Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 Study
Phase: PHASE2
Conditions: Advanced Gastrointestinal Stromal Tumors
Sponsor: Institut Bergonié

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Efficacy and Safety of PD-0332991 in Patients 
with Advanced Gastrointestinal Stromal 
Tumors Refractory to Imatinib and Sunitinib: 
 A Phase 2 study  
 
CYCLIGIST 
 
Single-arm phase II study 
 
Version n°4.0 du |15|03|2017| – N° IB: |2013|–|01| 
 
Intégrant la modification substantielle N°1 du 06.06.2015 
Intégrant la modification substantielle N°2 du 05.11.2015 
Intégrant la modification substantielle N°3 du 11.03.2016 
Intégrant la modification substantielle N°4 du 15.03.2017 
 
EudraCT n° 2013-000283-28 
 
 
Cet essai est soutenu par l’Institut National du Cancer et la Fondation ARC 
pour la Recherche sur le Cancer.  
 
 
Coordinating Investigator 
Antoine ITALIANO, MD, PhD  
 
 
 
 
Medical Oncologist     
 
 
 
         Department of Medical Oncology 
Institut Bergonié 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
Tel: 05.56.33.33.33 – Fax: 05.56.33.04.85 – E-mail: a.italiano@bordeaux.unicancer.fr 
 
Clinical Research Unit 
Simone MATHOULIN-PÉLISSIER, MD, PhD  
Institut Bergonié, Bordeaux 
Head of the unit 
 
Carine BELLERA, PhD 
Institut Bergonié, Bordeaux 
Biostatisticien 
 
David JUZANX 
Institut Bergonié, Bordeaux 
Clinical Research Assistant 
 
Barbara LORTAL 
Emilie TOULZA  
 
 
 
 
 
 
Institut Bergonié, Bordeaux 
Pharmacists  
 
Pharmacovigilance 
R&D Unicancer, Paris           
 
 
 
 
 
     
 
SPONSOR  
INSTITUT BERGONIÉ

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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................... 19 
1.1 OVERVIEW OF DISEASE PATHOGENESIS, EPIDEMIOLOGY AND CURRENT TREATMENTS ................................. 19 
1.2 INTRODUCTION TO INVESTIGATIONAL TREATMENT(S) AND STUDY RATIONALE ........................................... 20 
1.2.1 
Overview of PD-0332991 ..................................................................................... 20 
1.2.2 
Study rationale and purpose ............................................................................... 23 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................... 24 
2.1 MAIN OBJECTIVE ............................................................................................................ 24 
2.2 SECONDARY OBJECTIVES .................................................................................................. 24 
3. 
STUDY DESIGN .............................................................................................. 25 
4. 
POPULATION ................................................................................................. 25 
4.1 PATIENT POPULATION....................................................................................................... 25 
4.2 INCLUSION CRITERIA ........................................................................................................ 25 
4.3 EXCLUSION CRITERIA ....................................................................................................... 26 
5. 
PLAN OF STUDY ............................................................................................. 27 
5.1 DURATION OF STUDY ....................................................................................................... 27 
5.2 DURATION OF TREATMENT .................................................................................................. 27 
5.3 SURVIVAL DATA COLLECTION .............................................................................................. 28 
5.4 DEFINITION OF END OF THE STUDY ......................................................................................... 28 
5.5 PROTOCOL DEVIATIONS .................................................................................................... 28 
5.6 REPLACEMENT OF PATIENTS ............................................................................................... 29 
6. 
TREATMENT .................................................................................................. 30 
6.1 INVESTIGATIONAL TREATMENT, OTHER STUDY TREATMENT, SUPPORTIVE TREATMENT ................................. 30 
6.1.1 
Dosing regimen ................................................................................................ 30 
6.1.2 
Ancillary treatments .......................................................................................... 30 
6.2 TREATMENT DURATION ..................................................................................................... 31 
6.3 DOSE MODIFICATIONS ...................................................................................................... 31 
6.3.1 
Dose modification and dose delay ........................................................................ 31 
6.3.2 
Treatment interruption and treatment discontinuation .............................................. 31 
6.4 CONCOMITANT MEDICATIONS ............................................................................................... 34 
6.4.1 
Permitted concomitant therapy ............................................................................ 34 
6.4.2 
Permitted concomitant therapy requiring caution and/or action .................................. 35 
6.5 STUDY DRUG SUPPLY ....................................................................................................... 35 
6.5.1 
Study drug preparation and dispensation .............................................................. 35 
6.5.2 
Study drug packaging and labeling ....................................................................... 35 
6.5.3 
Drug supply and storage .................................................................................... 35 
6.5.4 
Study drug compliance and accountability ............................................................. 36 
6.5.5 
Disposal and destruction .................................................................................... 36 
7. 
VISIT SCHEDULE AND ASSESSMENTS ................................................................ 36 
7.1 STUDY FLOW AND VISIT SCHEDULE ........................................................................................ 36 
7.1.1 
Pre-Screening phase and Screening ..................................................................... 38 
7.1.2 
Treatment period .............................................................................................. 41 
7.1.3 
End of treatment visit, including premature withdrawal and study discontinuation visit ... 41 
7.1.4 
Follow up period............................................................................................... 42 
7.2 ASSESSMENT TYPES ........................................................................................................ 42 
7.2.1 
Diagnosis ....................................................................................................... 42 
7.2.2 
Efficacy assessments ........................................................................................ 44 
7.2.3 
Safety and tolerability assessments ...................................................................... 46 
7.2.4 
Biomarkers ..................................................................................................... 49 
8. 
CRITERIA FOR STOPPING THE TREATMENT ........................................................ 49 
9. 
CRITERIA FOR STOPPING THE TRIAL ................................................................. 50 
10. SAFETY EVALUATION ..................................................................................... 50 
10.1 DESCRIPTION OF SAFETY EVALUATION PARAMETERS ..................................................................... 50 

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10.2 METHODS AND SCHEDULE TO MEASURE, COLLECT AND ANALYZE THE SAFETY EVALUATION PARAMETERS ........... 50 
10.2.1 
Definitions ...................................................................................................... 50 
10.2.2 
Serious adverse events and new information notification (responsibility of the investigator)
 
53 
10.2.3 
Non serious adverse events ................................................................................ 55 
10.2.4 
Pharmacovigilance Unit ..................................................................................... 55 
10.2.5 
Serious adverse events and new information notification (responsibility of the sponsor) . 55 
10.2.6 
Notification and registration of unexpected serious adverse events and new information 
(Responsibility of the sponsor) ........................................................................................ 57 
11. EVALUATION CRITERIA ................................................................................... 57 
11.1 PRIMARY ENDPOINT ......................................................................................................... 57 
11.2 SECONDARY ENDPOINTS.................................................................................................... 57 
12. STATISTICAL CONSIDERATIONS ....................................................................... 58 
12.1 SAMPLE SIZE CALCULATION ................................................................................................ 58 
12.2 STUDY POPULATIONS ....................................................................................................... 58 
12.3 STATISTICAL ANALYSIS ..................................................................................................... 59 
12.4 ENDPOINT ANALYSIS ........................................................................................................ 59 
12.5 INTERIM STATISTICAL ANALYSIS ............................................................................................ 59 
13. QUALITY INSURANCE AND TRIAL MONITORING ................................................... 60 
13.1 MONITORING OF THE TRIAL ................................................................................................. 60 
13.1.1 
Steering Committee .......................................................................................... 60 
13.1.2 
Independent Data Monitoring Committee ............................................................... 60 
13.2 QUALITY ASSURANCE ....................................................................................................... 61 
13.2.1 
Data collection ................................................................................................. 61 
13.2.2 
Monitoring ...................................................................................................... 61 
13.2.3 
Handling of missing data .................................................................................... 62 
13.2.4 
Audits ............................................................................................................ 63 
14. ETHICAL, LEGISLATIVE AND REGULATORY CONSIDERATIONS ............................... 63 
14.1 CLINICAL TRIAL AUTHORIZATION ........................................................................................... 63 
14.2 INSURANCE POLICY ........................................................................................................................................ 64 
14.3 INFORMING AND OBTAINING CONSENT FROM PATIENTS ....................................................................................... 64 
14.4 SPONSOR’S RESPONSIBILITIES ........................................................................................................................ 64 
14.5 INVESTIGATOR’S RESPONSABILITIES ................................................................................................................ 65 
14.6 AUTHORITY TO EXECUTE THE TRIAL ................................................................................................................. 65 
14.7 REGULATIONS GOVERNING THE COLLECTION OF HUMAN BIOLOGICAL SAMPLES .................................................... 65 
14.8 FEDERATION DES COMITÉS DE PATIENTS POUR LA RECHERCHE CLINIQUE EN CANCEROLOGIE (FCPRCC) 
(FEDERATION OF PATIENT COMMITEES FOR CLINICAL RESEARCH IN ONCOLOGY) .............................................................. 66 
14.9 DATA PROCESSING ........................................................................................................................................ 66 
15. CONFIDENTIALITY AND OWNERSHIP OF DATA .................................................... 67 
16. REGULATIONS GOVERNING PUBLICATION .......................................................... 67 
16.1 FINAL REPORT ............................................................................................................................................... 67 
16.2 PUBLICATIONS ............................................................................................................................................... 67 
17. REFERENCES ................................................................................................ 68 
18. APPENDIX ..................................................................................................... 73 
 

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APPROVAL AND SIGNATURES OF PROTOCOL 
Study Title: Efficacy and Safety of PD-0332991 in Patients with Advanced Gastrointestinal 
Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 study 
 
Competent 
Authority 
Name : ANSM 
Référence : 
Autorisation initiale 
13/11/2013 
131145A-12 
Autorisation MSA1 
18/09/2015 
Autorisation MSA2 
07/03/2016 
Autorisation MSA3 
12/05/2016 
Ethic Comittee 
Name :   CPP du Sud-
Ouest et d'Outre-Mer
III    
Référence : 
Autorisation initiale 
30/10/2013 
2013/81 
Autorisation MSA1 
26/08/2015 
Autorisation MSA2 
16/12/2015 
Autorisation MSA3 
27/04/2016 
 
 
Autorisation MSI4 
26/04/2017 
   
Noms et Titres des    
Responsables 
Coordonnées 
Date 
Signature 
Managing Director 
Pr François-Xavier MAHON 
Institut Bergonié – Bordeaux  
Tél:05.56.33.33.33 / Fax: 05.56.33.33.30 
Mail : e.bussieres@bordeaux.unicancer.fr  
15/03/2017 
 
Coordinating 
Investigator 
Dr Antoine ITALIANO 
Institut Bergonie – Bordeaux 
Tel 05.56.33.78.05 / Fax : 05.56.33.04.85 
Mail : a.italiano@bordeaux.unicancer.fr 
15/03/2017 
 
Clinical Research 
Manager 
Pr Simone MATHOULIN-PELISSIER 
Institut Bergonié – Bordeaux  
Tél : 05.56.33.33.98 / Fax: 05.56.33.04.66 
Mail : s.mathoulin@bordeaux.unicancer.fr  
15/03/2017 
 
Biostatistician 
Carine BELLERA 
Institut Bergonie – Bordeaux 
Tel:05.56.33.04.95/Fax:05.56.33.04.85 
Mail : c.bellera@bordeaux.unicancer.fr  
15/03/2017 
 
Clinical Research 
Assistant 
David Juzanx 
Institut Bergonié – Bordeaux 
Tél : 05.24.07.19.25 / Fax : 05.56.33.04.85 
Mail : d.juzanx@bordeaux.unicancer.fr 
15/03/2017 
 
I acknowledge having read the whole protocol, and I pledge to lead this protocol in 
accordance with the Good Clinical Practice, the Public Health Law No. 2006-806 of August 
09, 2004 and the implementing Decree n° 2006-477 of April 26, 2006 and as described in 
this document. 
I assume my responsibilities as referent investigator including: 
- Collection of informed consent, dated and signed by patients before any selection 
procedure in the protocol, 
- Validation of case report forms, completed for each patient included in the study, 
- Direct access to source documents for verification by the clinical research assistant (CRA) 
commissioned by the sponsor, 
- Archiving of critical documents of the study for a 15 year-period. 
Name and address of the hospital: 
Name of the Coordinating Investigator: 
DATE : |__|__| |__|__| |__|__|__|__|  
 
 
 
SIGNATURE : 

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LIST OF INVESTIGATORS 
CENTRE 01 - Bordeaux 
Institut Bergonié  
Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest 
Département  d’Oncologie Médicale 
229, cours de l'Argonne 
CS 61283 
33076 Bordeaux Cedex 
Tél : 05.56.33.32.44– Fax : 05.56.33.04.85 
 
Dr. Antoine Italiano 
 
 
Mail : A.Italiano@bordeaux.unicancer.fr 
Dr Maud Toulmonde   
 
 
Mail : m.toulmonde@bordeaux.unicancer.fr  
Dr Sophie Cousin  
 
 
 
Mail : s.cousin@bordeaux.unicancer.fr 
 
CENTRE 02 – Dijon 
 
Centre Georges-François LECLERC 
Centre Régional de Lutte Contre le Cancer 
Département d’oncologie médicale 
1, rue Professeur Marioin – BP 77980 
21079 DIJON cedex 
Tel : 03.80.73.75.28 – Fax : 03.80.73.77.74 
 
Docteur Nicolas Isambert   
 
Mail : nisambert@dijon.cgfl.fr  
Docteur Sylvie Zanetta  
 
 
Mail : szanetta@dijon.cgfl.fr 
Docteur Alice Hervieu   
 
 
Mail : ahervieu@cgfl.fr  
 
 
 
CENTRE 03 - Lille 
 
Centre Oscar Lambret - Centre Régional de Lutte Contre le Cancer 
Département d’oncologie générale 
3 rue Frédéric Combemale  
BP 307 – 59020 LILLE Cedex 
Tél : 03.20.29.59.35 - Fax : 03.20.29.59.71 
 
Docteur Nicolas Penel                             
Mail : n-penel@o-lambret.fr  
Docteur Farid El Hajbi  
 
 
Mail : f-elhajbi@o-lambret.fr 
Docteur Yaovi(Eric) Amela  
 
 
Mail : e-amela@o-lambret.fr   
Docteur Frédrik Laestadius 
 
 
Mail : f-laestadius@o-lambret.fr 
Docteur Diane Pannier  
 
 
Mail : d-pannier@o-lambret.fr 
 
CENTRE 04 – Lyon  
 
Centre Léon Bérard - Centre Régional de Lutte Contre le Cancer 
Département d’oncologie médicale 
28 rue Laënnec  
69373 LYON Cedex 08 
Tél : 04.78.78.27.57 – Fax : 04.78.78.28.51 
 
Professeur Jean-Yves Blay                
Mail : jean-yves.blay@lyon.unicancer.fr   
Docteur Isabelle Ray-Coquart 
 
 
Mail : isabelle.ray-coquard@lyon.unicancer.fr  
Docteur Pierre Biron 
 
 
 
Mail : pierre.biron@lyon.unicancer.fr  
Docteur Philippe Cassier 
 
 
Mail : philippe.cassier@lyon.unicancer.fr  
Docteur Louis  Tassy 
 
 
 
Mail : louis.tassy@lyon.unicancer.fr  
Docteur Olivia Bally 
 
 
 
Mail: olivia.bally@lyon.unicancer.fr 
Docteur Mehdi Brahmi  
 
 
Mail: medhi.brahmi@lyon.unicancer.fr 
 

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CENTRE 05 – Marseille 
 
Hôpital de la Timone - CHU 
Département d’oncologie médicale 
254 rue Saint Pierre  
13385 MARSEILLE Cedex 05 
Tél : 04.91.38.57.08 – Fax : 04.91.76.58.xx 
 
Professeur Florence  Duffaud            
Mail : florence.duffaud@mail.ap-hm.fr   
Docteur Sébastien Salas 
 
 
Mail : sebastien.salas@ap-hm.fr         
 
CENTRE 06– Nancy 
 
Institut de Cancérologie de Lorraine – Alexis VAUTRIN 
Service d’Oncologie Médicale 
6 Avenue de Bourgogne - Cs 30519 
54 519 VANDOEUVRE-LES-NANCY Cedex 
Tél : 03.83.59.85.74 Fax : 03.83.59.83.59 
  
Docteur Maria Rios    
 
 
Mail : m.rios@nancy.unicancer.fr 
Docteur Cyril Abdeddaim  
 
 
Mail : c.abdeddaim@nancy.unicancer.fr 
 
CENTRE 07 – Nantes 
 
Institut de Cancérologie de l’Ouest - Site René Gauducheau  
Département d’oncologie médicale 
Boulevard Jacques Monod 
44805 NANTES SAINT HERBLAIN cedex 
Tél : 02.40.67.99.39 – Fax : 02.40.67.97.76 
 
Docteur Emmanuelle Bompas 
 
Mail : emmanuelle.bompas@ico.unicancer.fr 
Docteur Frédéric Rolland 
 
 
Mail : frederic.rolland@ico.unicancer.fr  
Docteur Damien Vansteene 
 
 
Mail : damien.vansteene@ico.unicancer.fr  
Docteur Carole Gourmelon  
 
 
Mail : carole.gourmelon@ico.unicancer.fr  
Docteur Akila Dandec 
 
 
 
Mail : akila.dandec@ico.unicancer.fr 
Docteur Marie Robert 
 
 
 
Mail : marie.robert@ico.unicancer.fr 
 

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CENTRE 09 - Reims 
 
CHU de Reims - Hôpital Robert Debré 
Centre de Recherche et d'Investigation Clinique (CRIC) - Site HRD 
unité 73 -7ième étage 
Avenue du Général Koenig  
51092 Reims Cedex  
Tel : +33 (0) 3 26 78 78 14 - Fax : +33 (0) 3 26 78 92 19  
 
Professeur Olivier Bouché    
 
Mail : obouche@chu-reims.fr  
Docteur Julien Volet  
 
 
Mail : jvolet@chu-reims.fr  
 
CENTRE 10 – Villejuif 
 
Institut Gustave Roussy 
Centre Régional de Lutte Contre le Cancer 
Département d’oncologie médicale 
39 rue Camille Desmoulins  
94800 VILLEJUIF 
Tél: 01.42.11.43.16 – Fax: 01.42.11.52.19 
 
Docteur Axel Le Cesne                          
 Mail : axel.lecesne@gustaveroussy.fr     
Docteur Julien Domont 
 Mail : julien.domont@gustaveroussy.fr    
Docteur Olivier Mir 
 Mail : olivier.mir@gustaveroussy.fr  
Docteur Sarah Dumont 
 Mail : sarah.dumont@gustaveroussy.fr 
 

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SYNOPSIS 
 
Title of the study 
Efficacy and Safety of PD-0332991 in Patients with Advanced 
Gastrointestinal Stromal Tumors Refractory to Imatinib and 
Sunitinib: A Phase 2 study 
Abbreviation 
of 
the trial 
CYCLIGIST 
Sponsor 
Identification 
Institut Bergonié  
Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest 
229, cours de l'Argonne 
33076 Bordeaux Cedex 
Coordinating 
Investigator 
Docteur Antoine Italiano 
Department of Medical Oncology 
Number of 
investigational 
sites planned 
9 Sites (France): 
- Institut Bergonié – Bordeaux 
- Centre Georges-François Leclerc – Dijon 
- Centre Oscar Lambret - Lille 
- Centre Léon Bérard – Lyon 
- Hôpital de la Timone – Marseille 
- Centre Alexis Vautrin – Nancy 
- Centre René Gauducheau – Nantes 
- Hôpital Robert Debré - Reims 
- Institut Gustave Roussy – Villejuif 
Medical 
Conditions  
Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory 
to Imatinib and Sunitinib 
Study Design 
Exploratory, one-arm, multicenter, phase II clinical trial based on two-
stage Simon’s design 
Number of 
Patients 
63 patients will be recruited. 
Duration of the 
study 
• Beginning of inclusion: January 2014 
• Inclusion period: January 2014 to June 2017 (42 months) 
• Length of patient participation: 18 months 
• Study length: 60 months 
Objectives 
Main objective 
To assess the antitumor activity of PD-0332991 in terms of non-
progression at 16 weeks (after centralized review) in patients with 
documented disease progression while on therapy with imatinib and 
sunitinib for unresectable and/or metastatic GIST. 
Secondary objectives   
• To assess the antitumor activity of PD-0332991 in terms of : 
o Objective response rate (ORR) (as per  RECIST v1.1 criteria) 
o Progression-free survival (PFS) (as per  RECIST v1.1 criteria) 
o Non progression rate and ORR assessed using CHOI criteria 
o Overall survival 
• To assess correlation between ORR-RECIST and  ORR-CHOI 
• To assess the safety of PD-0332991: Incidence of adverse events 
(AEs), serious adverse events (SAEs) and abnormal laboratory results 
(hematology, blood chemistry) will be assessed by the Common 
Terminology Criteria for Adverse Events (CTCAE), v4.0 
• To assess the pharmacodynamic (PD) effect of PD-0332991 on gene 
expression profile in patient consenting to research biopsies (Optional 
study) before starting treatment and on treatment. 
Inclusion Criteria Patients eligible for inclusion in this study have to meet all of the following 

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criteria: 
1. 
Male or female patients ≥ 18 years of age 
2. 
Histologically confirmed GIST of any anatomical location and 
confirmed by the RRePS Network ; positive immunohistochemical 
staining for c-KIT (CD117); or negative staining for KIT, but with either 
positive staining for DOG1 or an identified mutation of KIT or PDGFRA 
gene 
3. 
Homozygous or heterozygous CDKN2A gene deletion assessed 
by array-comparative genomic hybridization (array-CGH)  
4. 
Unresectable 
and/or metastatic 
disease 
with 
documented 
progression according to modified RECIST criteria (see section 7.2.1.5 of 
protocol) after 1st line imatinib and 2nd line sunitinib. Progression on the 
last line of treatment should be confirmed by central review with two 
radiological assessments identical (CT scans or MRI) obtained at less 
from 4 months interval within the 24 months before inclusion.  
5. 
At least one measurable GIST lesion according to RECIST (v1.1 
Appendix 3). A previously irradiated lesion is eligible to be considered as 
a measurable lesion provided that there is objective evidence of 
progression of the lesion prior to starting PD-0332991. 
6. 
A performance status of 0, 1 or 2 according to the Eastern 
Cooperative Oncology Group (ECOG) scale(Appendix 1) 
7. 
Recovery from Grade 2 to 4 toxicity related to prior line of 
treatment assessed according to NCICTCAE v.4.0 (Appendix 2) 
8. 
Adequate bone marrow function as shown by: 
 
Blood absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
Blood platelets ≥ 100 x 109/L 
 
Blood hemoglobin (Hgb) > 9 g/dL 
9. 
Adequate liver function as shown by: 
 
Serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the 
presence or absence of metastases) 
 
Serum or plasma total bilirubin: ≤ 1.5 x ULN (excepted for patients 
with Gilbert’s syndrome) 
10. 
Adequate renal function as shown by serum creatinine ≤ 2 x ULN 
11. 
Patients who give a written informed consent obtained according 
to French and European regulations. 
12. 
Patients affiliated to the French Social Security 
Exclusion 
Criteria 
1. 
Homozygous RB1 gene deletion assessed by array-comparative 
genomic hybridization (array-CGH) 
2. 
Patients who received anti-cancer drugs ≤ 5 days prior to starting 
PD-0332991  
3. 
Patients who are treated or planned to be treated concomitantly 
with other cytotoxic or antineoplastic treatments, such as chemotherapy, 
immunotherapy, biological response modifiers, or radiotherapy 
4. 
Patients with another primary malignancy within 2 years prior to 
starting the study drug, with the exception of adequately treated in-situ 
carcinoma of the uterine cervix, or completely excised (R0 resection) 
basal or squamous cell carcinoma of the skin 
5. 
Patients with a corrected QT interval using Bazett’s formula 
(QTcB) > 470 msec.  
6. 
Current use or anticipated need for food or drugs that are known 
strong cytochrome P450 (CYP)3A4 inhibitors (i.e. grapefruit juice, 
verapamil, 
ketoconazole, 
miconazole, 
itraconazole, 
posaconazole, 
erythromycin, clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, 
diltiazem, and delaviridine) 
7. 
Patients with impairment of gastrointestinal (GI) function or GI 

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disease that may significantly alter the absorption of PD-0332991 (e.g. 
severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or extensive (>1m) small bowel resection, 
inability to swallow oral medications). Prior partial gastrectomy is not an 
exclusion criterion. 
8. 
Patients with prior complete gastrectomy 
9. 
Any of the following in the previous 6 months: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident, 
transient ischemic attack or symptomatic pulmonary embolism. 
10. 
Patients with any clinically significant medical or surgical condition 
which, according to investigators’ discretion, should preclude participation 
- i.e. active or uncontrolled infection, uncontrolled diabetes, active or 
chronic liver disease (cirrhosis, chronic active hepatitis or chronic 
persistent hepatitis) - hepatitis B or C virus carriers with normal liver 
function tests, can be included 
11. 
Known diagnosis of human immunodeficiency virus (HIV) 
infection. HIV testing is not mandatory 
12. 
Patients who are currently receiving anticoagulation treatment with 
therapeutic doses • of warfarin or equivalent anticoagulant (e.g. high dose 
aspirin or clopidogrel or other) • or have an INR >1.5. Treatment with 
acetylsalicyclic acid 100 mg daily or low molecular weight heparin 
(LMWH) is allowed 
13. 
Pregnant or breast-feeding women 
14. 
Women of child-bearing potential not employing two effective 
methods of birth control. Effective contraception must be used throughout 
the trial and 24 weeks after the end of PD-0332991 (e.g. condom with 
spermicidal jelly, foam suppository or film; diaphragm with spermicide; 
male condom and diaphragm with spermicide, oral, implantable, or 
injectable contraceptives). Women of child-bearing potential defined as 
sexually mature women who have not undergone a hysterectomy or who 
have not been naturally postmenopausal for at least 12 consecutive 
months (i.e. who has had menses any time in the preceding 12 
consecutive months), must have a negative serum pregnancy test ≤ 21 
days prior to starting study drug.  
15. 
Fertile males not willing to use contraception as stated above 
16. 
Patients unwilling or unable to comply with the protocol. 
Study drug 
formulation 
PD-0332991 is formulated as gelatin capsules of 125 mg, 100 mg 75mg 
and 25 mg respectively. 
Route of 
administration 
PD-0332991 will be administrated orally 
Administered 
dose 
PD-0332991 dosed on a flat scale of 125 mg. 
Patients should be instructed to administrate PD-0332991 with a sufficient 
amount of water at least 1 hour prior to a meal or at least 2 hours 
following a meal and to swallow the required number of capsules at 
approximately the same time on each day. 
If the patient forgets to take the study treatment as described, he/she 
should skip the dose for that day and resume taking the PD-0332991 on 
the next scheduled day. 
The investigator or designee must instruct the patient to take PD-0332991 
exactly as prescribed. All study treatments prescribed and dispensed to 
the patient and all dose changes during the study must be recorded on 
the CRF. 
Patients must be advised to bring their unused PD-0332991 capsules to 
the investigational site at each visit. 
Treatment 
PD-0332991 will be administrated on a 21 days on / 7 days off dosing 

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schedule 
schedule. 
One cycle is considered to consist of 4 weeks of PD-0332991 
administration. 
Patients will be treated with PD-0332991 until progression of disease, 
unacceptable toxicity, death or discontinuation for any other reason. 
Dose 
modification and 
dose delay 
If the patient forgets to take the study treatment as described, he/she 
should skip the dose for that day and resume taking the PD-0332991 on 
the next scheduled day. 
For patients who do not tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to allow the patient to continue 
the study treatment. The following guidelines need to be applied. 
Table 2 : Dose reduction* 
 
Starting dose level - 0 
Dose level - 1 
Dose level - 2 
PD-0332991 
125 mg 
100 mg 
75 mg 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 75 mg is not allowed. 
 
Treatment 
interruption and 
treatment 
discontinuation 
o Interruption 
If the administration of PD-0332991 must be interrupted because of an 
unacceptable toxicity, study drug dosing will be interrupted or modified 
according to rules described in Table 3 (section 6.3.2.2 of protocol). A 
patient who requires a dose interruption (regardless of the reason for the 
interruption) lasting > 28 days (counting from the first day when a dose 
was missed) must discontinue PD-0332991. All treatment interruption 
must be recorded on the CRF. 
Patients whose treatment is interrupted due to an adverse event or 
abnormal laboratory value must be followed at least once a week for 28 
days and subsequently at 28 day intervals, until resolution or stabilization 
of the event, whichever comes first. 
o Discontinuation 
PD-0332991 will be discontinued for any of the following reasons: 
• Disease progression 
• Consent withdrawal 
• Unacceptable adverse events 
• Major violation of the protocol 
• A dose interruption of > 28 days or a dose delay of > 28 days from the 
intended day of the next scheduled dose 
• Intercurrent illness that prevent further administration of treatment 
• Pregnancy 
• Need for any other types of anticancer therapy 
• General or specific changes in the patient’s condition which render the 
patient unacceptable for further treatment at the discretion of the 
investigator 
• Lost to follow-up 
• Death. 
If PD-0332991 is permanently discontinued, the patient will be considered 
to have completed study treatment. All patients must have safety 
evaluations for 28 days after the last dose of PD-0332991. 
Patients who discontinue PD-0332991 should be scheduled for an End of 
Treatment Visit, whenever possible, after discontinuing PD-0332991, at 
which time all of the assessments listed for the End of Treatment Visit will 
be performed. The date and reason for stopping the study treatment 

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should be recorded on the CRF. 
Efficacy 
evaluation 
Tumor assessment and response will be assessed according to RECIST 
v1.1, with same type of exam in regard of baseline. 
All potential sites of tumor lesions (target and non-target lesions) will be 
assessed using MRI or CT Scan with IV contrast of the Thorax Abdomen 
and Pelvis using a 5mm slice thickness with a contiguous reconstruction 
algorithm (a PET scan is not acceptable for radiological evaluation).  
Evaluation will be assessed: 
- at baseline within 21 days before the first dose of PD-0332991  
- at D(28) of Cycle 1, at D(28) of Cycle 2 then every 8 weeks until month 
six and then every 12 weeks until disease progression or starting other 
treatment. A time window of 7 days is allowed for the radiologist to give 
his/her statement. 
Clinical suspicion of disease progression at any time requires a physical 
examination and radiological confirmation to be performed promptly 
rather than waiting for the next scheduled radiological assessment. 
Response regarding the first endpoint will be assessed by central 
radiology review. 
Whenever the criteria of response are met (Complete Response (CR) or 
Partial Response (PR)), the appropriate imaging tests will be repeated at 
least four weeks later in order to confirm the response. 
The decision regarding patient management will remain with the local 
investigator. 
In addition to RECIST v1.1 evaluation, all subject data acquired using 
contrast-enhanced CT will be evaluated according to Choi criteria. Choi 
reading will be performed locally. 
Safety evaluation 
Safety will be monitored by assessing all adverse events, including 
serious adverse events, the regular monitoring of hematology, blood 
chemistry, cardiac assessments and regular monitoring of vital signs and 
physical condition. These assessments should be performed ± 3 days of 
the scheduled day of assessment except for adverse events that will be 
evaluated continuously through the study (Refer to Table 5 of protocol). 
Scheduling of safety assessments for PD-0332991 cannot be changed 
due to dose interruptions. Refer to Section 6.3 of protocol for permitted 
PD-0332991 adjustments as well as collecting of the adverse events at 
every visit. For details on AE collection and reporting, refer to Section 
10.2 of protocol. 
Biomarkers 
(optional) 
Fresh tumor biopsies FFPE (Formalin-Fixed Paraffin-Embedded) at 
screening and at Day 21 of Cycle 1 are encouraged to be collected. Once 
collected, the samples may be profiled by IHC, and array gene 
expression analysis to identify the pharmacodynamics activity of PD-
0332991 in GIST patients.  
As this is an active area of research, several biomarkers may be analyzed 
if justified by results of internal or external research activities. 
Each sample will be sent to sponsor. All samples will be stored before 
they are analyzed (see section 7.2.4 of protocol for additional details). 
Outcome 
variables 
Primary endpoint  
Efficacy is assessed based on 4-month non progression. Non progression 
is defined as complete or partial response (CR, PR) or stable disease 
(SD), using the Response Evaluation Criteria in Solid Tumors (RECIST 

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v1.1). Non-progression rate will be calculated as the number of alive and 
progression free patients divided by the number of eligible and 
assessable patients for the efficacy analysis.  
Eligible and assessable populations are described in corresponding 
section of protocol.  
As recommended by RECIST v1.1, all claimed response will be centrally 
reviewed by an expert of the study. The results of the centralized 
radiological review will be used for the analysis of the primary endpoint.  
Secondary endpoints 
• Objective response is defined as complete response (CR) or partial 
response (PR) according to RECIST v1.1. 
• Progression-free survival is defined as the time from the first 
administration of treatment to progression (as per RECIST v1.1) or death 
of any cause, whichever occurs first 
• Overall survival is defined as the time from the first administration of 
treatment to death. 
• Progression will also be assessed using CHOI criteria  
• Safety of PD-0332991 will be assessed by the Common Terminology 
Criteria for Adverse Events (CTCAE), v4.0  
Statistical 
considerations 
Sample size calculation 
The primary evaluation endpoint is the non-progression rate at 4 months. 
- We rely on an optimal two-stage Simon’s design (Simon, 1989). Based 
on the following hypotheses under PD-0332991 treatment:  
• 25% non-progression rate (null hypothesis),  
• 45% acceptable non-progression rate (alternative hypothesis),  
• 5% type I error rate,   
• 90% power, 
A total of 57 assessable subjects will be necessary, with 22 assessable 
subjects recruited to the first stage.  
- Stage 1: Following the inclusion of the first 22 assessable patients, if 6 
or less patients are progression-free (complete response, partial 
response or stable disease), the study will be terminated early. 
Otherwise, the second group of 35 subjects will be recruited.  
- Stage 2: If at the end of recruitment, 20 patients or more are 
progression-free (out of the 57 evaluable patients), PD-0332991 will be 
considered worthy of further testing in this disease. 
Eligible and assessable populations are described in corresponding 
section of protocol. 
Given the disease is rare and the absence of standard treatment in this 
indication, inclusion will not be suspended after the recruitment of the first 
22 patients. Inclusion will be pursued, while data on the first 22 patients 
will be analyzed. 
In order to account for not evaluable patients (+/- 10%), 63 patients will be 
recruited. 
The anticipated accrual rate is 3-4 patients/months. 
 
Duration of 
Study period 
(per patient) 
Patients will be evaluated at scheduled visits in up to three study periods:  
• Pre-treatment (PRE TT): from signature of informed consent to the first 
treatment by PD-0332991. 
• Treatment (TT): from the first treatment by PD-0332991 to the first 28 
days following the last PD-0332991 administration. 
• Follow-up (FUP): after treatment discontinuation, all patients must be 
followed up for 28 days after the last dose of the study drug for safety 
assessment (AEs and/or SAEs). 
Patients will be considered to be on-study from the signature of the 

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informed consent to the end of follow-up period. 
All patients will be followed up every 3 months for survival for one year 
and information will be documented in the source documents and in CRF. 
Patients will be followed for progression. Any patient who is discontinued 
from PD-0332991 for any reason (except for death, disease progression, 
lost to follow-up, subject/guardian decision [withdrawal of consent], or 
study termination) will continue to have tumor assessments performed 
every 3 months until radiological progression, start of new anticancer 
therapy or death 

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Schedule of assessments and procedures 
 
Pre-
Screening 
phase 
Screening/Baseline 
Cycle 1 
Cycle 
N 
End of Study 
Treatment 
Survival 
Follow-
Up 
Visit Name 
 
 
V1 
V2 
Vn 
 
 
Day of cycle 
 
-21 to -1 
Day 
1 
Day 
15 
Day 
1 
Within 28 days 
after 
discontinuation 
of 
study drug 
 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
CDKN2A gene 
deletion assessed 
by array-CGH 
(centralized to 
Bergonie Institute) 
X 
 
 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
X 
 
 
 
 
 
Relevant medical 
history/current 
medical 
conditions 
 
X 
 
 
 
 
 
Diagnosis and 
extent of cancer 
 
X 
 
 
 
 
 
Prior 
antineoplastic 
therapy 
 
X 
 
 
 
 
 
Prior/concomitant 
medications 
 
X 
Continuous until 28 days post-late dose 
of study drug 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
 
 
 
 
 
 
X 
Clinical exam 
 
 
 
 
 
 
 
Physical 
examination 
 
X 
X 
X 
X 
X 
 
Performance 
status 
 
X 
X 
X 
X 
X 
 
Height/Weight 
 
X 
X 
X 
X 
X 
 
Vital signs 
 
X 
X 
X 
X 
X 
 
Laboratory 
assessments 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
X 
X 
Days 
1 and 
15  
X 
 
Chemistry 
 
X 
X 
X 
X 
X 
 
Coagulation 
 
X 
X 
X 
X 
X 
 
Pregnancy test 
 
X 
X 
 
X 
X 
 
Imaging/Other 
assessments 
 
 
 
 
 
 
 
Tumor evaluation: 
CT scan or MRI 
 
Day-21 to -1 
D(28) of Cycle 1, D(28) of Cycle 2 
then every 8 weeks until month six 
and then every 12 weeks 
 
ECG 
 
X 
X 
X 
X 
X 
 
Safety 
 
 
 
 
 
 
 

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Adverse events 
 
 
Continuous until 28 days post-late 
dose of study drug 
 
Biomarkers 
(Optional study) 
 
 
 
 
 
 
 
Tumor biopsy 
Day –3 to Day -1 
Day 21 cycle 1 
 
X 
Day 21 Cycle 1 
 
 
Others 
 
 
 
 
 
 
 
PD-0332991 
administration 
 
 
21-days on, 7 days off 
 
 
Reason for 
withdrawal 
 
 
 
 
 
X 
 
Survival update 
every 3 months for 
one year 
 
 
 
 
 
 
X 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE(s) 
Adverse Event(s) 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
APTT 
Activated Partial Thromboplastin Time 
AST  
Aspartate Aminotransferase 
AUC 
Air Under Curb 
βhCGs 
Beta Human Chorionic Gonadotrophins 
BCRP 
Breast Cancer Resistant Protein 
BSC 
Best Supportive Care 
BUN 
Blood Urea Nitrogen 
CDK 
Cyclin-dependent Protein Kinase 
CGH 
Comparative Genomic Hybridization 
CPK  
Creatine Phosphokinase 
CR 
Complete Response 
CRP 
C-Reactive Protein 
CRF  
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of Variation 
DLT 
Dose-limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
ECG  
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMEA 
European MEdecin Agency 
EPO 
Transfusion and/or Erythropoietin 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FUP 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
GI 
Gastro Intestinal 
GIST 
Gastrointestinal Stromal Tumors 
HCG 
Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
HPLC 
High-performance Liquid Chromatography 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IC50 
Half-maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Investigational Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LPLV 
Last Patient Last Visit 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LMWH 
Low Molecular Weight Heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Overall Response Rate 

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OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
P-gp 
P-glycoprotein 
PR 
Partial Response 
PRE TT 
Pre-treatment 
PS 
Performance Status 
PT 
Prothrombin Time 
QD 
Quotidien Dose 
RBC 
Red Blood Cell 
RD 
Recommended Dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommend Phase 2 Dose 
RT 
Plasma-to-blood Ratio 
SAE(s) 
Serious Adverse Event(s) 
SCID 
Severe Combined Immunodeficiency 
SD 
Stable Disease 
STS 
Soft Tissue Sarcoma 
TKI 
Tyrosine Kinase Inhibitor 
TT 
Treatment 
TTP 
Time to tumor Progression 
ULN 
Upper Limit of Normality 
US 
United State 
USPI 
U.S. Package Inserts 
VEGF 
Vascular Endothelial Growth Factor 
VGPR 
Very Good Partial Response 
WBC 
White Blood Cells 
WHO 
World Health Organization 

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1. Background 
1.1 Overview of disease pathogenesis, epidemiology and current treatments 
Mesenchymal tumors of the gastrointestinal tract, most of which originally classified 
as leiomyoma or leiomyosarcoma, have been termed stromal tumors (Mazur and 
Clark 1983), (Hamilton and Aaltonen 2000), (Corless et al 2004). More recently, it 
has become clear that gastrointestinal stromal tumors (GIST) are the most frequent 
mesenchymal tumors of the gastrointestinal tract. GIST are thought to arise from the 
interstitial cells of Cajal (Perez-Atayde et al 1993) which compose the myenteric 
plexus found in the stomach and bowel. These tumors are most frequently located in 
the stomach (50–60%), small bowel (20–30%), and large bowel (10%), with the 
esophagus, mesentery, omentum, and retroperitoneum accounting for the remaining 
cases (Fletcher et al 2002). On the basis of population-based incidence rates in 
Sweden (Nilsson et al 2005), it has been estimated that approximately 5000 new 
cases of GIST are diagnosed each year in the US with similar incidence rates being 
reported in the EU (Corless et al 2004). GIST occur predominantly in middle-aged 
and older people, with a median age of approximately 60 years and no apparent 
gender preference (Hamilton and Aaltonen 2000, De Giorgi and Verweij 2005). 
GIST may display a variety of phenotypic features, many of which correlate with 
patient prognosis. Thus, there is an emphasis on tumor size and mitotic index for risk 
stratification of primary GIST, with such risk being correlated with tumor recurrence 
(Fletcher et al 2002). At the present time, risk stratification based on pathologic 
criteria is preferable to the use of such terms as benign or malignant GIST (Corless 
et al 2004). Patients with a gastric GIST seem to fare slightly better than those with 
intestinal primary tumors (Emory et al 1999). GIST have a tendency to recur both 
locally and in the form of peritoneal and liver metastases, with lymphnode 
metastases being infrequent (Corless et al 2004). Surgical resection is the mainstay 
of therapy for primary GIST, a disease that is typically refractory to cytotoxic 
chemotherapy (DeMatteo et al 2000, Plaat et al 2000). 
The diagnosis of GIST has been facilitated by the discovery that these tumors stain 
positively with an immunohistochemical marker (CD117) previously used to stain the 
interstitial cells of Cajal (Hirota et al 1998, Kindbolm et al 1998). The antibody used in 
the immunohistochemical reaction recognizes KIT, a membrane receptor for stem-
cell factor (Yarden et al 1987). Currently, KIT expression is a major diagnostic 
criterion for GIST, and few other KIT-positive mesenchymal tumors of the 
gastrointestinal tract are likely to be confused with GIST; notable exceptions include 
metastatic melanoma and malignant vascular tumors (Miettinen et al 2002). 
Approximately 95% of GIST stain positively for CD117 (Corless et al 2004). In most 
of these cases, somatic mutations can be found in the gene encoding the KIT 
protein, typically in exons 11 and 9 (more rarely in exon 13 or exon 17) (Hirota et al 
1998, Corless et al 2004). These mutations confer a gain of function to the receptor, 
which becomes constitutively activated regardless of the presence of its ligand, stem-
cell factor. In some cases of GIST, no mutation is found in KIT. The search for 
additional molecular abnormalities led to the discovery that in many KIT-negative 
GIST there is a somatic mutation in the gene encoding the platelet-derived growth-
factor receptor (PDGFR) (Heinrich et al 2003, Hirota et al 2003). PDGFR is closely 
related to KIT, and also belongs to the type III family of receptor tyrosine kinases 
(Rousset et al 1995). Mutated KIT or PDGFR confer a growth advantage to tumor 
cells, and have recently become targets for therapeutic intervention. 

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Imatinib is an oral tyrosine-kinase inhibitor that has revolutionized the treatment of 
GIST, since this drug is able to inhibit the tyrosine-kinase activities of KIT and 
PDGFR Buchdunger et al 1996, Heinrich et al 2003, Joensuu et al 2001). Imatinib 
was approved in February 2002 for the treatment of patients with metastatic and/or 
unresectable GIST, and the recommended dose was 400 or 600 mg daily (Dagher et 
al 2002). The approval was based on a pivotal Phase II trial, in which 147 patients 
with metastatic and/or unresectable GIST were randomized to treatment with daily 
doses of imatinib of 400 mg (N=73) or 600 mg (N=74). 
The combined response rate by Southwest Oncology Group criteria in the two arms 
of the study was 53.7% (Demetri et al 2002). More recently, imatinib was approved 
for the treatment of patients with GIST, who have had surgery to remove their cancer 
and are at significant risk of the cancer returning. Data supporting this new use for 
Glivec demonstrates that 98% of patients receiving 400mg Glivec daily for a year 
after surgery to remove their GIST did not experience their tumors returning after 12 
months compared to 83% of patients taking placebo. 
Some patients do not derive benefit from conventional-dose imatinib, while others 
develop resistance after several months of successful treatment. For all such 
patients, current therapeutic options are limited. Conventional modalities such as 
chemotherapy and radiation therapy have proven to have limited efficacy for the 
treatment of patients with GIST. Among patients with unresectable or metastatic 
disease at diagnosis, the ESMO guidelines recommend treatment with imatinib until 
disease progression (ESMO Guidelines, 2010). 
When there is disease progression, the ESMO guidelines recommend continuing 
tyrosine kinase inhibition with increased daily doses of imatinib (800 mg) or with 
sunitinib. However, resistance to imatinib may develop and represents a clinical 
challenge. Sunitinib has been approved in 2009 by the European Commission for 
patients whose disease has progressed or who are intolerant to imatinib therapy. A 
Phase III study of sunitinib versus placebo in patients who had progressed during 
imatinib therapy was terminated early because of positive interim results. Time to 
tumor progression (TTP) was 6.3 months on sunitinib versus 1.5 on placebo and 
sunitinib reduced the risk of death by approximately 50% compared to placebo 
(Demetri et al 2006). 
1.2 Introduction to investigational treatment(s) and study rationale 
1.2.1 
Overview of PD-0332991 
PD-0332991 is a highly selective inhibitor of CDK4/CYCLIND1 kinase activity (IC50: 
11 nM, Ki= 2nM) with little or no activity against a large panel of 34 other protein 
kinases including other CDKs and a wide variety of tyrosine and/serine threonine 
kinases. Cdk6, another enzyme that also complexes with cyclin-D subunits, is also 
commonly expressed in mammalian cells and tumors. Cdk6 is highly homologous to 
Cdk4 and can perform the same function by phosphorylating Rb, thus potentially 
creating a redundant mechanism to promote cell cycle progression. 
Consequently, inhibition of both enzymes is necessary to ensure complete 
suppression of Rb phosphorylation and the greatest possible spectrum of antitumor 
activity. Results indicate that PD-0332991 inhibits Cdk6 with equivalent potency to 
Cdk4. 
PD-0332991 inhibits tumor growth of several types of human xenograft tumors (SF-
295, MDA-MB-435, Colo-205, and others), grown in SCID mice. Estimated steady-
state plasma concentrations of 1000 ng/mL resulted in 80% to 90% inhibition of 

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phospho-Rb formation and 50% reduction of tumor growth. Reduction in phospho-Rb 
was rapidly reversible as plasma PD-0332991 concentrations declined. 
In nonclinical species (rat, dog, and monkey), PD-0332991 exhibits low to moderate 
plasma clearance, large volume of distribution, and moderate oral bioavailability 
ranging from 23% to 56%. Plasma protein binding of PD-0332991 is moderate in 
mouse, rat, dog, and human plasma. PD-0332991 shows a preferential distribution to 
red blood cells over plasma in humans, but similar distribution between red blood 
cells and plasma in nonclinical species. 
Radioequivalents were widely distributed to most rat tissues and fluids following an 
oral dose of [14C]PD-0332991, with radioactivity levels consistently greater than those 
observed in blood. PD-0332991 is metabolized to multiple metabolites in a 
qualitatively similar manner in rat, dog, and human liver microsomes. In vitro, PD-
0332991 is primarily metabolized by CYP3A enzymes. Following oral administration 
of [14C]PD-0332991 to intact and bile duct-cannulated rats, the metabolic pathways 
involve oxidation, glucuronidation, sulfation, and combinations of these reactions. 
Identified oxidative metabolites were qualitatively similar between in vitro and in vivo 
studies. In rats, [14C]PD-0332991 was mainly eliminated via the feces (>82% within 
168 hours); the high fecal elimination occurred via biliary excretion (53% to 82% 
within 72 hours recovery in bile). PD-0332991 and its oxidative metabolite, PF-
05089326, demonstrated little or no inhibition of CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, or CYP2D6 enzyme activities and thus, showed low potential for 
CYP-mediated pharmacokinetic drug interactions. However, PD-0332991 and PF-
05089326 caused time-dependent inhibition of CYP3A midazolam 1’-hydroxylase 
and testosterone 6β-hydroxylase activities with Ki and kinact values for PD-0332991 of 
10 μM, 0.036 min-1 and 19 μM, 0.087 min-1 and for PF-05089326 of 7.0 μM, 0.094 
min-1 and 6.4 μM, 0.15 min-1, respectively. Therefore, PD-0332991 and its metabolite 
may have the potential for pharmacokinetic drug interactions with compounds for 
which CYP3A-mediated metabolism constitutes the primary mechanism of clearance. 
The potential interaction of PD-0332991 with efflux transporters P-glycoprotein (P-gp) 
and breast cancer resistant protein (BCRP) was investigated in vitro using digoxin 
and talinolol substrates. The percent inhibition of digoxin and talinolol efflux reached 
42% and 71% for P-gp and 44% and 74% for BCRP at the highest measured PD-
0332991 concentration (6.09 μM). Therefore, PD-0332991 may have the potential to 
affect the absorption and/or pharmacokinetics of drugs that are substrates of P-gp or 
BCRP. 
PD-0332991 had no effect on heart rate, rhythm, or blood pressure in dogs given 
single oral doses of 10 and 30 mg/kg (200 and 600 mg/m2, respectively); however, 
evidence of QT prolongation was noted at both doses. Corresponding Cmax and 
AUC(0-24) values associated with these doses were 
511 ng/mL and 
8800 ng•h/mL, 
respectively. PD-0332991 inhibited hERG current in HEK293 cells and increased 
action potential duration at 90% repolarization in Purkinje fibers consistent with QT 
prolongation observed in vivo. 
Significant and transient pulmonary effects occurred in anesthetized dogs given a 
single IV dose of PD-0332991 at 5 mg/kg (100 mg/m2). Associated observed peak 
plasma drug concentrations were 
2040 ng/mL. These effects were consistent with 
centrally mediated respiratory depression. No changes in pulmonary function were 
noted in dogs with observed peak plasma concentrations 414 ng/mL at 1 mg/kg (20 
mg/m2). 
In pivotal repeated-dose toxicology studies, PD-0332991 was lethal in rats; 
associated steady-state AUC(0-24) values were 46,600 and 11,100 ng•h/mL in males 
and females, respectively. The reason for increased susceptibility of females for 

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lethality on an exposure basis is unknown. Reversible bone marrow pancytopenia 
occurred in male and female rats at 
50 mg/kg (300 mg/m2) and 
100 mg/kg (600 
mg/m2), respectively. Changes in males resulted in decreased peripheral blood cell 
counts. Testicular degeneration occurred in rats at 
50 mg/kg and was progressive 
in severity throughout the reversal period (1-month treatment-free observation 
period). Rales and tracheal mucosal atrophy occurred in male rats at 
50 mg/kg and 
in female rats at 
100 mg/kg. Target organ toxicity in rats generally occurred to a 
greater extent in males than in females at equivalent doses and may have been 
related to systemic drug exposures that were significantly higher in males (17,300 to 
46,600 ng•h/mL) than females (2530 to 11,100 ng•h/mL). Dose- and time-dependent 
decreases in hematology parameter values occurred in dogs given PD-0332991 at 
0.6 mg/kg (12 mg/m2); associated steady-state AUC(0-24) values were 
548 
ng•h/mL. Neutrophils and monocytes were most affected; the nadir occurred at the 
end of dosing, and all changes were reversible. Reversible bone marrow 
pancytopenia and lymphoid depletion occurred in dogs at 
0.6 mg/kg. Testicular 
degeneration occurred in dogs at 
0.6 mg/kg and was progressive in severity 
throughout the reversal period. 
PD-0332991 was not mutagenic in bacteria or clastogenic in human lymphocytes in 
vitro with or without metabolic activation. PD-0332991 was positive for micronucleus 
formation in vitro, and in male rats following oral administration. Additional work 
demonstrated that PD-0332991 may have aneugenic potential. 
Based on results from in vitro testing in the 3T3 neutral red uptake assay, PD-
0332991 is considered non-phototoxic. 
As of 30 September 2011, 4 clinical studies with PD-0332991 are ongoing: 
1. A Phase 1 dose-escalation single agent study in patients with advanced cancers 
or lymphomas (A5481001). Seventy-four patients have been dosed. Enrollment is 
closed. 
2. A Phase 1 single-agent study in patients with relapsed/refractory mantle cell 
lymphoma (A5481002). Seventeen patients have been dosed. Enrollment is closed. 
3. A Phase 1/2 study in combination with letrozole in patients with advanced breast 
cancer (A5481003). Sixty-four patients have been enrolled and treated in this study. 
4. A Phase 1/2 study in combination with bortezomib and dexamethasone 
(A5481004) in patients with relapsed/refractory multiple myeloma. Fifty-one patients 
have been enrolled and treated in this study. 
The Phase 1 dose-escalation study of PD-0332991 (A5481001) evaluated two 
different oral dosing schedules: Schedule 3/1 (3 weeks on treatment/1 week off 
treatment) and Schedule 2/1 (2 weeks on treatment/1 week off treatment). The 
recommended Phase 2 dose (RP2D) for Schedule 3/1 and Schedule 2/1 was 
determined to be 125 mg QD and 200 mg QD, respectively. Overall, the adverse 
events (AEs) reported in this study were manageable and reversible. The dose-
limiting toxicities (DLTs) that occurred during this study were similar between the two 
dosing 
schedules 
and 
consisted 
of 
myelotoxic 
events, 
i.e. 
neutropenia, 
thrombocytopenia, and/or anemia. The myelosuppression was reversible, not 
cumulative, and non complicated, and resulted in treatment discontinuation in only 
one patient. While the safety profile of the two schedules was comparable, greater 
long-term antitumor activity was observed with Schedule 3/1, therefore such regimen 
was selected for further clinical development. 
The safety profile observed thus far in the combination studies A5481003 and 
A5481004 appears consistent with that of PD-0332991 as a single agent and is 
mainly characterized by neutropenia, thrombocytopenia, and/or anemia. Nausea, 
diarrhea, constipation, and fatigue were also noted in PD-0332991 studies. 

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As far as antitumor activity is concerned, one patient with testicular cancer enrolled to 
study A5481001 achieved a confirmed partial response. In that same study, 32% of 
patients with a variety of tumor types experienced stable disease for two or more 
cycles of treatment, 24% for 4 or more cycles, and 13% for 10 or more cycles. A total 
of 5 patients experienced stable disease for 20 or more cycles. 
In patients with refractory mantle cell lymphoma (Protocol A5481002), as of 30 
September 2011, a total of 3 subjects achieved a best response of either PR (2 
subjects [12.5%]) or CR (1 subject [6.3%]). The overall ORR of the 16 patients 
evaluable for response was 18.8% (95% CI: 4.0% to 45.6%). Seven subjects (43.8%) 
had a best response of SD/no response. 
Both median time to progression (TTP) and progression-free survival (PFS) were 5.5 
months (95% CI: 2.0 to 18.6 months). The probability of being event-free at Month 12 
was 36.4% (95% CI: 11.1 to 61.6%). Due to the small number of subjects who had a 
response, duration of response (DR) was not calculated. 
The response data from the Phase 1 portion of Study A5481003 showed that of the 9 
patients with measurable disease (3 patients with bone only disease), 3 patients 
(33%) achieved a PR. 
Another 5 patients (42%) had stable disease for 
6 months, and the clinical benefit 
rate was 67% (PR + SD 
6 months). Response data for the Phase 2 portion of this 
trial is not mature and will not be presented at the time of this summary. 
The response data from the Phase 1 portion of Study A5481004 showed that 2 
patients achieved a very good partial response (VGPR). In Phase 2, of the 30 
patients treated, 25 patients were evaluable for response. Of the 25 patients, 1 
patient achieved a complete response (CR), 1 patient VGPR, and 3 patients 
achieved PR. 
Pharmacokinetic data from study A5481001 indicate that plasma pharmacokinetics of 
PD-0332991 are low to moderately variable with generally dose proportional 
exposures over the dose range evaluated. PD-0332991 is slowly absorbed with a 
half-life of ~27 hours. 
Renal excretion was determined to be a minor route of elimination. In the pilot food 
effect assessment, higher exposures and peak concentrations were observed in the 
fed state compared to the fasted state. Based on these data, it was concluded that 
since administration of PD-0332991 with a high fat meal may increase PD-0332991 
exposure, patients should be fasted from 1 hour before to 2 hours after dosing, 
unless otherwise indicated in clinical protocols. The effects of a non-fat meal on the 
pharmacokinetics of PD-0332991 have not been evaluated. 
Interpretation of these data and the possible risks associated with administration of 
PD-0332991 to humans are summarized in Section 7 of the ongoing Investigator’s 
Brochure. 
1.2.2 
Study rationale and purpose 
As mentioned in Section 1.1, the treatment of advanced GIST patients is based on 
imatinib followed with sunitinib in case of resistance/intolerance. However, the 
median progression-free survival (PFS) on sunitinib is frequently short, and after 
failure with both imatinib and sunitinib, treatment remains controversial. Patients who 
fail to respond or have progression after therapy with these two drugs have a grim 
prognosis. Given the limited options for the third-line treatment of patients with 
imatinib- and sunitinib-refractory/intolerant GIST, there is a need for novel therapeutic 
strategies.   
The so-called molecular signature “CINSARC” is a strong and validated predictor of 
metastasis in patients with GISTs (Lagarde et al., 2012). Remarkably, none of the 

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patients assigned to the good prognosis group developed metastases or relapsed. 
The CINSARC signature comprises 67 genes involved in maintenance of 
chromosome integrity and mitotic control, indicating that these processes play a 
crucial role in the development of metastasis in sarcomas (Chibon et al., 2010). The 
top-ranked gene being overexpressed in this signature was AURKA. The AURKA 
protein is a mitotic centrosomal protein kinase amplified in many cancer types 
(Marumoto et al., 2005). AURKA overexpression induces centrosome duplication and 
segregation abnormalities leading to aneuploidy and malignant transformation 
(Marumoto et al., 2005). Whole chromosome losses are the most frequently 
observed alterations in GISTs and are assumed to originate from unequal 
chromosome segregation, which can be induced by AURKA overexpression 
(Schvartzman et al. 2010). Contrary to the mechanism seen in other cancers, we 
have shown that AURKA overexpression in GISTs is not explained by gene 
amplification, but is instead a secondary change we postulate to be caused by 
defects in Restriction point control. Indeed, CDKN2A deletion is frequently deleted in 
GIST with metastatic relapse (Lagarde et al. 2012). In the few cases of high-risk gist 
lacking CDKN2A deletion, the RB1 gene is deleted. This suggests a strong 
association between CDKN2A deletion, RB1 deletion, AURKA expression, CINSARC 
score, and metastasis in GIST.  
CDKN2A is located at 9p21 chromosome and encodes 2 key tumor suppressor 
proteins, p16INK4a and the p14ARF, which regulate the Restriction point and p53, 
respectively. Previous studies on GISTs have linked 9p21 alterations to tumor 
progression (El-Rifai et al. 2000; Kim et al., 2000; Schneider-Stock et al., 2003; 
Schneider-Stock et al., 2005; Romeo et al. 2009; Haller et al., 2008) but the driver 
gene was not positively identified (CDKN2A, CDKN2B, or MTAP) (Astolfi et al., 2010; 
Belinsky et al., 2009; Perrone et al., 2005; Assamaki et al. 2007; Huang et al., 2009). 
A recent study has shown that homozygous 9p21 deletions target CDKN2A and more 
specifically p16INK4a 4. Most of the CINSARC genes are known to be under the 
transcriptional control of E2F. RB1 sequesters E2F, which is released from the 
complex upon RB1 phosphorylation by CDK4. CDK4 is, in turn, inhibited by 
p16INK4a. Hence, we hypothesize that alteration of the restriction point via deletion 
of p16INK4a (and more rarely of RB1: 20% of cases) gene in GISTs is likely to be a 
causative event that leads to the overexpression of CINSARC genes, which in turn 
induce chromosome instability and ultimately metastasis. Low p16INK4a expression 
was associated with response to PD-0332991 in several in vitro tumor models. 
(Konecny et al. 2011; Katsumi et al. 2011; Finn et al. 2009). Considering our 
molecular data, we believed that PD-0332991 warrants clinical investigation in 
advanced gastrointestinal stromal tumors with alteration of p16INK4a. This alteration 
is detectable by comparative genomic hybridization which is a technique highly 
manageable in the context of routine clinical care and clinical trial. 
2. Objectives and endpoints   
2.1 Main objective 
To assess the antitumor activity of PD-0332991 in terms of non-progression at 16 
weeks (after centralized review) in patients with documented disease progression 
while on therapy with imatinib and sunitinib for unresectable and/or metastatic GIST. 
2.2 Secondary objectives   
 To assess the antitumor activity of PD-0332991 in terms of : 
o Objective response rate (ORR) (as per  RECIST v1.1 criteria Appendix 3) 

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o Progression-free survival (PFS) (as per  RECIST v1.1 criteria Appendix 3) 
o Non progression rate and ORR assessed using CHOI criteria (Appendix 4 ) 
o Overall survival 
 To assess correlation between ORR-RECIST and  ORR-CHOI 
 To assess the safety of PD-0332991: Incidence of adverse events (AEs), serious 
adverse events (SAEs) and abnormal laboratory results (hematology, blood 
chemistry) will be assessed by the Common Terminology Criteria for Adverse Events 
(CTCAE), v4.0. (Appendix 4) 
 To assess the pharmacodynamic (PD) effect of PD-0332991 on gene expression 
profile in patient consenting to research biopsies (Optional study) before starting 
treatment and on treatment.  
3. Study design   
This is a multicentre single-arm Phase II study evaluating the efficacy and safety of 
orally PD-0332991, 125 mg/day, 21 days on/7 days off, in patients with documented 
disease progression while on therapy with 2nd line sunitinib for unresectable and/or 
metastatic GIST. Randomization, i.e., the use of a control group does not appear 
relevant. Indeed, the usual treatment for advanced Gastrointestinal Stromal Tumors 
Refractory to Imatinib and Sunitinib is best supportive care for which outcome data 
are already available (Demetri et al., 2012; Italiano et al., 2012). 
Sixty three patients will be included in 10 centres of the French Sarcoma Group over 
a period of 18 months of enrolment. 
4. Population 
4.1 Patient population 
Adult patients with documented disease progression 2nd line sunitinib for 
unresectable and/or metastatic GIST. 
Written informed consent is obtained prior to any screening procedures. The 
investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrolment in the study. 
4.2 Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Male or female patients ≥ 18 years of age 
2. Histologically confirmed GIST of any anatomical location and confirmed by the 
RRePS Network ; positive immunohistochemical staining for c-KIT (CD117); or 
negative staining for KIT, but with either positive staining for DOG1 or an 
identified mutation of KIT or PDGFRA gene 
3. Homozygous or heterozygous CDKN2A gene deletion assessed by array-
comparative genomic hybridization (array-CGH)  
4. Unresectable and/or metastatic disease with documented progression 
according to modified RECIST criteria (see section 7.2.1.5) after 1st line 
imatinib and 2nd line sunitinib. Progression on the last line of treatment should 
be confirmed by central review with two radiological assessments identical (CT 
scans or MRI) obtained at less from 4 months interval within the 24 months 
before inclusion.  
5. At least one measurable GIST lesion according to RECIST (v1.1 Appendix 3). 
A previously irradiated lesion is eligible to be considered as a measurable 
lesion provided that there is objective evidence of RECIST progression of the 
lesion prior to starting PD-0332991. 

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6. A performance status of 0, 1 or 2 according to the Eastern Cooperative 
Oncology Group (ECOG) scale(Appendix 1) 
7. Recovery from Grade 2 to 4 toxicity related to prior line of treatment assessed 
according to NCICTCAE v.4.0 (Appendix 2) 
8. Adequate bone marrow function as shown by: 
 Blood absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 Blood platelets ≥ 100 x 109/L 
 Blood hemoglobin (Hgb) > 9 g/dL 
9. Adequate liver function as shown by: 
 Serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the presence or 
absence of metastases) 
 Serum or plasma total bilirubin: ≤ 1.5 x ULN (excepted for patients with 
Gilbert’s syndrome) 
10. Adequate renal function as shown by serum creatinine ≤ 2 x ULN 
11. Patients who give a written informed consent obtained according to French 
and European regulations. 
12. Patients affiliated to the French Social Security  
4.3 Exclusion criteria 
1. Homozygous RB1 gene deletion assessed by array-comparative genomic 
hybridization (array-CGH) 
2. Patients who received anti-cancer drugs ≤ 5 days prior to starting PD-0332991  
3. Patients who are treated or planned to be treated concomitantly with other 
cytotoxic or antineoplastic treatments, such as chemotherapy, immunotherapy, 
biological response modifiers, or radiotherapy 
4. Patients with another primary malignancy within 2 years prior to starting the 
study drug, with the exception of adequately treated in-situ carcinoma of the 
uterine cervix, or completely excised (R0 resection) basal or squamous cell 
carcinoma of the skin 
5. Patients with a corrected QT interval using Bazett’s formula (QTcB) > 470 
msec.  
6. Current use or anticipated need for food or drugs that are known strong 
cytochrome P450 (CYP)3A4 inhibitors (i.e. grapefruit juice, verapamil, 
ketoconazole, 
miconazole, 
itraconazole, 
posaconazole, 
erythromycin, 
clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, 
atazanavir, 
amprenavir, 
fosamprenavir, 
nefazodone, 
diltiazem, 
and 
delaviridine) 
7. Patients with impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of PD-0332991 (e.g. severe ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, 
or extensive (>1m) small bowel resection, inability to swallow oral 
medications). Prior partial gastrectomy is not an exclusion criterion. 
8. Patients with prior complete gastrectomy 
9. Any of the following in the previous 6 months: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident, transient ischemic attack or 
symptomatic pulmonary embolism. 
10. Patients with any clinically significant medical or surgical condition which, 
according to investigators’ discretion, should preclude participation - i.e. active 
or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease 

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(cirrhosis, chronic active hepatitis or chronic persistent hepatitis) - hepatitis B 
or C virus carriers with normal liver function tests, can be included 
11. Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing 
is not mandatory 
12. Patients who are currently receiving anticoagulation treatment with therapeutic 
doses • of warfarin or equivalent anticoagulant (e.g. high dose aspirin or 
clopidogrel or other) • or have an INR >1.5. Treatment with acetylsalicyclic 
acid 100 mg daily or low molecular weight heparin (LMWH) is allowed 
13. Pregnant or breast-feeding women 
14. Women of child-bearing potential not employing two effective methods of birth 
control. Effective contraception must be used throughout the trial and 24 
weeks after the end of PD-0332991 (e.g. condom with spermicidal jelly, foam 
suppository or film; diaphragm with spermicide; male condom and diaphragm 
with spermicide, oral, implantable, or injectable contraceptives). Women of 
child-bearing potential defined as sexually mature women who have not 
undergone a hysterectomy or who have not been naturally postmenopausal 
for at least 12 consecutive months (i.e. who has had menses any time in the 
preceding 12 consecutive months), must have a negative serum pregnancy 
test ≤ 21 days prior to starting study drug.  
15. Fertile males not willing to use contraception as stated above 
16. Patients unwilling or unable to comply with the protocol. 
5. Plan of study 
5.1 Duration of Study 
 
 Beginning of inclusion: January 2014  
 Inclusion period: January 2014 to June 2017 (42 months) 
 Length of patient participation: 18 months 
 Study length: 60 months 
5.2 Duration of treatment 
Patient must provide a signed Informed Consent Form (ICF) (Appendix 14) prior to 
any study specific screening evaluations. Table 5 lists study procedures to be 
completed at the baseline screening visit. The screening/baseline visit will occur from 
-21 to -1 days prior to the Day 1 of the first dose of PD-0332991. 
Patients will be evaluated at scheduled visits in up to three study periods:  
 Pre-treatment (PRE TT): from signature of informed consent to the first 
treatment by PD-0332991. 
 Treatment (TT): from the first treatment by PD-0332991 to the first 28 days 
following the last PD-0332991 administration. 
 Follow-up (FUP): after treatment discontinuation, all patients must be followed 
up for 28 days after the last dose of the study drug for safety assessment (AEs 
and/or SAEs). 
Patients will be considered to be on-study from the signature of the informed consent 
to the end of follow-up period. 

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5.3 Survival data collection 
All patients will be followed up every 3 months for survival for one year after the end 
of treatment and information will be documented in the source documents and in 
CRF. 
5.4 Definition of end of the study 
The study end (Last Patient Last Visit) is planned by December 2017. 
Patients will be followed for progression or survival. Any patient who is discontinued 
from PD-0332991 for any reason (except for death, disease progression, lost to 
follow-up, subject/guardian decision [withdrawal of consent], or study termination) will 
continue to have tumor assessments performed every 3 months until radiological 
progression, start of new anticancer therapy or death 
5.5 Protocol Deviations 
A protocol deviation is defined as any departure from what is described in the 
protocol of a clinical trial approved by an Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) and Competent Authorities. Therefore, this applies to 
deviations related to patient inclusion and clinical procedures (e.g., assessments to 
be conducted or parameters to be determined), and also to other procedures 
described in the protocol that concern the Good Clinical Practice (GCP) guidelines or 
ethical issues (e.g., issues related to obtaining the patients’ Informed Consent, data 
reporting, the responsibilities of the investigator, etc.). 
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as: 
 Deviations that might affect the clinical trial objectives, such as those involving 
the inclusion/exclusion criteria (which could mean that the patient is not 
eligible for the trial) and those having an effect on patient evaluability. 
 Deviations that might affect the patient’s well-being and/or safety, such as an 
incorrect dosing of the investigational medicinal product (PD-0332991) due to 
not following dose adjustment specifications. 
 Deviations related to the following of GCP guidelines as described in the 
protocol and regulations in force, such as deviations when obtaining the 
Informed Consent or not following the terms established for reporting serious 
adverse events, etc. 

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 Process schedule of protocol deviation: 
The investigators may suggest to the Sponsor by email for the authorization of 
certain protocol deviations, especially if they are related to the inclusion/exclusion 
criteria or if they may have an effect on the evaluability of the patients. As a general 
rule, NO deviations that may have an effect on the risk/benefit ratio of the clinical trial 
will be authorized. Protocol deviations considered particularly relevant, which are 
related to ethical issues, fulfillment of GCP guidelines and trial procedures, will be 
notified to the pertinent IEC/IRB and, if pertinent, to the relevant authorities as 
established by local regulations. 
Contact to request protocol deviation: 
The sponsor will send by email the response of requested deviation. 
5.6 Replacement of patients 
Patients must be replaced if they are considered not fully evaluable for the 
assessment of the primary endpoint due to following circumstances: 
- 
They are withdrawn from the study before receiving any administration of PD-
0332991 on the first day (Day 1) of the first cycle of the scheduled treatment 
(“evaluable cycle”), OR  
- 
They did not receive at least one complete or two incomplete treatment cycles of 
PD-0332991 OR 
- 
There is a protocol deviation resulting in an impossibility of concluding anything 
regarding the antitumor activity of PD-0332991 (e.g.: disease is not measurable 
as per RECIST or disease is only measurable within a previous irradiated field, 
CNS involvement, progressive disease at inclusion not confirmed by central 
review) OR 
- 
Patients who received at least one administration of PD-0332991 AND unrelated 
AEs AND without any tumor assessments after the start of study treatment OR  
- 
Patients who received at least one administration of PD-0332991 AND who 
refused to continue on study for any reason AND without any tumor assessments 
after the start of study treatment  
However, any patient who received at least one administration of PD-0332991 will be 
included in the safety analysis. 
David JUZANX (CRA) 
 Mail: d.juzanx@bordeaux.unicancer.fr -  Tel : + 33 5 24.07.19.25 
or Sabrina SELLAN-ALBERT (CRA Back-up), Mail – s.albert@bordeaux.unicancer.fr ) 

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6. Treatment 
6.1 Investigational treatment, other study treatment, supportive treatment 
6.1.1 
Dosing regimen 
Table 1 Dose and treatment schedule 
Study Treatment 
Pharmaceutical 
Form and Route of 
Administration 
Dose 
Frequency and/or Regimen 
PD-0332991 
Capsule, oral use 
125 mg Daily 21 days on/7 days off  
(28 day cycles)  
 
PD-0332991 dosed on a flat scale of 125 mg will be administrated orally o.d on a 21 
days on / 7 days off dosing schedule.  One cycle is considered to consist of 4 weeks 
of PD-0332991 administration. 
Patients should be instructed to administrate PD-0332991 with a sufficient amount of 
water at least 1 hour prior to a meal or at least 2 hours following a meal and to 
swallow the required number of capsules at approximately the same time on each 
day. 
If the patient forgets to take the study treatment as described, he/she should skip the 
dose for that day and resume taking the PD-0332991 on the next scheduled day. 
The investigator or designee must instruct the patient to take PD-0332991 exactly as 
prescribed. All study treatments prescribed and dispensed to the patient and all dose 
changes during the study must be recorded on the CRF. 
Patients must be advised to bring their unused PD-0332991 capsules to the 
investigational site at each visit. 
6.1.2 
Ancillary treatments 
In addition to receiving PD-0332991, all patients should receive best supportive care 
(BSC), as per standard local practice for the treatment of pre-existing medical 
conditions or adverse events that may arise during the study. BSC is defined as drug 
or non-drug therapies, nutritional support, physical therapy or any other treatment 
alternative that the investigator believes to be in the patient’s best interest, but 
excluding other antineoplastic treatments. All medications and non-drug therapies 
(including physical therapy, oxygen and blood transfusions) administered to the 
patient prior (within 28 days of the first dose of PD-0332991 or during the course of 
the study, and until 28 days after the last dose of PD-0332991 must be reported on 
CRF. 
Patients must be instructed not to take additional medications (including over-the-
counter products and herbal/alternative medications during the study without prior 
consultation with the investigator). 
Permitted treatments during the study include, but are not limited to the following: 
• Pain medication to allow the patient to be as comfortable as possible 
• Nutritional support or appetite stimulants (e.g. megestrol) 
• Oxygen therapy and blood products or transfusions 
• Prophylactic anti-emetics are allowed for patients who, at the discretion of the 
investigator, have experienced ≥ grade 1 nausea or vomiting 
• Hematopoietic growth factors should be used according to investigator practice. 
• Concurrent use of other investigational drugs is not permitted 

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• The administration of other antineoplastic therapy (e.g. chemotherapy, hormone 
therapy, immunotherapy, targeted therapy, monoclonal antibodies and radiation 
therapy) is not permitted. Patients requiring radiation therapy after the start of the 
study are considered as having progression of disease and must discontinue study 
treatment. 
6.2 Treatment duration 
Patients will be treated with PD-0332991 until progression of disease, unacceptable 
toxicity, death or discontinuation for any other reason.  
6.3 Dose modifications 
6.3.1 
Dose modification and dose delay 
If the patient forgets to take the study treatment as described, he/she should skip the 
dose for that day and resume taking the PD-0332991 on the next scheduled day. 
For patients who do not tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to allow the patient to continue the study 
treatment. The following guidelines need to be applied. 
Table 2 : Dose reduction* 
 
Starting dose level - 0  
Dose level - 1  
Dose level - 2 
PD-0332991 
125 mg 
100 mg 
75 mg 
*Dose reduction should be based on the worst toxicity demonstrated at the last 
dose. 
**Dose reduction below 75 mg is not allowed. 
6.3.2 
Treatment interruption and treatment discontinuation 
6.3.2.1 Interruption 
If the administration of PD-0332991 must be interrupted because of an unacceptable 
toxicity, study drug dosing will be interrupted or modified according to rules described 
in Table 3. A patient who requires a dose interruption (regardless of the reason for 
the interruption) lasting > 28 days (counting from the first day when a dose was 
missed) must discontinue PD-0332991. All treatment interruption must be recorded 
on the CRF. 
Patients whose treatment is interrupted due to an adverse event or abnormal 
laboratory value must be followed at least once a week for 28 days and subsequently 
at 28 day intervals, until resolution or stabilization of the event, whichever comes first. 
6.3.2.2 Discontinuation 
PD-0332991 will be discontinued for any of the following reasons: 
• Disease progression 
• Consent withdrawal 
• Unacceptable adverse events 
• Major violation of the protocol 
• A dose interruption of > 28 days or a dose delay of > 28 days from the intended day 
of the next scheduled dose 
• Intercurrent illness that prevent further administration of treatment 
• Pregnancy 
• Need for any other types of anticancer therapy 

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• General or specific changes in the patient’s condition which render the patient 
unacceptable for further treatment at the discretion of the investigator 
• Lost to follow-up 
• Death. 
If PD-0332991 is permanently discontinued, the patient will be considered to have 
completed study treatment. All patients must have safety evaluations for 28 days 
after the last dose of PD-0332991. 
Patients who discontinue PD-0332991 should be scheduled for an End of Treatment 
Visit, whenever possible, after discontinuing PD-0332991, at which time all of the 
assessments listed for the End of Treatment Visit will be performed. The date and 
reason for stopping the study treatment should be recorded on the CRF. 
Table 3 : Criteria for dose adjustment, interruption and re-initiation of PD-0332991 
Worst Toxicity 
CTCAE v4.0 Gradea unless otherwise 
specified (Value) 
During a cycle of therapy 
No toxicity 
Maintain dose level 
Hematologic 
Neutropenia (ANC) 
 
Grade 1 – 2 
Maintain dose level 
Grade 3 – 4 
Delay PD-0332991 until resolved to ≤ 
grade 2, then: 
If resolved by ≤ 7 days after suspending 
PD-0332991 , maintain dose level 
If resolved by > 7 days after suspending 
PD-0332991 ↓ 1 dose level 
Thrombocytopenia 
 
Grade 1 – 2 
Maintain dose level 
Grade 3 
Delay PD-0332991 until resolved to ≤ 
grade 1, then: 
If resolved by ≤ 7 days after suspending 
PD-0332991 , maintain dose level 
If resolved by > 7 days after suspending 
PD-0332991 ↓ 1 dose level 
Grade 4 
Delay PD-0332991 until resolved to ≤ 
grade 1, then ↓ 1 dose level 
Febrile neutropenia (Grade 3 or 4) 
Delay PD-0332991 until resolved, then ↓ 
1 dose level 
Cardiac - Prolonged QTc interval 
 
During cycle 1 
 
No QTcF change from baseline > 60 
msec 
Maintain dose level and ECG monitoring 
as specified for subsequent cycles in 
Table 5. 
QTcF change from baseline > 60 msec 
(but absolute QTcF < 500 msec) 
Maintain dose level. ECG monitoring 
assessments will be performed every 
week for 4 weeks, and then every two 
weeks for the next 8 weeks. After 12 
weeks, ECGs will be performed as 
indicated for subsequent cycles in Table 
5, or more frequently as clinically 
indicated by the investigator. 

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During any cycle 
 
QTcF ≥ 500 msec as identified by the 
investigator on the automated site ECG 
reading 
 
 
 
 
 
 
 
 
 
 
 
For all patients with a new absolute 
QTcF ≥ 500 msec duration, occurring at 
any time during study, as identified by 
the investigator on the automated site 
ECG reading, an immediate evaluation of 
that ECG will be obtained and if 
confirmed (QTcF ≥ 500), then dosing 
with PD-0332991 will be suspended. The 
Sponsor should be notified immediately. 
The patient will be hospitalized or 
monitored by the investigator with hourly 
ECGs until the QTcF has returned to < 
30 msec from baseline. Immediate 
attention to potassium, magnesium, and 
other 
clinical 
factors 
such 
as 
oxygenation, ischemia, and the like will 
be addressed. 
Once QTc prolongation has resolved, 
patients may be re-treated at the next 
lower dose level with frequent ECG 
monitoring. 
If the ECGs obtained in the first cycle 
after dose reduction are without any 
QTcF change from baseline > 60 msec, 
then ECG monitoring will be performed 
as indicated in Table 5 for all subsequent 
cycles. 
If, in the first cycle after dose reduction 
the patient had a QTcF change from 
baseline > 60 msec, but absolute QTcF < 
500 msec, then ECG monitoring will be 
performed every week for 4 weeks, and 
then every two weeks for the next 8 
weeks. After 12 weeks, ECGs will be 
performed as indicated for subsequent 
cycles in Table 5, or more frequently as 
clinically indicated by the investigator. 
Patients who experience absolute QTcF 
≥ 500 msec after dose reduction will be 
discontinued from study. 
Diarrhea 
 
Grade 1 (despite maximal antidiarrheal 
medication) 
Maintain dose level 
Grade 2 (despite maximal antidiarrheal 
medication) 
Delay PD-0332991 until resolved to ≤ 
grade 1, then re-start at the current dose 
level. 
If diarrhea returns as ≥ grade 2, then 
suspend dose until resolved to ≤ grade 1, 
then ↓ 1 dose level 
Grade 
3 
or 
4 
(despite 
maximal Delay PD-0332991 until resolved to ≤ 

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antidiarrheal medication) 
grade 1, then ↓ 1 dose level 
Nausea (Suspend dose for CTCAE 
grade 2-3 nausea only if it could not be 
controlled despite the use of standard 
anti-emetics.) 
 
Grade 1 (despite standard anti-emetics) 
Maintain dose level 
Grade 2 (despite standard anti-emetics) 
Delay PD-0332991, until resolved to ≤ 
grade 1, and then re-start at the current 
dose level. 
If nausea returns as ≥ grade 2, then 
suspend dose until resolved to ≤ grade 1, 
then ↓ 1 dose level. 
Grade 
3-4 
(despite 
standard 
anti-
emetics) 
Delay PD-0332991 until resolved to ≤ 
grade 1, then ↓ 1 dose level 
Vomiting (Suspend dose for CTCAE 
grade 2-4 vomiting only if it could not be 
controlled despite the use of standard 
anti-emetics.) 
 
Grade 1 (despite standard anti-emetics) 
Maintain dose level 
Grade 2 (despite standard anti-emetics) 
Delay PD-0332991, until resolved to ≤ 
grade 1, and then re-start at the current 
dose level. 
If vomiting returns as ≥ grade 2, then 
suspend dose until resolved to ≤ grade 1, 
then ↓ 1 dose level. 
Grade 
3-4 
(despite 
standard 
anti-
emetics) 
Delay PD-0332991 until resolved to ≤ 
grade 1, then ↓ 1 dose level 
Other adverse events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay PD-0332991 until resolved to ≤ 
grade 1 or baseline, then maintain dose 
level or ↓ 1 dose level at the discretion of 
the investigator 
Grade 4 
Delay PD-0332991 until resolved to ≤ 
grade 1 or baseline, then ↓ 1 dose level 
or discontinue PD-0332991  at the 
discretion of the investigator 
All dose modifications should be based on the worst preceding toxicity. 
Patients are allowed two dose reductions: a dose reduction from 125 mg to 100 mg, 
and, if necessary, a dose reduction from 100 mg to 75 mg. 
6.4 Concomitant medications 
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug) 
and significant non-drug therapies (including physical therapy and blood 
transfusions) administered during the study must be listed on CRF  
 
 

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6.4.2 
Restricted concomitant therapy  
In vitro data indicate that CYP3A are mainly involved in the metabolism of PD-
0332991. PD-0332991 is a weak time-dependent inhibitor of CYP3A. Concomitant 
administration of agents known to inhibit strongly CYP3A isoenzymes (eg, 
ketoconazole, miconazole, itraconazole, posaconazole, clarithromycin, erythromycin, 
tilithromycin, nefazodone, diltiazem, verapamil, indinavir, saquinavir, ritonavir, 
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and grapefruit juice) may 
increase PD-0332991 exposure and should be avoid. . Concomitant administration of 
agents known to induce strongly CYP3A isoenzymes (e.g., phenytoin, rifampicin, 
carabamazepin and St-John Wort) may decrease PD-0332991 exposure and should 
be avoid. Moreover, concomitant use of moderate CYP3A inducers (e.g., bosentan, 
efavirenz, etravirine, modafinil, and nafcillin) should be avoid. The following website 
may be referenced for a more extensive list of P450 inhibitors and inducers: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
6.5 Study drug supply 
6.5.1 
Study drug preparation and dispensation 
PD-0332991 will be provided by the designee of the sponsor to the participating site. 
Table 4: Preparation and dispensing 
Study Treatment 
Packaging 
Labeling (and dosing 
frequency) 
PD-0332991 
Capsules (125mg, 100mg, 
75mg and 25 mg)  
Labelled asd PD-0332991 
6.5.2 
Study drug packaging and labelling 
PD-0332991 is formulated as gelatin capsules of 125mg, 100 mg, 75mg and 25 mg 
respectively. Medication labels will comply with the French legal requirements and 
are printed in French. The label contains PD-0332991 identifying information (e.g. 
formulation, batch number, and expiration date), the patient number (to be entered by 
the investigator or designee) and storage conditions. 
6.5.3 
Drug supply and storage 
PD-0332991 is supplied by the Sponsor. It must be received by a designated person 
at the study site, handled and stored safely and properly, and kept in a secured 
location to which only the investigator and designated assistants have access. Upon 
receipt, PD-0332991 should be stored according to the instructions specified on the 
drug labels. PD-0332991 capsules should be stored at 15-30°C in a secured, limited 
access area.  

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6.5.4 
Study drug compliance and accountability 
 Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each 
patient visit. 
To accurately determine the patient’s drug exposure throughout the study, the 
following information must be reported on a patient diary (Appendix 17). 
 Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability ledger. Drug accountability will 
be noted by the field monitor during site visits and at the completion of the study. 
Patients will be asked to return all unused study treatment and packaging on a 
regular basis, at the end of the study or at the time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the 
investigator will return all used and unused study treatment, packaging, drug labels, 
and a copy of the completed drug accountability ledger to the Sponsor designee 
provided in the investigator folder at each site. 
6.5.5 
Disposal and destruction 
The drug supply can be destroyed at the local of Sponsor designee as appropriate. 
Destruction at the site is allowed only if permitted by French regulations and 
authorized by the Sponsor. 
7. Visit schedule and assessments 
7.1 Study flow and visit schedule 
Table 5 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. All assessments have a ±3 days window unless 
otherwise indicated. In the event of public holiday there is a ±5 days window on all 
assessments. Every effort must be made to follow the schedule of assessments 
within the windows outlined in the protocol. 
 
 
Pre-
Screening 
phase 
Screening/Baseline 
Cycle 1 
Cycle 
N 
End of Study 
Treatment 
Survival 
Follow-
Up 
Visit Name 
 
 
V1 
V2 
Vn 
 
 
Day of cycle 
 
-21 to -1 
Day 
1 
Day 
15 
Day 
1 
Within 28 days 
after 
discontinuation 
of 
study drug 
 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
CDKN2A gene 
deletion assessed 
by array-CGH 
(centralized to 
Bergonie Institute) 
X 
 
 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
Inclusion/exclusion 
 
X 
 
 
 
 
 

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criteria 
Relevant medical 
history/current 
medical 
conditions 
 
X 
 
 
 
 
 
Diagnosis and 
extent of cancer 
 
X 
 
 
 
 
 
Prior 
antineoplastic 
therapy 
 
X 
 
 
 
 
 
Prior/concomitant 
medications 
 
X 
Continuous until 28 days post-late dose 
of study drug 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
 
 
 
 
 
 
X 
Clinical exam 
 
 
 
 
 
 
 
Physical 
examination 
 
X 
X 
X 
X 
X 
 
Performance 
status 
 
X 
X 
X 
X 
X 
 
Height/Weight 
 
X 
X 
X 
X 
X 
 
Vital signs 
 
X 
X 
X 
X 
X 
 
Laboratory 
assessments 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
X 
X 
Days 
1 and 
15  
X 
 
Chemistry 
 
X 
X 
X 
X 
X 
 
Coagulation 
 
X 
X 
X 
X 
X 
 
Pregnancy test 
 
X 
X 
 
X 
X 
 
Imaging/Other 
assessments 
 
 
 
 
 
 
 
Tumor evaluation: 
CT scan or MRI 
 
Day-21 to -1 
D(28) of Cycle 1, D(28) of Cycle 2 
then every 8 weeks until month six 
and then every 12 weeks 
 
ECG 
 
X 
X 
X 
X 
X 
 
Safety 
 
 
 
 
 
 
 
Adverse events 
 
 
Continuous until 28 days post-late 
dose of study drug 
 
Biomarkers 
(Optional study) 
 
 
 
 
 
 
 
Tumor biopsy 
Day –3 to Day -1 
Day 21 cycle 1 
 
X 
Day 21 Cycle 1 
 
 
Others 
 
 
 
 
 
 
 
PD-0332991 
administration 
 
 
21-days on, 7 days off 
 
 
Reason for 
withdrawal 
 
 
 
 
 
X 
 
Survival update 
every 3 months for 
one year 
 
 
 
 
 
 
X 

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7.1.1 
Pre-Screening phase and Screening 
 Pre-screening phase 
In this study, a pre-screening is necessary to confirm homozygous or heterozygous 
CDKN2A gene deletion assessed by array-comparative genomic hybridization (array-
CGH) (see section 7.1.1.3.1). 
Patient must provide a signed Informed Consent Form (ICF) (Appendix 14) prior to 
any study specific evaluations. 
 Screening 
The screening/baseline visit will occur maximum 21 days prior to the Day 1 of first 
dose of study treatment PD-0332991. 
The investigator must review the checklist of inclusion/exclusion criteria. 
When information from procedures (for example imaging assessments) that may 
have been previously performed as part of the patient’s routine disease care (prior to 
enrolling in the trial) is allowed to be used to satisfy inclusion criteria, if it was 
performed <21 days before the start of study treatment. 
7.1.1.1 Eligibility screening 
Patient’s eligibility is checked locally.  
7.1.1.2 Patient demographics and other baseline characteristics 
The following assessments and procedures will be performed prior the start of study 
screening phase (see section 7.1.1.3.2): 
• Obtain patient’s written informed consent form  
• Confirm by the RRePS Network the histological diagnosis of GIST, the positive 
immunohistochemical staining for c-KIT (CD117) or if negative, either positive 
staining for DOG1 or identified mutation on KIT or PDGRA gene 
• Confirm CDKN2A gene deletion assessed by array-comparative genomic 
hybridization (array-CGH)  
The following assessments and procedures will be performed within 21 days prior the 
start of study treatment: 
• Confirm disease progression by central review (see section 7.2.1.5) after the last 
line of treatment. 
• Radiological tumor assessment 
• Demographic data and relevant medical history, current medical conditions 
• Prior antineoplastic therapies 
• Cardiovascular assessment 
o Electrocardiogram (ECG) 
• Physical examination 
o Vital signs 
o Height and weight 
o Performance status 
• Laboratory investigations: 
o Hematology: hemoglobin, platelet count, a complete red blood cell count 
(RBC), total white blood count (WBC) with differential (total neutrophil 

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[including bands], lymphocyte, monocyte, eosinophil, and basophil 
counts). 
o Coagulation: Prothrombin time (PT, described as INR) and APTT 
o Chemistry : urea/BUN, creatinine, calcium, sodium, magnesium, 
potassium, phosphorous, fasting glucose, albumin, total bilirubin, alkaline 
phosphatase, GGT, AST, and ALT, LDH, amylase, lipase and 
triglycerides. 
• Biomarkers collection (optional study): Tumor biopsy at Day –3 to Day -1  
• Pregnancy test if applicable: serum blood of pregnancy test 
7.1.1.3 Patient registration 
7.1.1.3.1 
Pre-Screening phase : 
Upon signature of consent, screened patient will be entered on study centrally at the 
Bergonie Institute Coordinating Center by the Study Coordinator. 
The following documents should be faxed or e-mail as soon as possible to the 
Bergonie Institute Data Center: 
_ Pre-Screening form (Appendix 7): 
 Institution number 
 Name of the responsible investigator 
 Patient’s code (2 letters of name, 2 letters of first name) 
 Patient’s birth date (day/month/year) 
 Date of signed consent form 
 Date of signed consent form for optional study , if applicable 
 
Clinical Trial and Epidemiology Unit – Institut Bergonie- Protocol CYCLIGIST 
FAX : +33 5 56 33 04 85 
From Monday through Friday - From 9.00 am to 5.00 pm 
Contact : David JUZANX - Tel : + 33 5 24.07.19.25 – Mail: 
d.juzanx@bordeaux.unicancer.fr 
and Sabrina SELLAN-ALBERT (CRA Back-up), Mail – s.albert@bordeaux.unicancer.fr 
 
Each site will send to Bergonie Institute within 7 Days after signature of informed 
consent: 
o 
Pathology request form completed (Appendix 9) 
o 
FFPE (Formalin-Fixed Paraffin-Embedded) of initial block of specimen 
tumor sampling (see section 7.2.1.3) 
o 
Initial pathology report with patient code and date of birth (including 
macroscopic description) and pathology report of molecular biology(see 
section 7.2.1.4) 
To complete the registration process, the Coordinator will assign a patient pre-
screening number. 
Upon results of pathological will be available, (see section 7.2.1.4) the CRA at 
Bergonie Institute should inform site by e-mail and/or fax and return results. 
 
In case of an array-comparative genomic hybridization (array-CGH) to assessed 
homozygous or heterozygous CDKN2A gene deletion is already done, each site will 
send to Bergonie Institute the informatics file corresponding of genomic profile. A 

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validation is necessary by Department of tumoral genetic pathology, F.Chibon and 
collaborators, Bordeaux, France. 
7.1.1.3.2 
Screening phase: 
Upon confirmation of pre-screening results are positive (see section 7.1.1.3.1), the 
investigator must review the checklist of inclusion/exclusion criteria. 
In case of pre-screening results are negative, patient will be on screening failures.  
The screening/baseline visit will occur maximum 21 days prior to the Day 1 of first 
dose of study treatment PD-0332991. 
Each site will send to Bergonie Institute for central review before registration (see 
section 7.2.1.5.2): 
o Anonymized CD of CT-scan or MRI of two radiological assessments 
identical obtained at less from 4 months interval within the 24 months 
before inclusion  
o “Baseline Clinical Subject Profile” (Appendix 11) with the first shipment.  
o “Radiology Referral Form” (Appendix 12). 
Upon results of radiological assessment, the CRA at Bergonie Institute should inform 
site by e-mail and/or fax and return results. 
7.1.1.3.3 
Inclusion 
With pre-screening and screening results, all eligible patients will be registered on 
study centrally by the Study Coordinator. 
To register a patient, the following documents should be faxed or e-mail to the 
Bergonie Institute Data Center: 
_ Registration form (Appendix 8): 
 Institution number 
 Name of the responsible investigator 
 Patient’s code (2 letters of name, 2 letters of first name) 
 Patient’s birth date (day/month/year) 
 Pre-Screening number 
 Eligibility criteria 
 Data foreseen for protocol treatment start 
Clinical Trial and Epidemiology Unit – Institut Bergonie- Protocol CYCLIGIST 
FAX : +33 5 56 33 04 85 
From Monday through Friday - From 9.00 am to 5.00 pm 
Contact : David JUZANX - Tel : + 33 5 24.07.19.25 – Mail: d.juzanx@bordeaux.unicancer.fr 
and Sabrina SELLAN-ALBERT (CRA Back-up), Mail – s.albert@bordeaux.unicancer.fr 
This must be done before the start of the protocol treatment which should begin 
within one week (7 days) following registration. 
To complete the registration process, the CRA will: 
_ Assign a patient study number 
_ Register the patient on the study 
_ Fax and/or e-mail the patient study number 

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The patient study number attributed at the end of the registration procedure identifies 
the patient and must be reported on all case report forms. 
7.1.2 
 Treatment period 
Patients will receive PD-0332991 after the last line of treatment washout period of at 
least 5 days, on an outpatient basis at the dose of 125 mg qd for 21 days followed by 
7 days off, for cycle of 4 weeks (28d) until disease progression documented by 
RECIST v1.1 (Appendix 3), unacceptable toxicity, or consent withdrawal. Patients will 
be required to swallow the required number of capsules of PD-0332991 at 
approximately the same time on each dosing day, with sufficient amount of water and 
at least 1 hour prior to a meal and at least 2 hours following a meal. If a dose is 
missed for any reason, including vomiting, patients should resume taking the study 
medication with the next scheduled day. 
The following assessments and procedures will be performed prior the start of study 
treatment: 
• Current medical conditions 
• Radiological tumor assessment by CT Scan or MRI: D(28) of Cycle 1, D(28) of 
Cycle 2 then every 8 weeks until month six and then every 12 weeks 
• Cardiovascular assessment 
o Electrocardiogram (ECG) 
• Physical examination 
o Vital signs 
o Weight 
o Performance status 
• Laboratory investigations: 
o Hematology: hemoglobin, platelet count, a complete red blood cell count 
(RBC), total white blood count (WBC) with differential (total neutrophil 
[including bands], lymphocyte, monocyte, eosinophil, and basophil 
counts). 
o Coagulation: Prothrombin time (PT, described as INR) and APTT 
o Chemistry : urea/BUN, creatinine, calcium, sodium, magnesium, 
potassium, phosphorous, fasting glucose, albumin, total bilirubin, alkaline 
phosphatase, GGT, AST, and ALT, LDH, amylase, lipase and 
triglycerides. 
• Biomarkers collection (optional): Tumor biopsy at Day 21 cycle 1 
• Pregnancy test if applicable: serum blood of pregnancy test 
All assessments have a ±3 days window unless otherwise indicated. In the event of 
public holiday there is a ±5 days window on all assessments. Every effort must be 
made to follow the schedule of assessments within the windows outlined in the 
protocol. 
7.1.3 
End of treatment visit, including premature withdrawal and study 
discontinuation visit 
Patients who discontinue PD-0332991 for any reason should be scheduled for a visit 
within 28 days after discontinuation of study drug.  
The following assessments and procedures will be performed: 
• Current medical conditions 

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• Radiological tumor assessment 
• Cardiovascular assessment: electrocardiogram (ECG) 
• Physical examination 
• Vital signs 
• Weight 
• Performance status 
• Laboratory investigations: 
o Hematology: hemoglobin, platelet count, a complete red blood cell count 
(RBC), total white blood count (WBC) with differential (total neutrophil 
[including bands], lymphocyte, monocyte, eosinophil, and basophil 
counts). 
o Coagulation: Prothrombin time (PT, described as INR) and APTT 
o Chemistry : urea/BUN, creatinine, calcium, sodium, magnesium, 
potassium, phosphorous, fasting glucose, albumin, total bilirubin, alkaline 
phosphatase, GGT, AST, and ALT, LDH, amylase, lipase and 
triglycerides. 
• Pregnancy test if applicable: serum blood of pregnancy test 
An End of Treatment CRF page should be completed, giving the date and reason for 
stopping the study treatment. At a minimum, all patients who discontinue study 
treatment, including those who refuse to return for a final visit, will be contacted for 
safety evaluations during the 28 days following the last dose of study treatment. 
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator 
must determine the primary reason for a patient’s premature withdrawal from the 
study and record this information on the End of Treatment CRF page. 
If a patient discontinues study treatment, but continues study assessments, the 
patient remains on study until such time as he/she completes protocol criteria for 
ending study assessments. 
At that time, the reason for study completion should be recorded on the CRF. 
7.1.4 
Follow up period 
All patients must be followed up for 28 days after the last dose of study drug for 
safety assessment (AEs and/or SAEs). 
Patient who discontinued study drug for disease progression, a follow-up survival 
update must be done every 3 months during a year, until death or study termination. 
Any patient who is discontinued from PD-0332991 for any reason (except for death, 
disease progression, lost to follow-up, subject/guardian decision [withdrawal of 
consent], or study termination) will continue to have tumor assessments performed 
every 3 months until radiological progression, start of new anticancer therapy or 
death. 
All new anticancer therapies given after the last dose of the study drug PD-0332991 
will be recorded on CRF pages designed to capture antineoplastic therapies since 
discontinuation from the study. 
7.2 Assessment types 
7.2.1 
Diagnosis  
7.2.1.1 Diagnosis of GIST 

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Diagnosis of Gastro Intestinal Stromal Tumor (GIST) must be histologically confirmed 
of any anatomical location; positive immunohistochemical staining for c-KIT (CD117); 
or negative staining for KIT, but with either positive staining for DOG1 and an 
identified mutation of KIT or PDGFRA gene 
If diagnosis of GIST was not confirmed by the RRePS Network (Appendix 16), 
missing analysis will be performed by Bergonie Institute, Pr. Coindre and 
collaborators, Department of Pathology, Bordeaux, France. The reviewer will assess 
pathological diagnosis, document the results on the “Pathology request form” 
response completed (Appendix 9) and sign this form. 
Every discrepancy will be discussed between referral investigator, principal 
investigator, Pr. Coindre or collaborators and medical responsible from the Sponsor, 
until a final decision is reached.  
Patients with pathological diagnosis different from GIST after central review will be 
considered ineligible and will not be included in the study. 
7.2.1.2 Array-CGH analysis  
The analysis of CDKN2A gene deletion assessed by array-comparative genomic 
hybridization (array-CGH) will be performed by Bergonie Institute, Department of 
tumoral genetic pathology, F.Chibon and collaborators, Bordeaux, France. 
7.2.1.3 Pathological specimen sampling necessary to array-CGH analysis  
Available tumor samples obtained at diagnosis or at relapse, FFPE (Formalin-Fixed 
Paraffin-Embedded) of block is mandatory to analysis CDKN2A gene deletion.  
7.2.1.4 Array-CGH 
analysis 
process 
schedule 
and 
practical 
implementation 
Each site will send to Bergonie Institute within 7 Days after signature of informed 
consent: 
o 
Pathology request form completed (Appendix 9) 
o 
FFPE (Formalin-Fixed Paraffin-Embedded) of block of specimen tumor 
sampling 
o 
Initial pathology report with patient code and date of birth (including 
macroscopic description) and pathology report of molecular biology 
 Pr. Coindre and collaborators, Department of Pathology Bordeaux France, will 
assess homozygous or heterozygous CDKN2A gene deletion, document the 
results on the “Pathology request form” response completed (Appendix 9) and 
sign this form. 
All Pathological specimens sampling with documents must be sent to: 
Institut Bergonié-Service Pathologie- 
Technicienne Anapath Recherche Clinique 
Protocole CYCLIGIST 
229 cours de l’Argonne-33076 Bordeaux Cedex, France 
Tél: 05.56.33.78.53  
 In case of an array-comparative genomic hybridization (array-CGH) to assessed 
homozygous or heterozygous CDKN2A gene deletion is already done, each site 
will send to Bergonie Institute the informatics file corresponding of genomic 
profile. A validation is necessary by Department of tumoral genetic pathology, 

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F.Chibon and collaborators, Bordeaux, France and signed by Pr. Coindre and 
collaborators, Department of Pathology Bordeaux France. 
7.2.1.5 Diagnosis of Progressive Disease – central review before 
registration 
Centralized radiological review will be performed to confirm progressive disease 
status at inclusion time. Progressive disease should be confirmed according to 
RECIST 1.1 modified as follows for the purpose of this study: no lymph nodes will be 
chosen as target lesions—no bone lesions will be chosen as target lesions. 
Additionally a progressively growing new tumour nodule within a pre-existing tumour 
mass have to meet the following criteria to be regarded as unequivocal evidence of 
progression according to our modification to RECIST 1.1: the lesion is at least 2 cm 
in size and definitely a new active GIST lesion (eg, enhanced with contrast or other 
criteria to rule out artefact); or the lesion have to be expanding on at least two 
sequential imaging studies. 
This will be performed by centrally reviewing two radiological assessments identical 
(CT scans or MRI) obtained at less from 4 months interval within the 24 months 
before inclusion 
7.2.1.5.1 
General procedure 
Review process will be centralized at Bergonie Institute and will be performed by one 
radiologist expert in Gastro Intestinal Stromal Tumor. 
The results of the centralized radiological review will be used for the diagnosis of 
progressive disease. 
7.2.1.5.2 
Review process schedule and practical 
implementation at baseline 
With regards to inclusion scan, the progressive disease status at baseline must be 
confirmed by central review. 
o Each site will send two-imaging CD (two radiological assessments identical 
(CT scans or MRI ) obtained at less from 4 months interval within the 24 
months before inclusion) to Institut Bergonié  
o Each site must send the completed “Baseline Clinical Subject Profile” 
(Appendix 11) with the first shipment.  
o For each shipment, each media should be accompanied by the completed 
“Radiology Referral Form” (Appendix 12). 
 The reviewer will assess baseline status, document the results on the “Baseline 
Radiology Review Form” (Appendix 13) and sign this form. 
Patient’s information must be recorded on an imaging CD. 
All CDs and document must be sent to: 
David Juzanx 
Clinical Research Assistant 
Institut Bergonié – 229 cours de l’Argonne – 33076 Bordeaux Cedex, France 
Phone: +33 5 24 07 19 25 – Mail: d.juzanx@bordeaux.unicancer.fr  
7.2.2 
Efficacy assessments 
Tumor assessment and response will be assessed according to RECIST (version 
1.1-Appendix 3), with same type of exam in regard of baseline. 

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All potential sites of tumor lesions (target and non-target lesions) will be assessed 
using MRI or CT Scan with IV contrast of the Thorax Abdomen and Pelvis using a 
5mm slice thickness with a contiguous reconstruction algorithm (a PET scan is not 
acceptable for radiological evaluation).  
Evaluation will be assessed: 
- at baseline within 21 days before the first dose of PD-0332991  
- at D(28) of Cycle 1, at D(28) of Cycle 2 then every 8 weeks until month six and 
then every 12 weeks until disease progression or starting other treatment. A time 
window of 7 days is allowed for the radiologist to give his/her statement. 
Clinical suspicion of disease progression at any time requires a physical examination 
and radiological confirmation to be performed promptly rather than waiting for the 
next scheduled radiological assessment. 
Response regarding the first endpoint will be assessed by central radiology review. 
Whenever the criteria of response are met (Complete Response (CR) or Partial 
Response (PR)), the appropriate imaging tests will be repeated at least four weeks 
later in order to confirm the response. 
The decision regarding patient management will remain with the local investigator. 
For the evaluation of lesions at baseline and throughout the study, the lesions are 
classified at baseline as either target or non-target lesions. The investigator and/or 
the local radiologist selects the target (a bone lesion is not acceptable for a target 
lesion) and non-target lesions at baseline and follows each of the selected lesion (s) 
at each subsequent tumor assessment until the patient presents with disease 
progression. 
All patients should have at least one measurable lesion (nodal or non-nodal) by CT 
scan or MRI. 
For optimal evaluation of patients the same methods of tumor assessment and 
technique (CT scan with contrast or MRI) should be used to characterize each 
identified and reported lesion at baseline and during follow-up. A change in 
methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-
versa, regardless of the justification for the change) or a change in technique (e.g. 
from CT to MRI), or a change in any other imaging modality. 
Moreover, a new nodule within a preexisting tumor mass will be considered as 
unequivocal evidence of progression when the lesion is at least 2 cm in size and 
radiologically compatible with a GIST lesion, or the lesion is growing in at least 2 
successive scans/MRI and radiologically compatible with a GIST lesion. 
In addition to RECIST v1.1 (Appendix.3) evaluation, all subject data acquired using 
contrast-enhanced CT will be evaluated according to Choi criteria. (Appendix.4) Choi 
reading will be performed locally. 
 Review process schedule and practical implementation at first end point 
With regards to inclusion scan, the response regarding the first endpoint will be 
assessed by central radiology review  
o Each site will send imaging CD (radiological assessments identical (CT scans 
or MRI ) obtained at each evaluation) to Institut Bergonié  
o For each shipment, each media should be accompanied by the completed 
“Radiology Referral Form” (Appendix 12). 

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Patient’s information must be recorded on an imaging CD. 
All CDs and document must be sent to: 
David Juzanx 
Clinical Research Assistant 
Institut Bergonié – 229 cours de l’Argonne – 33076 Bordeaux Cedex, France 
Phone: +33 5 24 07 19 25 – Mail: d.juzanx@bordeaux.unicancer.fr  
7.2.3 
Safety and tolerability assessments 
Safety will be monitored by assessing all adverse events, including serious adverse 
events, the regular monitoring of hematology, blood chemistry, cardiac assessments 
and regular monitoring of vital signs and physical condition. These assessments 
should be performed ± 3 days of the scheduled day of assessment except for 
adverse events that will be evaluated continuously through the study (Refer to Table 
5). 
Scheduling of safety assessments for PD-0332991 cannot be changed due to dose 
interruptions. Refer to Section 6.3 for permitted PD-0332991 adjustments as well as 
collecting of the adverse events at every visit. For details on AE collection and 
reporting, refer to Section 10.2. 
 
7.2.3.1 Physical examination 
A complete physical examination includes a major review of body systems (general 
appearance, skin, neck including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, and extremities), a neurological examination only 
performed at baseline. 
Information for all physical examinations must be included in the source 
documentation at the study site. Significant findings that are present prior to start PD-
0332991 must be included in the CRF. Significant findings made after starting PD-
0332991 which meet the definition of an Adverse Event must be recorded on the 
Adverse Event CRF pages. 
A physical examination will be performed and recorded in source documents at: 
• Baseline ≤ 21 days prior to the first dose of PD-0332991  
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment 
• As clinically indicated. 
7.2.3.2 Vital signs 
Vital signs will be recorded on the appropriate CRF pages. Body temperature, sitting 
pulse rate, and sitting blood pressure will be measured at each visit. Vital signs will 
be measured at: 
• Baseline ≤ 21 days prior to the first dose of PD-0332991  
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment 
• As clinically indicated. 
Vital signs are measured according to normal medical practice. 
 

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7.2.3.3 Height and weight 
Height will be measured only at screening. Height will be measured in centimeters 
(cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without 
shoes). 
Weight will be measured at: 
• Baseline ≤ 21 days prior to the first dose of PD-0332991  
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment 
• As clinically indicated. 
7.2.3.4 Performance status 
The performance status will be scored using the ECOG Performance Status 
assessment scales (Appendix 1) 
Performance status will be assessed at: 
• Baseline ≤ 21 days prior to the first dose of the study treatment 
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment 
• As clinically indicated. 
7.2.3.5 Laboratory evaluations 
Laboratory evaluations must be performed locally at every protocol required visit 
(Table 5) or as frequently as clinically indicated.  
If the baseline laboratory assessments occurred within 48 hours of cycle 1 day 1, the 
laboratory evaluation does not need to be repeated at that time. 
 Hematology 
Hematology tests include hemoglobin, platelet count, a complete red blood cell count 
(RBC), total white blood count (WBC) with differential (total neutrophil [including 
bands], lymphocyte, monocyte, eosinophil, and basophil counts). 
Hematological tests will be performed at: 
• Baseline ≤ 21 days prior to the first dose of PD-0332991  
• Days 1 and 15 in cycle 1 
• Day 1 and Day 15 in subsequent cycles 
• End of treatment and study 
• As clinically indicated. 
If the baseline blood sample collection occurred within the previous 48 hours of cycle 
1 day 1, the hematology does not need to be repeated at that time. 
In case of hematological toxicities > Grade 2 that require study treatment 
modifications or interruptions, hematological tests should be repeated until recovery 
to the baseline value or ≤ grade 2. Refer to Table 3 for PD-0332991 treatment 
adjustments 
 Coagulation 
Prothrombin time (PT, described as INR) and APTT are examined as coagulation 
assessments. 
They will be performed at: 

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• Screening 
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment and study 
• As clinically indicated. 
If the baseline blood sample collection occurred within the previous 48 hours of cycle 
1 day 1, the coagulation assessments do not need to be repeated at that time.  
 Clinical chemistry 
Biochemistry consists of urea/BUN, creatinine, calcium, sodium, magnesium, 
potassium, phosphorous, glucose, albumin, total bilirubin, alkaline phosphatase, 
GGT, AST, and ALT, LDH, amylase, lipase and triglycerides. 
• Baseline ≤ 21 days prior to the first dose of PD-0332991  
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of treatment and study 
• As clinically indicated. 
If the baseline blood sample collection occurred within the previous 48 hours of cycle 
1 day 1, the biochemistry does not need to be repeated at that time. 
In the event of >Grade 2 non-hematological toxicities that require study treatment 
dose modifications or interruptions, hematological tests should be repeated until 
recovery to the baseline value or ≤ Grade 2. Refer to Table 3 for PD-0332991 
treatment adjustments. 
 Pregnancy and assessments of fertility 
All females of childbearing potential should complete a serum pregnancy test at 
baseline ≤ 21 days prior to administration of PD-0332991, and at Day 1 of each 
cycle. Serum blood for pregnancy testing will be sent to the local laboratory. 
Adequate contraception must be used while on study and for 24 weeks after the last 
dose on PD-0332991.   
To be considered “of non-childbearing potential”, it is advised that postmenopausal 
women be amenorrheic for at least 12 months or have a serum FSH > 40 mIU/ml or 
be at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy. 
In case of pregnancy while on the study, the patient must be discontinued from the 
study. 
If the baseline pregnancy test occurred within the previous 48 hours of cycle 1 day 1, 
the test does not need to be repeated at that time. 
Pregnancy should be recorded on the Pregnancy Notification Form (Appendix 6) and 
reported by the investigator to the Sponsor.  
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment of any pregnancy 
outcome. 
Any SAE experienced during pregnancy must be reported on the SAE Notification 
Form (Appendix 5). The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or 
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7.2.3.6 Cardiac assessments 
 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at the time points specified below. 
Interpretation of the tracing must be made by a qualified physician and documented 
on the ECG section of the CRF. Each ECG tracing should be labeled with the study 
number, patient initials, patient number, date, and kept in the source documents at 
the study site. Clinically significant abnormalities noted on the screening ECG should 
be recorded on the Medical History CRF page.  
Any clinically significant findings must be discussed with the Sponsor and the 
Coordinating Investigator prior to enrolling the patient in the study. Clinically 
significant abnormalities noted at any point during the study should be recorded on 
the AE CRF. 
ECG will be performed at: 
• Baseline ≤ 21 days prior to the first dose of PD-0332991 
• Days 1 and 15 in cycle 1 
• Day 1 in subsequent cycles 
• End of study 
• Then as clinically indicated. 
7.2.4 
Biomarkers (optional) 
Fresh tumor biopsies FFPE (Formalin-Fixed Paraffin-Embedded) at screening and at 
Day 21 of Cycle 1 are encouraged to be collected. Once collected, the samples may 
be profiled by IHC, and array gene expression analysis to identify the 
pharmacodynamics activity of PD-0332991 in GIST patients.  
As this is an active area of research, several biomarkers may be analyzed if justified 
by results of internal or external research activities. 
Each site will send samples to Bergonie Institute with “Optional Pathology Request 
Form” (Appendix 10) completed for each sample. 
All samples will be stored before they are analyzed.  
The sample collection information must be captured on the appropriate CRF page(s)  
All Pathological specimens sampling with documents must be sent to: 
Institut Bergonié-Service Pathologie- 
Technicienne Anapath Recherche Clinique 
Protocole CYCLIGIST 
229 cours de l’Argonne-33076 Bordeaux Cedex, France 
Tél: 05.56.33.78.53  
 
8. Criteria for stopping the treatment 
Treatment may continue until one of the following criteria applies: 

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 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse events(s), 
 Patient decides to withdraw from the study, or 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
Patients will be followed for 4 weeks after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
9. Criteria for stopping the trial 
The trial can be suspended or stopped by the promoter (Institut Bergonié), in 
accordance with the coordinator, or upon request of the Competent Authority (ANSM) 
and/or the Ethics committee (Comité de Protection des Personnes), for the following 
reasons : 
 an unexpected frequency and/or severity of the toxicity, 
 an insufficient patient recruitment rate, 
 A poor quality of the data collection. 
10. 
Safety evaluation  
10.1 
Description of safety evaluation parameters 
The safety evaluation will comprise an evaluation of the patient’s general condition 
(ECOG Appendix 1), a physical exam, regular blood tests and the recording of 
adverse events occurring throughout the study. Toxicity will be evaluated using the 
CTCAE version 4 (Appendix 2). 
In an emergency situation, the patient, his/her friends/family or treating physician will 
contact the investigator to report an event and/or to discuss the treatments to be 
implemented. 
10.2 
Methods and schedule to measure, collect and analyze the safety 
evaluation parameters 
Patients will be seen for consultation every four weeks over the study period (every 
two weeks during the first cycle).  
Blood tests are also planned every 2 to 4 weeks.  
10.2.1 
Definitions 
10.2.1.1 
Adverse event 
An adverse event is defined as any untoward medical occurrence which occurs in a 
patient, a clinical investigation subject. Adverse events include, but are not limited to: 
• 
abnormal test findings, 
• 
clinical symptoms and signs,  
• 
changes in physical examination findings,  
• 
hypersensitivity, 
• 
progression/worsening of underlying disease, 

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• 
lack of efficacy (for clinical trials, refer to the protocol), 
• 
drug abuse, 
• 
drug dependency 
• 
death, 
• 
hospitalization. 
• 
any suspected transmission of an infectious agent via a Pfizer product. 
 
As well as signs and symptoms resulting from: 
• 
drug overdose, 
• 
drug withdrawal, 
• 
drug misuse, 
• 
off-label use 
• 
drug interactions, 
• 
extravasation, 
• 
exposure during pregnancy, 
• 
exposure during breastfeeding, 
• 
medication error, 
• 
occupational exposure. 
10.2.1.2 
Serious adverse event 
A serious adverse event is defined as an adverse event regardless of the dose and 
that: 
• 
results in death and/or, 
• 
is life-threatening and/or, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
and/or, 
• 
results in persistent or significant disability/incapacity and/or, 
• 
results n congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization. However, if it is determined that 
the event may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above, the important medical event should be 
reported as serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Any suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is assessed as a serious adverse event with the seriousness 
criterion important medical event. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. 
Whether or not corresponding to the above-mentioned criteria, any other adverse 
event considered as serious by any Pfizer agent, any healthcare professional or any 
investigator should be handled as a serious adverse event. 

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10.2.1.3 
Not serious adverse event  
- A non-serious adverse event is an adverse event whose characteristics do not meet 
the criteria of a serious adverse event. 
10.2.1.4 
Adverse effect 
- An adverse effect is any untoward and unintended responses to an experimental 
drug regardless of the dose. 
10.2.1.5 
Expected/unexpected character :  
- An unexpected adverse event is an event whose nature, severity/intensity or 
outcome does not correspond to the information shown within the reference 
document for the study. 
In practice, the term “new effect” is sometimes used as a synonymous of 
“unexpected adverse effect. 
10.2.1.6 
Special Considerations  
Certain product safety monitoring reports should be forwarded even if there is no 
associated adverse event. These reports involve circumstances that may increase 
the patient/consumer’s risk of developing adverse events.  
These circumstances include: 
 Lack of efficacy, 
 medication errors, 
 off-label use, 
 exposure during pregnancy, 
 exposure during breastfeeding, 
 overdose, 
 misuse, 
 extravasation, 
 occupational exposure 
Some of these special circumstances are considered in more details below. 
 
Lack of efficacy: it is a failure to demonstrate pharmacological or therapeutic 
expected benefit. 
 
Medications errors: a medication error is any preventable event that may 
cause or lead to inappropriate medication use or patient harm while the medication is 
in the control of the healthcare professional, patient, or consumer. Such events may 
be related to professional practice, healthcare products, procedures, and systems, 
including: prescribing; order communication; product labeling, packaging, and 
nomenclature; compounding; dispensing; distribution; administration; education; 
monitoring; and use. 
A medication error does not necessarily involve the administration of the product (e.g. 
the error may have been corrected prior to administration of the product). 
Potential medication errors or “near-misses,” which are individual reports of 
information or complaints about product name, labeling, or packaging similarities that 
do not involve a patient, are also reportable. 
 
Exposure during pregnancy: exposure during pregnancy refers to pregnancies 
where the fetus (from pre-embryo to birth) may have been exposed at a given time 
during pregnancy to a product from the Pfizer group (or a blinded treatment). Even if 

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there is no associated adverse event, exposure during pregnancy must always be 
reported. It can indeed provide the opportunity to obtain pregnancy outcome 
important information where appropriate. 
Exposure during pregnancy may occur either: 
 
- Through maternal exposure  
a female becomes, or is found to be, pregnant either: 
• while receiving a medicinal product 
• after discontinuing a medicinal product 
• during or following environmental exposure to a product from the 
Pfizer group (eg, a nurse reports she is pregnant and that she 
was exposed to chemotherapy drugs via inhalation or after 
accidentally overturning a bottle) 
or 
 
-Through paternal exposure 
 
 
a male has been exposed to a medicinal product (either due to 
treatment or environmental circumstances) prior to or around the time of conception 
and/or is exposed during the partner pregnancy. 
 
Exposure during breastfeeding: exposure during breastfeeding occurs where 
an infant or child may have been exposed through breast milk to a medicinal product 
from the Pfizer group during breastfeeding by a female taking the product from the 
Pfizer group. 
All drug exposure during breastfeeding cases are reported, whether or not there is an 
associated adverse event 
Hospitalization or surgery planned before the patient's entry into the study does not 
be related as an SAE. Hospitalization for observation without associated adverse 
events should not be transmitted. 
10.2.2 
Serious adverse events and new information notification 
(responsibility of the investigator) 
The investigator will notify the Vigilance Unit without delay about any serious adverse 
events or new events occurring: 
- From the date of the informed consent is signed, 
- During the whole patient follow-up period as defined by the research, 
- Until 30 days after the end of patient follow-up period as defined by the research, if 
the event is likely to be research-related. 
 
Type of Event 
Reporting procedure 
Deadline for reporting to the 
sponsor 
SAE 
SAE report form + written 
form if necessary 
To be reported immediately to 
the sponsor 
New information 
Written report form 
To be reported immediately to 
the sponsor 
Pregnancy 
Written report form 
As soon as pregnancy is 
confirmed 
The investigator must complete the “Serious Adverse Event Reporting Form” 
(Appendix 5) immediately, in English, and assess the relationship with the study 

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treatment. The form must then be dated, signed and sent by fax to the following 
address without delay to: 
CELLULE DE VIGILANCE (VIGILANCE UNIT) - Unicancer 
Fax: + 33 1 44 23 55 70 
Or Contact: R&D Unicancer – E-mail: pv-R&D@unicancer.fr 
For each event, the investigator will record: 
 - A description of the event that is as clearly as possible, using medical terminology, 
 - The date the event started and ended, 
 - The patient’s relevant medical history, 
 - The steps taken and whether or not corrective treatment was required, whether or 
not the investigational treatment was discontinued, etc. 
 - Concomitant medications / therapies 
 The CTEP Active Version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE Appendix 2) will be utilized for AE reporting. The CTEP Active 
Version of the CTCAE is identified and located on the CTEP website at 
http://ctep.info.nih.gov/reporting/ctc.html. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4. 
 - The causal link between this event and the trial treatment, disease treated or an 
intercurrent disease or treatment, or any obligation imposed by the research (a 
treatment-free period, additional examinations requested as part of the research 
etc.), 
 - Clinical course. If the event was not fatal, it should be monitored until recovery, until 
the patient has returned to his/her previous condition, or until any sequelae have 
stabilized, 
 - Whenever possible, the investigator must also attach the following with the serious 
adverse event report: 
- A copy of the hospitalization or extended hospitalization report, 
- A copy of the autopsy report, if required, 
- A copy of all the results of any additional tests performed, including relevant 
negative results, along with the normal laboratory values, 
- Any other document he or she considers useful and relevant. 
All these documents must be anonymized. Additional information may be requested 
(by fax, by telephone or during a visit) by the CRA and/or by the Vigilance Unit using 
the Data Query form. 
The investigator is responsible for providing appropriate medical follow-up for 
patients until resolution or stabilization of the adverse event or until the patient’s 
death. Sometimes this may mean that follow-up will extend beyond the patient’s 
withdrawal from the trial. 
The investigator keeps the documents about the presumed adverse effect so that the 
information previously sent can be added to if necessary. 
The investigator responds to requests for additional information from the Vigilance 
Unit in order to document the original observation. 
 
 
 
 

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10.2.3 
Non serious adverse events 
TYPE OF EVENT 
REPORTING 
PROCEDURES 
DEADLINE FOR 
REPORTING TO THE 
SPONSOR 
Non-serious AE 
Case report/record form 
Does not need to be 
reported immediately 
Non-serious adverse events will be reported by the investigator in the patient’s CRF 
and will be followed up until complete resolution. The CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE Appendix 2) will be 
utilized for AE reporting. The CTEP Active Version of the CTCAE is identified and 
located 
on 
the 
CTEP 
website 
at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate treatment areas should have access to a copy of the CTCAE version 4. 
If an adverse event becomes serious, it should be reported and followed-up as 
mentioned in the previous reporting procedures. 
If the investigator would like to decrease trial treatment dose or temporarily stop 
study management without respecting protocol procedures, he/she should have 
previously discussed with the coordinator. 
However, symptomatic treatment can be prescribed to manage the adverse event. 
Any definitive interruption of the procedure has to be immediately notified to the 
sponsor. The patient remains in the study and is followed-up according to the 
procedures described in the protocol. 
10.2.4 
Pharmacovigilance Unit 
The Vigilance Unit will analyze each SAE to define: 
 - Severity grading, 
 - Degree of relationship with study treatment, 
 - Whether expected or unexpected according the characteristics of study drug. 
10.2.5 
Serious adverse events and new information notification 
(responsibility of the sponsor) 
10.2.5.1 
SAE documentation 
Sponsor undertakes to obtain from the investigators they report him immediately 
SAEs as defined above  
10.2.5.2 
Terms and SAEs transmission delays to Pfizer 
 
SAEs must be notified to Pfizer, even if the information is incomplete, then the 
following information will be brought to sponsor’s attention: 
- 
An identifiable patient: notification must contain enough information on the 
involvement of a specific individual or a known number of specific individuals. 
A patient or a defined number of patients are considered identifiable if at least 
one of the following characteristics is known: sex, age, age group, date of 
birth, initials, or identification number the patient (in case of clinical trials) is 
available. 

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- 
A suspect product: notification shall appoint (or clearly refer to) a product of 
Pfizer. 
- 
A serious adverse event: notification must contain at least a description of 
SAE such as signs and symptoms, diagnosis, or circumstances involving a 
risk event with or without associated adverse events, such as exposure during 
pregnancy, exposure during lactation, overdose, misuse, medication error and 
extravasation. 
- 
An identifiable notifier: notifier must be identifiable and have had direct 
contact with the identifiable patient (that is to say that the notification is not 
based on a rumor). Notifier is considered identifiable if at least one of the 
following is available: name or initials, address or qualification (eg GP, dentist, 
pharmacist). 
In cases of pregnancy, the notification must include the expected date of delivery. 
The subject will be followed until the end of pregnancy and Pfizer will be notified via a 
supplementary report to the outcome of pregnancy. 
- 
Particular condition: medication error  
If there has been no administration of product, medication error should be reported 
when existing an identifiable notifier, a suspect product and a proven medication 
error or medication error risk; 
When there is involvement of a patient, we need the three criteria described above, 
and the patient must be identifiable to report the case. 
Case of lack of efficacy: 
Cases of lack of efficacy must be reported if they are associated with an SAE. 
 
Only disease progression resulting in death must be transmitted. Progression of the 
disease leading to hospitalization should not be reported. 
The Promoter shall transmit to the pharmacovigilence department of Pfizer, 
regardless of causality, all SAEs occurring over a defined period in a subject 
receiving the product object of research within 24 hours after taking knowledge of the 
event. Transmission of deaths or life-threatening event must be immediate upon 
taking knowledge. 
For SAEs transmission to Pfizer, sponsor will use the SAE declaration form of 
UNICANCER and the declaration of pregnancy of UNICANCER, accompanied by a 
letter indicating the number of transmitted pages, complete coordinates of sender, 
name of research, the sequence of report (initial or supplementary report), and if it is 
a death or a life-threatening event. Transmission occurs preferentially by fax. 
10.2.5.3 
Recipient of declarations 
The coordinates of Pharmacovigilance notification recipients are: 
PFIZER – Département Pharmacovigilance 
Téléphone: 01 58 07 33 89 / 0800 39 84 50 
Fax: 01 70 74 57 33 
Transmission occurs preferentially by fax. 
10.2.5.4 
 Reporting period of SAEs 

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SAEs subject to these reporting obligations to Pfizer are SAEs occurring between the 
first dose of a Pfizer product up to twenty-eight (28) days after the last dose of the 
Pfizer product. The end of the period may be extended after twenty-eight (28) days 
depending on product characteristics (eg, long half-life) or in terms of safety profile, 
this extension is specified in the protocol. End of this period can’t be less than twenty-
eight (28) days after the last administration. 
All SAEs considered related will be reported regardless of the time of onset (during or 
after the end of the study). 
10.2.5.5 
SAEs monitoring and complementary informations 
Sponsor undertakes to obtain from the principal investigators that they provide him all 
complementary information in the same way as the initial information. The 
pharmacovigilance department of Pfizer may need reasonably contact with the 
Promoter for monitoring SAE. Additional information will be provided on the same 
terms and the same time that the initial information. 
10.2.5.6 
Competent authorities SAEs reporting 
SAEs’ Pfizer transmission doesn’t absolve sponsor to declare them to ANSM and 
CPP, and competent authorities of other countries in which research takes place, 
possibly in the context of its obligations as Sponsor . 
10.2.5.7 
Use of data by Pfizer 
Pfizer may freely use information about these SAEs under continuous evaluation of 
the benefit / risk ratio. 
10.2.6 
Notification and registration of unexpected serious adverse events 
and new information (Responsibility of the sponsor) 
The sponsor notifies unexpected serious adverse events and new information to the 
Regulatory Authorities (in person, or through an organization which has received 
allowances for this task) according to the usual notification procedures  
11. 
Evaluation criteria  
11.1 
Primary endpoint  
Efficacy is assessed based on 4-month non progression. Non progression is defined 
as complete or partial response (CR, PR) or stable disease (SD), using the 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1 Appendix 3). Non-
progression rate will be calculated as the number of alive and progression free 
patients divided by the number of eligible and assessable patients for the efficacy 
analysis.  
Eligible and assessable populations are described in section 12.2  
As recommended by RECIST v1.1 (Appendix 3), all claimed response will be 
centrally reviewed by an expert of the study. The results of the centralized 
radiological review will be used for the analysis of the primary endpoint.  
11.2 
Secondary endpoints 
 Objective response is defined as complete response (CR) or partial response 
(PR) according to RECIST v1.1 (Appendix 3). 
 Progression-free survival is defined as the time from the first administration of 
treatment to progression (as per RECIST v1.1 Appendix 3) or death of any cause, 
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 Overall survival is defined as the time from the first administration of treatment to 
death. 
 Progression will also be assessed using CHOI criteria ( Appendix 4) 
 Safety of PD-0332991 will be assessed by the Common Terminology Criteria for 
Adverse Events (CTCAE), v4.0 (Appendix 2). 
12. Statistical considerations  
12.1 
Sample size calculation 
The primary evaluation endpoint is the non-progression rate at 4 months. 
- 
We rely on an optimal two-stage Simon’s design (Simon, 1989). Based on the 
following hypotheses under PD-0332991 treatment:  
• 
25% non-progression rate (null hypothesis),  
• 
45% acceptable non-progression rate (alternative hypothesis),  
• 
5% type I error rate,   
• 
90% power, 
A total of 57 assessable subjects will be necessary, with 22 assessable subjects 
recruited to the first stage.  
- 
Stage 1: Following the inclusion of the first 22 assessable patients, if 6 or less 
patients are progression-free (complete response, partial response or stable 
disease), the study will be terminated early. Otherwise, the second group of 35 
subjects will be recruited.  
- 
Stage 2: If at the end of recruitment, 20 patients or more are progression-free 
(out of the 57 evaluable patients), PD-0332991 will be considered worthy of further 
testing in this disease. 
Eligible and assessable populations are described in section 12.2 
Given the disease is rare and the absence of standard treatment in this indication, 
inclusion will not be suspended after the recruitment of the first 22 patients. Inclusion 
will be pursued, while data on the first 22 patients will be analyzed. 
In order to account for not evaluable patients (+/- 10%), 63 patients will be recruited. 
The anticipated accrual rate is 3-4 patients/months. 
12.2 
Study populations 
Eligible population: All patients included without major violation of eligibility criteria. 
Population evaluable for efficacy: All patients eligible and for whom the following 
conditions are satisfied: 
 Received at least one complete or two incomplete treatment cycles, 
 At least one disease measurement recorded not less than four weeks after 
treatment onset. 
 Diagnosis of GIST established either by (i) a center of the RREPS network, or 
(ii) Pr JM Coindre or collaborators. 
The following patients will also be included in the population evaluable for efficacy; 
they will be considered as failures for the primary endpoint (i.e. disease progression 
at four months) and not be replaced in the primary efficacy analysis:  

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o Any eligible patients who received at least one treatment cycle or two 
incomplete and experienced disease progression or died due to disease 
progression prior to any radiological evaluation (will be considered as an “early 
progression”). 
o Patients who study-drug treatment definitively stopped due to toxicity of PD-
0332991, without any tumor assessments after the start of study treatment. 
o Patients who received at least one administration of PD-0332991 and study-
drug treatment definitively stopped due to significant clinical deterioration of 
unknown reason and without any tumor assessments after the start of study 
treatment. 
For a definition of patients' replacement, see section 5.6. 
 
Safety population: all patients having received at least one administration of PD-
0332991. 
12.3 
Statistical analysis  
The patients entered into the study will be described according to the following 
characteristics: 
- Compliance with eligibility criteria, 
- Epidemiological characteristics, 
- Clinical and laboratory characteristics, 
- Treatment characteristics. 
12.4 
Endpoint analysis  
 The primary efficacy endpoint will be analyzed at 4 months based on the 
population assessable for the primary endpoint (see chapter 11.1 for 
definition). 
 As regards the other efficacy endpoints, the analyses will be carried out in the 
assessable population. 
 The safety analysis will be performed on the safety population. 
 Quantitative variables will be described using mean and standard errors if the 
normality assumption is satisfied, else other descriptive statistics (median, 
range, quartiles) will be used. 
 Qualitative variables will be described using frequency, percentage and 95% 
confidence interval (binomial law). 
 Survival endpoints will be analyzed using the Kaplan-Meier method. The 
median survival rates will be reported with a 95% confidence interval. Median 
follow-up will be calculated using the reverse Kaplan-Meier method. 
Multivariate analyses can also be carried out based on Cox’s proportional risk 
method and after checking the risk proportionality hypothesis. 
12.5 
Interim statistical analysis  
An interim statistical analysis will be carried out after the inclusion of the first 22 
eligible and assessable patients. The trial will be terminated if 6 or less patients are 
progression-free (complete response, partial response or stable disease). Otherwise, 
the second group of 35 subjects will be recruited. A statistical report will be produced 
by the statistician of the study. Inclusion will not be suspended during this interim 
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13. Quality Insurance and Trial Monitoring 
13.1 
Monitoring of the trial 
13.1.1 
Steering Committee 
The study will be supervised and monitored by a Steering Committee comprising 
members participating in the study: 
 Dr A. Italiano, Co-ordinating Investigator and Chairman of the Commitee,  
 Dr BN. Bui, Investigator and medical oncologist, 
 Pr S. Mathoulin-Pélissier, Head of the Clinical Research and Epidemiology Unit, 
 C. Bellera, Biostatistician, 
 Dr B. Lortal, Pharmacist 
 D. Juzanx, Coordinating Clinical research assistant   
This committee must ensure the following:  
 Implementation and regular follow-up of the study 
 Patient protection, 
 That the trial is conducted ethically, in accordance with the protocol, 
 That the trial benefit/risk ratio is evaluated and the scientific results are checked 
during or at the end of the trial.  
It decides on any relevant amendment to the protocol that is required in order to 
continue the trial (protocol amendments prior to submission to the EC and the 
relevant Health Authorities, decisions on whether to open or close research sites, 
discussion of results and the strategy for the publication of these results). It must 
inform the sponsor of any decisions taken. Decisions concerning a major amendment 
or a change to the budget must be approved by the sponsor. 
13.1.2 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (IDMC) will be created at the request of 
the relevant Authority, the sponsor or the Steering Committee. The IDMC plays an 
advisory role for the Sponsor, who has the final decision regarding the 
implementation of recommendations put forward by the IDMC. 
Composition of the IDMC 
 This Committee must comprise one qualified oncologist, one pharmacologist and 
one statistician : 
- Qualified oncologist (Dr Sophie Piperno Neumann) 
- Pharmacologist (Dr Driss Berdaï) 
- Statistician (Mrs Sophie Gourgou) 
All of whom will have experience in the monitoring and analysis of clinical trials. One 
of these members will be appointed as the Trial Rapporteur.  
 Each of these members must be unconnected with the trial and cannot, therefore, 
belong to a centre of the trial. 
 These members are appointed by the Sponsor in consultation with the trial co-
ordinator and the Steering Committee.  
Responsibilities of the IDMC 
The IDMC is responsible for the following: 

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 Analysing preliminary efficacy and safety data, 
 Making recommendations on the continuation, early discontinuation (in the case 
of toxicity or lack of efficacy) or publication of the trial results, 
 Drafting the minutes after each meeting and monitoring their confidentiality. 
Any recommendation from the IDMC that can be made public will be announced by 
the Sponsor and not by the Steering Committee. The Sponsor is responsible for 
sending IDMC recommendations to the regulatory authorities [ANSM (French Agency 
for the Safety of Health Care Products) and EMEA (European Medicines Evaluation 
Agency)].  
13.2 
Quality assurance 
13.2.1 
Data collection  
The data will be collected on an electronic case report form and directly input via the 
Internet. Only the investigators and the Investigator’s Clinical Research Assistants 
(CRAs) appointed by the later and duly authorized by the sponsor will be authorized 
to enter the data. 
Data will be handled by online trial management software on the Internet (Macro v4, 
Infermed Company); it will be transferred and monitored remotely in real time. 
The study CRA and/or any other person appointed by the sponsor will be available to 
assist the investigators in carrying out the study and to ensure that the trial is carried 
out in accordance with the protocol. 
The study CRA will contact the investigators regarding the study implementation visit.  
All the study-related documents will be available on the Internet site: protocol, pre-
selection form, randomization form, informed consent form, serious and non-serious 
adverse event report form, centralized tube dispatch form, etc. 
All of the necessary data will be collected on an electronic case report form provided 
by the sponsor. The generic names of the concomitant medication will be given in 
French. 
Corrections made to the original data must be justified. These corrections will be 
automatically dated and signed by the authorized member of staff via the 
personalized password allocated at the start of the study. 
The case report form will be validated by the investigator or the CRA at the 
authorized center whenever data is entered. 
Laboratory data exceeding normal limit values will be commented upon if they are 
considered clinically significant. Data other than that requested within the scope of 
the protocol can be collected as additional data; their interest will be specified. 
13.2.2 
Monitoring 
In order to guarantee the authenticity and credibility of the data in accordance with 
the principles of GCP (Good Clinical Practice) dated 24 November 2006, the sponsor 
shall implement a quality assurance system comprising: 
 the management and monitoring of the trial in accordance with the procedures 
stipulated by the Institut Bergonié, 
 the quality control of the research site data by the CRA whose role is to: 

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o check compliance with the protocol, GCP and current legislation and 
regulations, 
o check the consent and eligibility of each patient taking part in the trial, 
o check the consistency and coherence of case report form date against 
the source documents. 
o check that each serious adverse event is reported, 
o monitor the traceability of the study medication (dispensation, storage 
and drug accountability), 
o check, where applicable, that the persons likely to take part in the trial 
are not already participating in another trial that could prevent them 
from being included in the clinical trial proposed. The CRA shall also 
ensure that the patients have not participated in a trial for which an 
exclusion period currently applies. 
 The possible audit of study centers 
 The centralized review of certain protocol criteria. 
The check procedures will include: 
 Study progression, 
 Protocol compliance, 
 The updating of information on the Internet site. 
The checking of data by comparing the information on the electronic case report form 
and the original clinical or laboratory data is one of the monitoring procedures. 
The following will be checked, in particular, for each patient (100% level): patient 
identification, informed consent (procedure and signature), selection criteria, 
therapeutic procedure, adverse events, principal response variables. The personal 
data relating to each patient shall remain confidential. On the electronic case report 
form or any other form dispatched, the patients will be identified solely by their initials 
(2/name – 2/surname) and an inclusion number. However, the investigators must 
keep a list identifying the patients in their folders. 
The CRAs responsible for the quality control of this clinical trial are duly appointed by 
the sponsor for this particular purpose and must have access, with the consent of 
those involved, to individual trial participant data required strictly in accordance with 
this control procedure. The CRAs are subject to professional secrecy under the 
conditions defined by Articles 226-13 and 226-14 of the French penal code. The 
traceability of monitoring visits is guaranteed by a written monitoring report. 
The investigators shall undertake to give CRAs direct access to the medical records 
of each patient in order to allow the CRAs to ensure optimal quality control of the trial. 
The same applies to health authority representatives. 
13.2.3 
Handling of missing data 
The monitoring of data for adverse events will be carried out regularly in order to 
effectively limit the amount of missing data likely to prevent or hamper trial 
implementation and analysis. 
 
 
 

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13.2.4 
Audits 
The sponsor, the local authorities or the authorities to which information about this 
study has been submitted can decide to have an audit. All the documents relating to 
this study must be available for such an inspection after prior notification. 
14. Ethical, legislative and regulatory considerations 
Clinical Research Management Unit – Institut Bergonié 
Contacts: Pauline Beaufrere – Tel.: +33 5 56 33 32 70 – e-mail: 
p.beaufrere@bordeaux.unicancer.fr 
or Marie-Laure Marty – Tel.: +33 5 47 30 60 79 – e-mail: 
m.marty@bordeaux.unicancer.fr 
 
The study will be carried out in accordance with: 
 The ethical principles of the current version of the “Declaration of Helsinki” 
 Good Clinical Practice (GCP): I.C.H. version 4 of 1 May 1996 and decision dated 
24 November 2006 (Official Bulletin of 30 November 2006, text 64). 
 European Directive (2001/20/EC) on clinical trial procedures. 
 Huriet’s law (No. 88-1138) dated 20 December 1988, concerning the protection of 
persons taking part in Biomedical Research with the provisions of the Public 
Health law (No. 2004-806) of 9 August 2004 and implementation decree No. 
2006-477 of 26 April 2006 relating to biomedical research. 
 The French law on Data Protection and Civil Liberties, No. 78-17 of 6 January 
1978 modified by law No. 2004-801, dated 6 August 2004, concerning the 
protection of persons with regards to the processing of personal data. 
 The application of Circular DHOS/INCA/MOPRC/2006/475 of 7 November 2006: 
the Sponsor shall undertake to register the Trial and thus make it accessible to 
the general public, in the INCa (French Cancer Institute) register via the Internet 
site: www.e-cancer.fr. Each trial published in the INCa register will be sent to the 
NCI for registering on the following site: www.clinicaltrials.gov. The trial will be 
registered before the first patient is entered into the study. The Sponsor is 
responsible for updating the study data in order to guarantee the reliability of the 
information available on-line. 
 Law no. 2004-800 dated 6 August 2004, concerning bioethics amended by law 
No. 2012-387, dated 22 March 2012. 
14.1 
Clinical trial authorization 
This trial is registered under Eudract N° 2013-000283-28 
The protocol has been approved by the South West and Overseas Territories III 
Ethics Committee, Bordeaux.  Approval was given on 30/10/2013. 
The Relevant Authority, the Agence Nationale de Sécurité du Médicament et des 
Produits de Santé (ANSM - French Agency for the Safety of Health Care Products) 
authorized the clinical trial on 13/11/2013. 
Any amendments to the protocol concerning study objectives, patient population and 
principal methods will require an amendment, which must be approved by the EC 

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and l'ANSM.  The sponsor will inform the EC and ANSM of expected and/or 
unexpected serious adverse events in accordance with current regulations. 
The sponsor will send the summary of the final report to the relevant Authority within 
one year of completion of the trial. 
14.2 
Insurance policy 
The Institut Bergonié has taken out an insurance policy (policy No.0100871914011-
130002-10998) with the HDI GERLING France Company, TOUR OPUS 12, 77, 
Esplanade de la Défense 92914 Paris LA DEFENSE through an insurance broker, 
namely Biomédic Insure (Parc d'Innovation Bretagne Sud, CP 142, 56038 Vannes, 
tel. 02 97 69 19 19) in case compensation is payable to investigators or patients 
taking part in the study. 
14.3 
Informing and obtaining consent from patients 
The investigator in charge of the patient will provide the latter with relevant 
information relating to the study objectives, potential benefits and possible adverse 
events. The study methods will be outlined. The patient can refuse treatment before 
or at any time during the study, without experiencing any adverse repercussions in 
terms of his/her subsequent care. 
The patient’s written consent will be informed prior to entry into the study. Three 
copies will be available: one for the patient, the second for the investigator and the 
third for the sponsor. This written consent form will be kept for 15 years by the 
investigator. 
The Patient Information Leaflet and Informed Consent Form must be combined in the 
same document in order to ensure that all of the information is given to the trial 
participant. 
The consent form must be personally dated and signed by the trial participant and 
the investigator. The participant must also initial all of the pages in the Patient 
Information Leaflet. The original will be archived in the investigator’s folder and the 
duplicate will be sent to the trial participant. 
14.4 
Sponsor’s responsibilities 
The sponsor of the clinical trial, the Institut Bergonié, will take the initiative for this 
clinical trial. The Institute will manage the trial and ensure that finance is provided. 
The sponsor’s main responsibilities are to: 
 Take out civil liability insurance, 
 Obtain the Eudract No. and register the trial in the European database (European 
Drug Regulatory Authorities Clinical Trials), 
 Obtain clinical trial authorization for the initial project and any amendments from 
the DC and ANSM; approval by the EC and decision taken by ANSM.  
 give trial-related information to the site directors, pharmacists and investigators, 
 notify the relevant authority of the trial start and end dates, 
 draft the final trial report and sent the summary to ANSM, 
 send to Pfizer all SAEs collected from the clinical trial, 
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 Archive essential trial documents in the sponsor’s folder for a minimum period of 
15 years after the trial has ended. 
 
 
14.5 
 Investigator’s responsabilities 
The senior investigator of each establishment concerned undertakes to conduct the 
clinical trial in accordance with the protocol that was approved by the ethics 
committee and the relevant authority (ANSM). 
The investigator must not make any changes to the protocol without the written 
consent of the sponsor or without the ethics committee and the relevant authority 
having authorized the proposed changes. 
It is the responsibility of the senior investigator is: 
 to provide the sponsor with his/her curriculum vitae as well as those of his/her co-
investigators, 
 to identify the members of his/her team who are participating in the trial and to 
define their responsibilities, 
 to start patient recruitment after authorization has been obtained from the 
sponsor, 
 to ensure that he/she is available for “monitoring” purposes and for investigators’ 
meetings. 
It is the responsibility of each investigator: 
 to comply with the confidential nature of the trial, 
 to obtain informed consent, signed and dated personally by each trial participant, 
before any screening procedures specific to the trial are carried out, 
 to regularly complete the case report forms (CRFs) for each of the patients 
enrolled in the trial and to allow the Clinical Research Assistant (CRA) direct 
access to source documents so that the latter can validate the data on the CRF, 
 to promptly notify Unicancer of any serious adverse event and/or new information 
occurring during the trial, 
 to date, correct and validate corrections on the case report forms (CRFs) and the 
Data Query Forms (DQFs). 
14.6 
Authority to execute the trial 
The investigator shall certify that he/she is authorized to enter into this agreement 
and that the terms and conditions of the protocol and agreement do not conflict with 
other work contracts that the investigator may have entered into with any other party, 
or any other arrangement agreed by the Institution where the investigator is 
employed. 
14.7 
Regulations governing the collection of human biological samples 
During the medical procedures to be carried out, samples will be collected for 
medical purposes. A fraction of these samples will be kept and used for scientific 
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The patient will be informed of this research and provided that he/she approves by 
signing an informed consent, these samples intended for research will be: 
 Initially prepared and stored using a specific technique to preserve them under 
excellent conditions. 
 and secondly, used within the scope of this research.   
The preparation, storage and use of these samples will not in any way affect current 
or future medical care administered to the patient for the purpose of diagnosis or 
treatment. 
The results of this research may, in future, appear in scientific publications.  All of the 
data shall remain anonymous. 
 
Obtaining and using additional samples 
This biomarker study is made up of exploratory research that is described in the 
section “Ancillary Study”. 
On completion of the trial, provided that the patient agrees and provided that not all 
of the samples have been used, the said samples can be used for subsequent 
scientific research purposes without the approval of the Ethics Committee (EC) and 
the signing of a new consent form by the patients included. 
14.8 
Federation des comités de patients pour la recherche clinique en 
cancerologie (FCPRCC) (Federation of patient commitees for clinical research 
in oncology) 
The Fédération des Comités de Patients pour la Recherche Clinique en Cancérologie 
(FCPRCC) (Federation of Patient COmmittees for Clinical Research in Oncology) 
was created on the initiative of the Fédération des Centers de Lutte Contre le Cancer 
(FNCLCC) (Federation of Anti-Cancer Centers) and the Ligue Nationale Contre le 
Cancer (National Anti-Cancer League) in order to review clinical trial protocols in 
oncology. This Federation of Patient Committees is co-ordinated by the Office for 
Clinical and Therapeutic Trials and groups together the League patient committees 
as well as other health care establishments. It undertakes to review the protocol and 
to propose improvements focusing primarily on the quality of the information leaflet, 
the availability of a treatment and monitoring plan and the suggestion of measures 
aimed at improving patient comfort. 
14.9 
Data processing  
In accordance with the revision of the French Data Protection and Liberties Act of 06 
August 2004 and its implementation decree, the Sponsor shall follow the 
methodology of reference MR001 of the Commission Nationale de l’Informatique et 
des Libertés (French National Commission for Data Protection and Liberties). 
Furthermore, if the biomedical research data is computer processed or managed by 
computerized systems, each Center: 
 shall check and document the fact that the computerized systems used in the 
research comply with requirements drawn up in relation to data integrity, accuracy 
and reliability, as well as compliance with expected performances (i.e. validation); 
 shall implement and ensure the monitoring of standard operating procedures 
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 shall ensure that the design of these systems allows for data to be amended such 
that the amendments are documented and that any item of data input cannot be 
deleted (i.e. maintaining data and amendment audit trail) ; 
 shall implement and ensure the monitoring of a secure system that prevents any 
unauthorized data access; 
 shall update the list of persons authorized to amend the data; 
 shall keep appropriate back-up copies of the data; 
 shall maintain blind status, where applicable (e.g. during data entry and 
processing); 
 shall ensure that personal data used within the scope of the trial is processed in 
accordance with the conditions defined by law No. 78-17 dated 6 January 1978 
relating to data processing, files and liberties modified by law No. 2004-801 of 6 
August  2004 and regulatory texts applicable to its application. 
If the data is converted during processing, it must always be possible to compare the 
original data and observations with the data after conversion. 
The system used to identify subjects taking part in the trial must not present with any 
ambiguity and must allow all of the data collected for each of these subjects to be 
identified whilst maintaining the confidentiality of the personal data, in accordance 
with law No. 78-17, duly amended. 
15. Confidentiality and ownership of data 
All of the information communicated or obtained and the data and results generated 
by the trial legally belong to the Institut Bergonié, which can use this data at its own 
discretion. The trial cannot be the subject of any written or verbal comments without 
the sponsor’s consent. 
Any unpublished data sent to the investigator is confidential. These documents must 
not be disclosed to a third party without the consent of the Institut Bergonié. The 
submission of these documents to the EC is formally authorized. The Institut 
Bergonié is free to submit the trial data and results to governments and other 
accredited authorities.  
The investigator must treat as confidential all of the information acquired or deduced 
during the trial and shall take the necessary steps to avoid any violation of this 
confidentiality, with the exception of information that must be disclosed in accordance 
with the legislation. 
16. Regulations governing publication 
16.1 
Final report 
The biostatistician(s) will compile a final report. It will include tables giving the raw 
data and the statistical report on the data. This report will be submitted to the 
Steering Committee and Senior Investigators for approval and signature. A report of 
the overall results of the study will be issued so that the investigator can send it to 
patients who wish to know these results.  
 
 
16.2 
Publications 

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All of the information arising from this study shall be considered confidential at least 
until the appropriate analysis and subsequent checks have been completed by the 
trial sponsor, co-ordinating investigator and statistician. 
All forms of publication must be submitted to the Steering Committee for review and 
approval prior to publication (allowing at least 15 working days for abstracts and oral 
presentations, and 45 working days for written publications). The Steering Committee 
shall check the accuracy of the information submitted (in order to avoid any 
inconsistency with that submitted to the Health Authorities), and ensure that 
confidential information is not inadvertently disclosed.  It will also provide additional 
information as required.  
Furthermore, all memos, manuscripts or presentations must comprise a heading 
referring without fail to the Institut Bergonié, all of the institutions, investigations, co-
operating groups and learned societies that have contributed to the implementation 
of the trial, and listing any organizations that have provided financial support. 
For the principal publication, either in French or English, the authors are: 
 the study coordinator (first or last if an insufficient number of patients is recruited) 
 the investigators will be listed on a pro rata basis according to the number of 
patients recruited, regardless of the co-operating group. Each investigator site 
shall allocate a member of staff who will act as author for official 
presentations/publications. 
 a representative of each co-operating group not listed amongst the study centers 
having the largest patient cohorts 
 a representative of the trial statistics unit (in the first 3 positions according to 
degree of involvement in the preparation of publications) 
As required for multicenter studies, the first publication will present the data collected 
in all of the participating centers after the information has been analyzed in 
accordance with the protocol by a biostatistician, and not by the investigators.  
Similarly, publications of additional results (laboratory study) shall include the name 
of the person who carried out the additional work as well as the names of all the other 
persons involved in this additional work. 
Correspondents in the recruitment centers with lower patient cohorts not cited in the 
main publication should ideally be included in subsequent publications. 
Unless granted special authorization by the Steering Committee, the investigators 
cannot publish the results collected in only one or two centers before the first official 
version, containing all of the data, is published. 
17. 
References 
Angevin E, Grünwald V, Lin C et al (2010) A Phase I/II Study of Dovitinib (TKI258), 
an FGFR and VEGFR Inhibitor, in Patients With Advanced or Metastatic Renal Cell 
Cancer (mRCC): Preliminary Phase II Ann Oncol, 21: Abstract 507P 
 
Assamaki R, Sarlomo-Rikala M, Lopez-Guerrero JA, et al. (2007) Array comparative 
genomic hybridization analysis of chromosomal imbalances and their target genes in 
gastrointestinal stromal tumors. Genes Chromosomes Cancer 46:564–76. 
 
Astolfi A, Nannini M, Pantaleo MA, et al. (2010) A molecular portrait of 
gastrointestinal stromal tumors: an integrative analysis of gene expression profiling 
and high-resolution genomic copy number. Lab Invest 90:1285–94. 

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Belinsky MG, Skorobogatko YV, Rink L, et al. (2009) High density DNA array 
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sarcomas and multiple types of cancer on the basis of a gene expression signature 
related to genome complexity. Nat Med 16:781–7. 
 
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tumors. J Clin Oncol; 22: 3813-3825. 
 
Dagher GD, Cohen M, Williams G, et al (2002) Approval summary: imatinib mesylate 
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(GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 
Lancet, In Press. 
 
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in solid tumors: Revised RECIST guideline (version 1.1). EJC; 45: 228-247  
 
El-Rifai W, Sarlomo-Rikala M, Andersson LC,  et al. (2000) DNA sequence copy 
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muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol; 23: 82-87. 
 
Finn RS, Dering J, Conklin D et al. (2009) PD 0332991, a selective cyclin D kinase 
4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive 
human breast cancer cell lines in vitro. Breast Cancer Res. 11:R77. 
 
Fletcher CD, Berman JJ, Corless C, et al (2002) Diagnosis of gastrointestinal stromal 
tumors: A consensus approach. Hum Pathol; 33: 459-465. 
 
Haller F, Lobke C, Ruschhaupt M, et al. (2008) Loss of 9p leads to p16INK4A down-
regulation and enables RB/E2F1-dependent cell cycle promotion in gastrointestinal 
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Heinrich MC, Corless CL, Duensing A, et al (2003) PDGFRA activating mutations in 
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Heinrich MC, Griffith DJ, Druker BJ, et al (2000) Inhibition of c-kit receptor tyrosine 
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18. 
APPENDIX 
APPENDIX 1: ECOG PERFORMANCE STATUS ASSESSMENT SCALE 
Grade 
Activity 
0 
Able to carry on all normal activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out light work.  
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 

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APPENDIX 2: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) V4 
TOXICITY EVALUATION CRITERIA The CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) 
You can download this document in PDF: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 

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APPENDIX 3: EVALUATION OF RESPONSE. THE RECIST V1.1 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009]. Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
DEFINITIONS 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
DISEASE PARAMETERS  
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with 
CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area are not considered 
measurable. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are present 
in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  

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METHODS FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
RESPONSE CRITERIA 
 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 

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Definition of the Best Response 
The best response determination in trial where confirmation of complete or partial response is 
required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). In this circumstance, the best 
overall response can be interpreted as in Table below. 
 
 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size 
(<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR (complete 
response) may not have a total sum of ‘zero’ on the case report form (CRF). 
 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
detioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response: it 
is a reason for stopping study therapy. The objective response status of such patients is to be 
determined by evaluation of target and non-target disease as shown in Tables belows. 

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APPENDIX 4: SUMMARY OF THE CHOI CRITERIA 
Response  
Definition  
CR 
Disappearance of all lesions 
  
No new lesions 
PR 
A decrease in size 
10% or a decrease in tumour attenuation (HU) 
15% 
on CT 
  
No new lesions 
  
No obvious progression of non-measurable disease 
SD 
Does not meet criteria for CR, PR, or PD 
  
No symptomatic deterioration attributed to tumour progression 
PD 
An increase in tumour size 
10% and does not meet criteria of PR by 
tumour attenuation on CT 
  
New lesions 
 Abbreviations: CR=complete response; PR=partial response; SD=stable disease; 
PD=progressive disease; HU=Hounsfield unit. 
 

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APPENDIX 5: REPORTING OF AN EXPECTED OR UNEXPECTED SERIOUS 
ADVERSE EVENT (ESAE) 

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APPENDIX 6: PREGNANCY REPORT FORM 

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APPENDIX 7: PRE-SCREENING FORM 

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APPENDIX 8: REGISTRATION FORM 

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APPENDIX 9: PATHOLOGY REQUEST FORM 
 

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APPENDIX 10: OPTIONAL PATHOLOGY REQUEST FORM  

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APPENDIX 11: BASELINE CLINICAL SUBJECT PROFILE 

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APPENDIX 12: RADIOLOGY REFERRAL FORM 

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APPENDIX 13: BASELINE RADIOLOGY REVIEW FORM 

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APPENDIX 14: INFORMED CONSENT – PRINCIPAL STUDY 
 
Note d’information destinée aux personnes participant au 
protocole de Recherche Biomédicale 
« CYCLIGIST » 
 
Etude principale 
Titre de l’essai : Efficacité et tolérance du PD-0332991 chez les patients atteints d’une Tumeur Stromale 
Gastro-intestinale (GIST) localement avancée, réfractaire à Imatinib et Sunitinib : essai de phase 2 
 
Promoteur : Institut Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Investigateur Coordonnateur : Dr Antoine ITALIANO, Département d’Oncologie Médicale, Institut 
Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Madame, Mademoiselle, Monsieur, 
Votre médecin vous propose de participer à une recherche biomédicale dont le nom du promoteur est 
l’Institut Bergonié. Avant de prendre une décision, il est important que vous lisiez attentivement ces 
pages qui vous apporteront les informations nécessaires concernant les différents aspects de cette 
recherche. N’hésitez pas à poser à votre médecin toutes les questions que vous jugerez utiles. 
Votre médecin vous a expliqué que vous étiez porteur d’une tumeur stromale gastro-intestinale, un 
cancer du système digestif qui touche 600 à 900 nouvelles personnes par an en France, plus 
couramment appelée GIST (pour Gastro Intestinal Stromal Tumor en anglais). Dans votre cas, cette 
tumeur est évolutive. Nous vous proposons de participer à un protocole de traitement concernant 
votre maladie. 
Votre participation est entièrement volontaire. Si vous ne désirez pas prendre part à cette recherche, 
vous continuerez à bénéficier de la meilleure prise en charge médicale possible, conformément aux 
connaissances actuelles. 
Pourquoi mon médecin me propose-t-il de participer à  cette étude ? 
Nous vous proposons cette étude car vous avez une tumeur stromale gastro-intestinale nécessitant un 
traitement médical. 
Le PD-0332991 est une molécule développée par les Laboratoires Pfizer et qui a la propriété d’inhiber 
la croissance des tumeurs. Des données scientifiques récentes permettent de penser que ce 
médicament est efficace dans le traitement des tumeurs stromale gastro-intestinale évolutives. 
L’objectif de cette étude est donc d’évaluer l’efficacité et la tolérance (effets secondaires) du PD-
0332991 dans le traitement des tumeurs stromales gastro-intestinales évolutives. 
Comment cette étude se déroule-t-elle ? 
Elle prévoit la participation d’environ 63 patients de 10 centres français qui seront inclus sur une durée 
estimée à 18 mois. 
Avant d’entrer dans l’étude… 
Pour participer à cette étude, vous devez être bénéficiaire d’un régime de sécurité sociale en tant 
qu’assuré ou ayant-droit. Vous ne serez inclus dans l’étude que si vous datez et signez le 

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consentement qui vous est remis. Vous ne pourrez participer en même temps à une autre recherche 
biomédicale. Vous pouvez ensuite vous retirer à tout moment de l’essai sans justification, sans 
conséquence sur la suite de votre traitement ni sur la qualité des soins qui vous seront fournis et sans 
conséquence sur la relation avec votre médecin ; vous pourrez être suivi par la même équipe 
médicale. 
 
Si vous souhaitez participer à cette étude, nous vous demandons de signer un formulaire de 
consentement de participation attestant simplement que vous avez été informé(e) de cette étude et 
que vous y participez librement. Vous en conserverez un exemplaire. 
Vous serez ensuite enregistré comme participant et des analyses et examens seront effectués afin de 
déterminer si vous pouvez recevoir le traitement (examen clinique, prélèvements sanguins, test de 
grossesse si vous êtes une femme en âge d’avoir des enfants, électrocardiogramme et scanner ou 
IRM). 
Si les résultats de ces divers examens vous permettent de participer à cette étude en toute sécurité, 
vous pourrez commencer le traitement par PD-0332991. 
Durant l’étude… 
D’autres examens habituellement réalisés en routine dans ce type de prise en charge, seront effectués 
pendant la durée de votre traitement : 
A chaque visite les examens suivant seront réalisés : 
 
un examen clinique toutes les 4 semaines, 
 
des bilans sanguins seront réalisés à la 2ème semaine de traitement du cycle 1, puis toutes les 4 
semaines pendant les 6 premiers mois, et toutes les 8 semaines après 6 mois de traitement, 
 
scanner ou IRM toutes les 8 semaines, 
 
et tout autre examen ou procédure que votre médecin jugera nécessaire dans votre intérêt. 
Quand vous aurez terminé le traitement… 
Dans le cadre de la surveillance de votre état de santé et de votre maladie, vous aurez une visite avec 
votre médecin pour un examen clinique et un prélèvement sanguin 4 semaines après la dernière prise 
du médicament. 
Le déroulement de l’étude est résumé ci-dessous : 
Dans cette étude, vous allez prendre le médicament PD-0332991 tous les jours pendant 21 jours 
consécutifs et le stopper durant 7 jours complets ensuite. Cette période de 28 jours est appelée un 
cycle. Vous devrez prendre le médicament ainsi pour chaque cycle de traitement. 
Lors du suivi de l’étude et dans certains cas (progression de votre maladie), votre médecin pourra 
décider d’interrompre le traitement en cours. 
Le schéma ci-après vous montre ce qu’il se passera durant ces cycles. 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 92 sur 102 
 
 
Avant le début du traitement 
Cycle 1 
Cycle 
n 
Fin de 
traitement 
Suivi 
Visites 
 
 
V1 
V2 
Vn 
 
 
Jours de cycle 
 
1 à 21 
jours avant 
le début du 
traitement 
Jour 
1 
Jour 
15 
Jour 1 
Dans les 28 
jours après 
arrêt du 
traitement 
 
Note information et 
consentement 
X 
 
 
 
 
 
 
Analyse génomique 
X 
 
 
 
 
 
 
Historique  
Données du patient (Age, 
sexe..) 
 
X 
 
 
 
 
 
Critères inclusion/exclusion  
 
X 
 
 
 
 
 
Antécédents médicaux 
pertinents / Etat de santé 
actuel 
 
X 
 
 
 
 
 
Diagnostic tumoral 
 
X 
 
 
 
 
 
Traitements 
antineoplastiques 
antérieurs 
 
X 
 
 
 
 
 
Traitements concomitants 
 
X 
En continu jusqu’à 28 jours après la dernière 
dose du traitement à l’étude 
 
Traitement antinéoplasique 
depuis arrêt du traitement 
à l’étude 
 
 
 
 
 
 
X 
Examen clinique 
Examen physique 
 
X 
X 
X 
X 
X 
 
Taille/Poids 
 
X 
X 
X 
X 
X 
 
Signes vitaux 
 
X 
X 
X 
X 
X 
 
Examens de laboratoire 
Hematologie 
 
X 
X 
X 
X 
Jour 1 
et 15 
X 
 
Biochimie 
 
X 
X 
X 
X 
X 
 
Coagulation 
 
X 
X 
X 
X 
X 
 
Test de grossesse si 
applicable 
 
X 
X 
 
X 
X 
 
Imagerie/Autre examen 
Evaluation tumorale CT 
scan ou IRM 
 
 
Jour 28 du Cycle 1, Jour 28 du Cycle 2 puis 
toutes les 8 semaines jusqu’au 6ème mois. 
Ensuite toutes les 12 semaines 
 
ECG 
 
X 
X 
X 
X 
X 
 
Tolérance 
Effets indésirables 
 
 
En continu jusqu’à 28 jours après la dernière 
dose du traitement à l’étude 
 
Biomarqueurs 
Biopsie tumorale 
(optionnel) 
Jour –3 à Jour -1 et Jour 
21 cycle 1 
 
1 à 3 jours 
avant le 
début du 
traitement 
Jour 21 du Cycle 1 
 
 
Autres 
Administration du  
PD-0332991  
 
 
Prise de la molécule pendant 21 
jours puis arrêt pendant 7 jours 
 
Raison de fin de traitement 
 
 
 
 
 
X 
 
Suivi tous les 3 mois 
pendant 1 an 
 
 
 
 
 
 
X 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 93 sur 102 
Est-ce que je peux arrêter de participer à cette étude ? 
Oui. Vous pouvez décider d’arrêter à n’importe quel moment. Appelez votre médecin 
si vous souhaitez arrêter le traitement.  
Ensemble, vous pourrez alors discuter des risques éventuels liés à cet arrêt. Quelle que soit 
votre décision, votre médecin vous conseillera sur les meilleurs traitements adaptés à votre situation 
et vous informera du suivi des examens nécessaires. 
Votre médecin peut décider à tout moment d’interrompre votre participation à l’étude s’il 
juge que cela est dans votre intérêt, ou si vous ne suivez pas les recommandations de 
l’étude, ou si l’étude est arrêtée. 
Quels sont les risques prévisibles de cette étude ?  
Comme tout médicament, l’administration de PD-0332991 peut être à l’origine d’effets secondaires 
indésirables. Peuvent ainsi survenir :  
- 
Fatigue 
- 
Chute des globules blancs, rouges et des plaquettes 
- 
Nausées et/ou vomissements 
- 
Diarrhées 
- 
Constipation 
- 
Eruption cutanée, sécheresse cutanée   
- 
Essoufflement 
- 
Perte d’appétit 
- 
Saignement 
- 
Frissons 
- 
Fièvre 
- 
Toux 
- 
Chute des cheveux 
- 
Œdèmes 
- 
Infections, notamment respiratoires 
- 
Troubles du goût 
- 
Inflammations de la muqueuse buccale (douleurs, aphes…) 
- 
Troubles oculaires (vision floue, larmoiement, sécheresse oculaire). 
Des effets secondaires non encore identifiés pourraient également survenir.  
Dans la mesure du possible, votre médecin prendra toutes les mesures nécessaires pour prévenir ou 
atténuer la survenue d’éventuels effets secondaires. Il pourra également diminuer la dose de 
traitement ou l’interrompre en cas de mauvaise tolérance ou à votre demande. 
Signaler à votre médecin tout événement indésirable, que vous pensez liés ou non au traitement. Il 
consignera ces informations. 
Votre médecin est bien sûr à votre disposition pour répondre à toutes vos demandes d’information sur 
les risques et effets secondaires du traitement.  
Quels sont les bénéfices prévisibles de cette étude ? 
Même si votre médecin espère que le traitement que vous allez recevoir sera efficace, il ne peut en 
avoir la certitude à l’avance. Le suivi prévu dans cette étude (bilans sanguins et radiologiques) 
permettra d’évaluer étroitement et régulièrement la bonne tolérance de votre traitement ainsi que son 
efficacité. 
 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 94 sur 102 
Quelle alternative ai-je, si je ne participe pas à cette étude ? 
Vous avez parfaitement le droit de ne pas participer à cette étude. Cela n’aura aucune conséquence 
sur votre prise en charge et sur votre relation avec votre médecin. Dans le cas d’un refus de votre 
part, votre médecin conviendra avec vous de la prise en charge thérapeutique alternative la plus 
adaptée à votre situation.  
 
Quels sont vos droits ? 
Votre médecin doit vous fournir toutes les explications nécessaires concernant cette recherche. Si 
vous souhaitez vous en retirer à quelque moment que ce soit, et quel que soit le motif, vous 
continuerez à bénéficier du suivi médical et cela n'affectera en rien votre surveillance future. 
Dans le cadre de la recherche biomédicale à laquelle l’Institut Bergonié vous propose de participer, un 
traitement informatique de vos données personnelles va être mis en œuvre pour permettre d’analyser 
les résultats de la recherche au regard de l’objectif de cette dernière qui vous a été présenté. A cette 
fin, les données médicales vous concernant seront transmises au promoteur de la recherche ou aux 
personnes ou sociétés agissant pour son compte, en France ou à l’étranger. Ces données seront 
identifiées par un code et/ou vos initiales. Ces données pourront également, dans des conditions 
assurant leur confidentialité, être transmises aux autorités de santé françaises ou étrangères et à 
d’autres entités de l’Institut Bergonié. 
Conformément aux dispositions de la loi relative à l’informatique, aux fichiers et aux libertés, vous 
disposez à tout moment d’un droit d’accès et de rectification des données informatisées vous 
concernant (loi n° 2004-801 du 6 août 2004 modifiant la loi n° 78-17 du 6 janvier 1978 relative à 
l’informatique, aux fichiers et aux libertés). Vous disposez également d’un droit d’opposition à la 
transmission des données couvertes par le secret professionnel susceptibles d’être utilisées dans le 
cadre de cette recherche et d’être traitées. Vous pouvez également accéder directement ou par 
l’intermédiaire du médecin de votre choix à l’ensemble de vos données médicales en application des 
dispositions de l’article L1111-7 du code de la santé publique. Ces droits s’exercent auprès du médecin 
qui vous suit dans le cadre de la recherche et qui connaît votre identité.  
Conformément à la loi n°2004-806 du 9 août 2004 relative à la Politique de Santé Publique (art 
L1121-1 à L1126-6 du code de la santé publique) : 
- cette recherche a obtenu un avis favorable du Comité de Protection des Personnes du Sud-Ouest et 
Outre-Mer III le 30/10/2013 et l’autorisation de l’Agence Nationale de Sécurité du Médicament et des 
produits de santé (ANSM) le 13/11/2013. 
- le promoteur de cette recherche, l'Institut Bergonié (Centre régional de Lutte Contre le Cancer du 
Sud-Ouest situé au 229, cours de l'Argonne, 33076 Bordeaux cedex), a souscrit une assurance de 
responsabilité civile auprès de HDI GERLING, TOUR OPUS 12, 77, Esplanade de la Défense 92914 
Paris LA DEFENSE, n° police 0100871914011-130002-10998, 
- les personnes ayant subi un préjudice après participation à une recherche biomédicale peuvent faire 
valoir leurs droits auprès des commissions régionales de conciliation et d’indemnisation des accidents 
médicaux, 
- lorsque cette recherche sera terminée, vous serez tenus informés personnellement des résultats 
globaux par votre médecin dès que ceux-ci seront disponibles, si vous le souhaitez. 
 
Après avoir lu cette note d’information, n’hésitez pas à poser à votre médecin toutes les questions que 
vous désirez. Après un délai de réflexion, si vous acceptez de participer à cette recherche, vous devez 
compléter et signer le formulaire de consentement de participation. Un exemplaire du document 
complet vous sera remis. 
 
Le Docteur ……………………………………… (Tél. …………………………..) se tient à votre disposition pour 
répondre à toutes vos éventuelles questions complémentaires. 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 95 sur 102 
 
Formulaire de recueil de consentement (1) destiné aux personnes participant au protocole 
de Recherche Biomédicale  
« CYCLIGIST» 
Etude principale 
Titre de l’essai : Efficacité et tolérance du PD-0332991 chez les patients atteints d’une Tumeur Stromale 
Gastro-intestinale (GIST) localement avancé, réfractaire à Imatinib et Sunitinib : essai de phase 2 
(1) Un exemplaire co-signé doit être remis à la personne qui participe à la recherche et à l'investigateur 
Promoteur : Institut Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Investigateur Coordonnateur : Dr Antoine ITALIANO, Département d’Oncologie Médicale, Institut Bergonié, 
229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Je soussigné(e) .................................................................................................. (nom, prénom) certifie avoir lu et compris 
la note d’information qui m’a été remise. 
J’ai eu la possibilité de poser toutes les questions que je souhaitais au Pr/Dr…………………………. (nom, 
prénom) 
qui m’a expliqué la nature, les objectifs, les risques potentiels et les contraintes liées à ma participation à cette 
recherche. 
Je connais la possibilité qui m’est réservée d’interrompre ma participation à cette recherche à tout moment sans avoir à 
justifier ma décision et je ferai mon possible pour en informer le médecin qui me suit dans la recherche. Cela ne 
remettra naturellement pas en cause la qualité des soins ultérieurs. 
J’ai eu l’assurance que les décisions qui s’imposent pour ma santé seront prises à tout moment, conformément à l’état 
actuel des connaissances médicales. 
Je suis informé(e) que la possibilité qu’une partie des prélèvements effectués à l’occasion de ce protocole de recherche 
soit conservée pour une utilisation ultérieure à des fins de recherche. J’ai également été informé(e) de mon droit à 
m’opposer à ce que cette conservation et cette utilisation ultérieure à des fins de recherche aient lieu. 
J’ai pris connaissance que cette recherche a reçu l’avis favorable du Comité de Protection des Personnes du Sud-Ouest 
et Outre-Mer III le 30/10/2013 et l’autorisation de l’ANSM le 13/11/2013 et a fait l’objet d’une déclaration à la 
Commission Nationale Informatique et Libertés (CNIL). 
Le promoteur de la recherche l'Institut Bergonié (Centre régional de Lutte Contre le Cancer du Sud-Ouest situé au 229, 
cours de l'Argonne, 33076 Bordeaux cedex) a souscrit une assurance de responsabilité civile en cas de préjudice auprès 
de la société HDI GERLING, TOUR OPUS 12, 77, Esplanade de la Défense 92914 Paris LA DEFENSE, n° police 
0100871914011-130002-10998. 
J’accepte que les personnes qui collaborent à cette recherche ou qui sont mandatées par le promoteur, ainsi 
qu’éventuellement le représentant des Autorités de Santé, aient accès à l’information dans le respect le plus strict de la 
confidentialité. 
J’accepte que les données enregistrées à l’occasion de cette recherche puissent faire l’objet d’un traitement informatisé 
sous la responsabilité du promoteur.  
J’ai bien noté que, conformément aux dispositions de la loi relative à l’informatique, aux fichiers et aux libertés, je 
dispose d’un droit d’accès et de rectification. Je dispose également d’un droit d’opposition à la transmission des 
données couvertes par le secret professionnel susceptibles d’être utilisées dans le cadre de cette recherche et d’être 
traitées. Ces droits s’exercent auprès du médecin qui me suit dans le cadre de cette recherche et qui connaît mon 
identité. 
Mon consentement ne décharge en rien l’investigateur et le promoteur de la recherche de leurs responsabilités à mon 
égard. Je conserve tous les droits garantis par la loi. 
Les résultats globaux de la recherche me seront communiqués directement, si je le souhaite, conformément à la loi du 4 
mars 2002 relative aux droits des malades et à la qualité du système de santé. 
Ayant disposé d’un temps de réflexion suffisant avant de prendre ma décision, j’accepte librement et 
volontairement de participer à la recherche Cycligist 
 
__ oui 
__ non 
Je pourrai à tout moment demander des informations complémentaires au médecin qui m’a proposé de 
participer à cette recherche, n° téléphone :  
 
Fait à ________________________________  
 
    Fait à ________________________________ 
Le  
└─┴─┘└─┴─┘└─┴─┴─┴─┘  
 
    Le  
└─┴─┘└─┴─┘└─┴─┴─┴─┘ 
Signature du patient : 
 
 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 96 sur 102 
APPENDIX 15: INFORMED CONSENT – OPTIONAL STUDY 
 
Note d’information destinée aux personnes participant au 
protocole de Recherche Biomédicale 
« CYCLIGIST » 
 
Etudes biologiques optionnelles 
Titre de l’essai : Efficacité et tolérance du PD-0332991 chez les patients atteints 
d’une Tumeur Stromale Gastro-intestinale (GIST) localement avancée, réfractaire à 
Imatinib et Sunitinib : essai de phase 2 
 
Promoteur : Institut Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Investigateur Coordonnateur : Dr Antoine ITALIANO, Département d’Oncologie Médicale, Institut 
Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Madame, Mademoiselle, Monsieur, 
Votre médecin va vous expliquer les détails de ce projet de recherche expérimentale qui fait partie de 
l’étude Cycligist. 
Après avoir pris connaissance de cette note d’information, il vous sera demandé de compléter le 
formulaire de consentement qui est joint et qui attestera que vous avez lu les informations contenues 
dans ce document, que vous avez compris les modalités de ces recherches et que vous avez librement 
accepté d’y participer. 
Vous êtes libre d’accepter ou de refuser de participer à cette recherche. Si vous êtes d’accord pour y 
participer, il vous sera demandé de dater et signer cette note. Sinon, cela ne vous empêche nullement 
de continuer votre participation à l’étude principale Cycligist. 
Si vous acceptez cette étude optionnelle, une biopsie tumorale sera effectuée : 
 
au début de l’étude, Jour1 du cycle 1, avant l’administration de la première dose de PD-
0332991.  
 
et au 21ème jour du Cycle 1. 
A PROPOS DU DON DE TISSU POUR LA RECHERCHE :  
Une partie du matériel biologique (échantillon tumoral) obtenu lors des procédures de diagnostic 
(biopsie ou chirurgie) que vous avez déjà eu et  les biopsies complémentaires réalisées dans le cadre 
de cette étude, pourront être utilisés pour la recherche.  
Si vous êtes d’accord, ce tissu pourra être conservé et ensuite utilisé pour améliorer les connaissances 
sur les tumeurs stromale gastro-intestinale. 
Les recherches qui pourront être entreprises à partir de votre tumeur permettront de mieux 
comprendre les mécanismes d’action et les effets du PD-0332991 dans les tumeurs stromales gastro-
intestinales. Elles pourront dans le futur aider les personnes atteintes du même cancer ou d’autres 
maladies. Les informations enregistrées à l’occasion de ces études exploratoires ne seront pas 
inscrites dans votre dossier médical et ne seront disponibles ni pour votre famille, ni pour votre 
médecin personnel, ni pour un tiers. 
Cette recherche n’affectera pas votre prise en charge.  
BUT DE L’ÉTUDE : 
Le but de cette étude est de mieux comprendre comment et pourquoi le PD-0332991 agit ou 
non sur votre cancer et d’identifier des caractéristiques des cellules cancéreuses permettant 
de prédire l’efficacité de ce médicament. Cela permettra peut-être de mettre au point des 
tests qui identifieront les personnes les plus susceptibles d’avoir un bénéfice potentiel au PD-
0332991 pour le traitement de leur maladie.  

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 97 sur 102 
QUE PENSER DE VOTRE PARTICIPATION À CETTE RECHERCHE ? 
Vous êtes libre d’accepter de donner vos échantillons tumoraux à la recherche. Quoi que vous 
décidiez, votre choix n’affectera en rien votre prise en charge.  
Pendant et après l’étude, vous resterez propriétaire des échantillons et vous aurez à tout moment le 
droit de demander la destruction de ces échantillons en contactant votre médecin de l’étude. Si vous 
décidez de faire détruire vos échantillons, les informations obtenues avant votre demande ne seront 
pas détruites, mais aucune étude supplémentaire ne sera réalisée. 
L’Institut Bergonié sera le propriétaire des données et des résultats dérivés de cette étude et sera 
responsable de la destruction du matériel génétique sur votre demande ou à la fin de la période de 
conservation. Suite à votre demande de destruction, l’Institut Bergonié confirmera par courrier à votre 
médecin investigateur que votre matériel génétique a été détruit. 
CONFIDENTIALITE  
Pour éviter toute mauvaise utilisation de ces données celles-ci resteront confidentielles. 
Pour que la confidentialité soit maximale, tous les échantillons et les informations se rapportant aux 
échantillons seront codés pour éviter l’exposition des informations vous concernant ainsi que votre 
identité. 
En outre, les informations qui concernent les échantillons sont conservées dans une base de données 
sécurisée tandis que les données génétiques sont conservées dans une base de données 
indépendante, elle aussi sécurisée et ne comportant aucune information relative à votre identité. 
Cependant vous serez identifié par vos initiales et un code patient uniquement. Vous ne serez pas 
identifié dans les rapports ou les publications issus de cette étude. 
Sauf si cela est exigé par les Autorités de Santé pour vérifier des informations, seul l’Institut Bergonié 
et les personnes autorisées par l’Institut Bergonié auront accès aux données issues de cette recherche 
sur les biomarqueurs. Les personnes autorisées par l’Institut Bergonié n’auront pas accès à des 
résultats identifiés par votre nom. 
BÉNÉFICES POTENTIELS  
Vous ne tirerez pas de bénéfices directs de cette étude. L’information recueillie permettra de faire 
avancer les connaissances médicales sur la mise au point de traitements plus efficaces et plus sûrs 
des cancers. 
RISQUES ET DÉSAGRÉMENTS  
Les biopsies seront réalisées avec toutes les précautions possibles afin de vous éviter tout 
désagrément. Néanmoins comme pour toute procédure médicale, des risques existent. Peuvent ainsi 
survenir de manière exceptionnelle :  
 Malaise  
 Douleur 
 Saignement 
 Infection 
 Ponction potentiellement grave et non désirée d’autres organes  
En cas de complication, votre médecin mettra tout en œuvre pour vous soigner et  éviter toute séquelle. 
 
PROTECTION DES PERSONNES PARTICIPANT A L'ETUDE  
Pour participer à cette étude, vous devez être bénéficiaire d’un régime de sécurité sociale en tant 
qu’assuré ou ayant-droit. Vous ne serez inclus dans l’étude que si vous datez et signez ce 
consentement qui vous est remis. Vous ne pourrez participer en même temps à une autre recherche 
biomédicale. Vous pouvez ensuite vous retirer à tout moment de l’essai sans justification, sans 
conséquence sur la suite de votre traitement ni sur la qualité des soins qui vous seront fournir et sans 
conséquence sur la relation avec votre médecin ; vous pourrez être suivi par la même équipe 
médicale. 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 98 sur 102 
Le promoteur de cette étude, qui en assure la gestion et la responsabilité, est l'Institut Bergonié, 
Centre régional de Lutte Contre le Cancer du Sud-Ouest situé au 229, cours de l'Argonne, 33076 
Bordeaux cedex. 
Conformément aux dispositions de la loi relative à l’informatique, aux fichiers et aux libertés, vous 
disposez à tout moment d’un droit d’accès et de rectification des données informatisées vous 
concernant (loi n° 2004-801 du 6 août 2004 modifiant la loi n° 78-17 du 6 janvier 1978 relative à 
l’informatique, aux fichiers et aux libertés). Vous disposez également d’un droit d’opposition à la 
transmission des données couvertes par le secret professionnel susceptibles d’être utilisées dans le 
cadre de cette recherche et d’être traitées. Vous pouvez également accéder directement ou par 
l’intermédiaire du médecin de votre choix à l’ensemble de vos données médicales en application des 
dispositions de l’article L1111-7 du code de la santé publique. Ces droits s’exercent auprès du médecin 
qui vous suit dans le cadre de la recherche et qui connaît votre identité.  
Conformément à la loi n°2004-806 du 9 août 2004 relative à la Politique de Santé Publique (art 
L1121-1 à L1126-6 du code de la santé publique) : 
- cette recherche a obtenu un avis favorable du Comité de Protection des Personnes du Sud-Ouest et 
Outre-Mer III le 30/10/2013 et l’autorisation de l’Agence Nationale de Sécurité du Médicament et des 
produits de santé (ANSM) le 13/11/2013, 
- le promoteur de cette recherche, l'Institut Bergonié (Centre régional de Lutte Contre le Cancer du 
Sud-Ouest situé au 229, cours de l'Argonne, 33076 Bordeaux cedex), a souscrit une assurance de 
responsabilité civile auprès de HDI GERLING, TOUR OPUS 12, 77, Esplanade de la Défense 92914 
Paris LA DEFENSE, n° police 0100871914011-130002-10998, 
- les personnes ayant subi un préjudice après participation à une recherche biomédicale peuvent faire 
valoir leurs droits auprès des commissions régionales de conciliation et d’indemnisation des accidents 
médicaux, 
- lorsque cette recherche sera terminée, vous serez tenus informés personnellement des résultats 
globaux par votre médecin dès que ceux-ci seront disponibles, si vous le souhaitez. 
L'Institut Bergonié a pris toutes les dispositions prévues par la loi relative à la protection des 
personnes se prêtant à des recherches biomédicales, loi Huriet (n°88-1138) du 20 décembre 1988 
modifiée par la loi de santé publique (n°2004-806) du 9 août 2004 et le décret d'application n°2006- 
477 du 26 avril 2006 relatif aux recherches biomédicales. 
Le Docteur ……………………………………… (Tél. …………………………..) se tient à votre disposition pour 
répondre à toutes vos éventuelles questions complémentaires. 
Dr.................................................................Tél...........................................................

 Institut Bergonié 
 Protocole CYCLIGIST 
 
Protocole Cycligist Version n°5.0 du |15|03|2017| 
 
Page 99 sur 102 
 
Formulaire de recueil de consentement(1) destiné aux personnes 
participant au protocole de Recherche Biomédicale  
« CYCLIGIST » 
 
Etudes biologiques optionnelles 
Titre de l’essai : Efficacité et tolérance du PD-0332991 chez les patients atteints d’une Tumeur 
Stromale Gastro-intestinale (GIST) localement avancé, réfractaire à Imatinib et Sunitinib : essai de 
phase 2 
 (1) Un exemplaire co-signé doit être remis à la personne qui participe à la recherche et à l'investigateur 
Promoteur : Institut Bergonié, 229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Investigateur Coordonnateur : Dr Antoine ITALIANO, Département d’Oncologie Médicale, Institut Bergonié, 
229 Cours de l’Argonne, 33076 BORDEAUX Cedex. 
Je soussigné(e) .................................................................................................. (nom, prénom) certifie avoir lu et compris 
la note d’information qui m’a été remise. 
J’ai eu la possibilité de poser toutes les questions que je souhaitais au Pr/Dr…………………………. (nom, 
prénom) 
qui m’a expliqué la nature, les objectifs, les risques potentiels et les contraintes liées à ma participation à cette 
recherche. 
Je connais la possibilité qui m’est réservée d’interrompre ma participation à cette recherche à tout moment sans avoir à 
justifier ma décision et je ferai mon possible pour en informer le médecin qui me suit dans la recherche. Cela ne 
remettra naturellement pas en cause la qualité des soins ultérieurs. 
J’ai eu l’assurance que les décisions qui s’imposent pour ma santé seront prises à tout moment, conformément à l’état 
actuel des connaissances médicales. 
Je suis informé(e) que la possibilité qu’une partie des prélèvements effectués à l’occasion de ce protocole de recherche 
soit conservée pour une utilisation ultérieure à des fins de recherche. J’ai également été informé(e) de mon droit à 
m’opposer à ce que cette conservation et cette utilisation ultérieure à des fins de recherche aient lieu. 
J’ai pris connaissance que cette recherche a reçu l’avis favorable du Comité de Protection des Personnes du Sud-Ouest 
et Outre-Mer III le 30/10/2013 et l’autorisation de l’ANSM le 13/11/2013 et a fait l’objet d’une déclaration à la 
Commission Nationale Informatique et Libertés (CNIL). 
Le promoteur de la recherche l'Institut Bergonié (Centre régional de Lutte Contre le Cancer du Sud-Ouest situé au 229, 
cours de l'Argonne, 33076 Bordeaux cedex) a souscrit une assurance de responsabilité civile en cas de préjudice auprès 
de la société HDI GERLING, TOUR OPUS 12, 77, Esplanade de la Défense 92914 Paris LA DEFENSE, n° police 
0100871914011-130002-10998. 
J’accepte que les personnes qui collaborent à cette recherche ou qui sont mandatées par le promoteur, ainsi 
qu’éventuellement le représentant des Autorités de Santé, aient accès à l’information dans le respect le plus strict de la 
confidentialité. 
J’accepte que les données enregistrées à l’occasion de cette recherche puissent faire l’objet d’un traitement informatisé 
sous la responsabilité du promoteur.  
J’ai bien noté que, conformément aux dispositions de la loi relative à l’informatique, aux fichiers et aux libertés, je 
dispose d’un droit d’accès et de rectification. Je dispose également d’un droit d’opposition à la transmission des 
données couvertes par le secret professionnel susceptibles d’être utilisées dans le cadre de cette recherche et d’être 
traitées. Ces droits s’exercent auprès du médecin qui me suit dans le cadre de cette recherche et qui connaît mon 
identité. 
Mon consentement ne décharge en rien l’investigateur et le promoteur de la recherche de leurs responsabilités à mon 
égard. Je conserve tous les droits garantis par la loi. 
Les résultats globaux de la recherche me seront communiqués directement, si je le souhaite, conformément à la loi du 4 
mars 2002 relative aux droits des malades et à la qualité du système de santé. 
Ayant disposé d’un temps de réflexion suffisant avant de prendre ma décision, j’accepte librement et 
volontairement de participer à la sous-étude Cycligist 
 
__ oui 
__ non 
Je pourrai à tout moment demander des informations complémentaires au médecin qui m’a proposé de 
participer à cette recherche, n° téléphone :  
Fait à ________________________________  
 
    Fait à ________________________________ 
Le  
└─┴─┘└─┴─┘└─┴─┴─┴─┘  
 
    Le  
└─┴─┘└─┴─┘└─┴─┴─┴─┘ 
Signature du patient : 
             Signature du médecin : 
 
 

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APPENDIX 16: PATHOLOGY EXPERT CENTERS IN SARCOMA 
  
Sites 
Structures anapath 
Spécificité 
Site Coordonnateur Institut Bergonié 
Institut Bergonié 
Département de Pathologie 
tout sarcome 
  
Hôpital Pellegrin Bordeaux 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Haut-Lévèque Pessac 
Service d'anatomie pathologique 
tout sarcome 
Site Coordonnateur Centre Léon Bérard 
Centre Léon Bérard 
Département d'anatomie 
pathologique 
tout sarcome 
  
Hôpital Edouard Herriot 
Laboratoire d'anatomie pathologique GIST* 
  
Hôpital de la Croix Rousse 
Service d'anatomie pathologique 
gynécopathologie** 
Site Coordonnateur Institut Gustave 
Roussy 
Institut Gustave Roussy 
Service de Pathologie Morphologique tout sarcome 
CRE AP-HP Ile de France 
Hôpital Ambroise Paré 
Service d'anatomie pathologique 
GIST* 
  
Hôpital Cochin 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Pitié-Salpétrière 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Saint-Antoine 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Saint-Louis 
Service d'anatomie pathologique 
sarcomes cutanés*** 
  
Hôpital Bichat - Claude Bernard 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Henri Mondor 
Service d'anatomie pathologique 
sarcomes cutanés*** 
  
CHU d'Amiens 
Service d'anatomie pathologique 
gynécopathologie** 
CRE Institut Curie 
Institut Curie 
Service de Pathologie 
tout sarcome 
CRE Strasbourg 
Centre Paul Strauss 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital de Hautepierre 
Département de Pathologie 
tout sarcome 
  
Hôpital Civil 
Laboratoire d'histopathologie 
cutanée 
sarcomes cutanés*** 
CRE Clermont Ferrand 
Centre Jean Perrin 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Gabriel Montpied 
Service de Pathologie 
tout sarcome 
CRE Caen 
CHRU de Caen 
Service d'anatomie pathologique 
tout sarcome 
  
Centre François Baclesse 
Service d'anatomie pathologique 
tout sarcome 
CRE Dijon  
Centre Georges François 
Leclerc 
Service d'anatomie pathologique 
tout sarcome 
  
CHRU de Dijon 
Service d'anatomie pathologique 
GIST* 
  
CHRU de Besançon 
Service d'anatomie pathologique 
tout sarcome 

 Institut Bergonié 
 Protocole CYCLIGIST 
 
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CRE Rennes 
Hôpital Pontchaillou 
Service d'anatomie pathologique 
tout sarcome 
CRE Tours 
Hôpital Trousseau 
Service d'anatomie pathologique 
tout sarcome 
CRE Brest 
Hôpital Morvan 
Service d'anatomie pathologique 
tout sarcome 
CRE Rouen 
Hôpital Charles Nicolle 
Service d'anatomie pathologique 
tout sarcome 
  
Centre Henri Becquerel 
Service d'anatomie pathologique 
tout sarcome 
CRE Montpellier 
Centre Val d'Aurelle 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Gui de Chauliac 
Laboratoire d'anatomie pathologique tout sarcome 
CRE Limoges 
Hôpital Dupuytren 
Laboratoire de Pathologie 
tout sarcome 
CRE Nancy 
Centre Alexis Vautrin 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Central de Nancy 
Laboratoire d'anatomie pathologique tout sarcome 
CRE Toulouse 
Institut Claudius Regaud 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Rangueil 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Purpan 
Laboratoire d'anatomie pathologique GIST* 
CRE Lille 
Centre Oscar Lambret 
Laboratoire d'anatomie pathologique tout sarcome 
  
CHRU de Lille 
Centre de Biologie Pathologie 
tout sarcome 
CRE Nantes 
Hôtel Dieu 
Service d'anatomie pathologique 
tout sarcome 
CRE Angers 
Centre Paul papin 
Service d'anatomie pathologique 
tout sarcome 
  
CHRU d'Angers 
Département de Pathologie 
tout sarcome 
CRE Marseille 
Institut Paoli Calmettes 
Département de Bio-Pathologie 
tout sarcome 
  
Hôpital La Timone 
Service d'anatomie pathologique 
tout sarcome 
  
Hôpital Nord Marseille 
Laboratoire d'anatomie pathologique gynécopathologie** 
CRE Nice  
Centre Antoine Lacassagne 
Unité d'anatomie pathologique 
tout sarcome 
  
Hôpital Pasteur 
Laboratoire d'anatomie pathologique tout sarcome 
 
 
 
 
 
 
 
 
GIST* : structure ne pouvant relire que des GIST  
 
 
Gynécopathologie** : structure ne pouvant relire que des sarcomes de la sphère gynécologique 
 
Sarcomes cutanés*** : structure ne pouvant relire que des sarcomes cutanés 
 
 
 
 
 
 

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APPENDIX 17: PATIENT DIARY