 
Handling of missing severity/grades of AEs 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered.  If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table as appropriate. 
Handling of potentially clinically significant abnormalities 
For PCSAs with 2 conditions, 1 based on a change from baseline value or a normal range and the 
other on a threshold value, the first condition being missing, the PCSA will be based only on the 
second condition. 
For PCSAs based on a threshold and/or a normal range, it will be derived using the threshold if the 
normal range is missing. 
Measurements flagged as invalid vy the laboratory will not be summarized nor will they be taken 
into account in the computation of PCSA values. 
2.5.5 Windows for time points 
Summaries by cycles focusing on laboratory data will be tabulated based on cycles as recorded in 
the case report form.  For specific measurements such as vital signs, a window defined around the 
date of treatment may be considered. 
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2.5.6 Unscheduled visits 
When appropriate, unscheduled visit measurements of laboratory data, vital signs, and ECG will 
be used for computation of baseline and worst values and/or grades. For the purpose of descriptive 
analyses of AE data, no distinction will be made between scheduled and unscheduled assessment. 
All data collected will be presented in the data listings. All data will be considered in the 
descriptive data summaries unless otherwise specified in this SAP. 
2.5.7 Pooling of centers for statistical analyses 
Not applicable. 
2.5.8 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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4 
DATABASE LOCK 
The database is planned to be locked within 4 to 8 weeks from the last subject last visit. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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6 
REFERENCES 
Not applicable. 
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