Clinical trial NCT01692496
Conditions: Advanced and / or Metastatic Liposarcoma
Keywords: Advanced Metastatic Liposarcoma Pazopanib
Sponsor: Grupo Espanol de Investigacion en Sarcomas
Start date: 2013-01-29; Completion date: 2018-03-02
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Soft tissue and bone sarcomas are rare malignant tumors, which encompasses a large family of more than 50 histologically distinct tumor subtypes, all of which share a putative mesenchymal origin. In the case of soft tissue sarcomas (STS) surgical excision is the mainstay of treatment, but despite curative surgery, around half of patients develop distant metastases and die from disease. Few therapeutic approaches are currently available to patients with unresectable, locally advanced, or metastatic STS and only anthracyclines, ifosfamide and trabectedin have shown activity, with response rates of 20-40% in previously untreated patients. Recent and ongoing trials have investigated a variety of combination chemotherapeutic regimens (variously employing ifosfamide, doxorubicin, gemcitabine, temozolomide, vincristine, cisplatin, and dacarbazine, among others) as well as targeted therapies, which in some cases have yielded improvements in response rate but which have had little impact on survival. No other medical option is currently available, and the median survival of patients with soft-tissue sarcoma with non-resectable metastases is around 12-15 months, and approximately 8 months after second line chemotherapy.

Liposarcomas are STS which account for at least 20% of all STS in adults. They can be further classified into 3 histologically and biologically different subtypes: well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT-WD), myxoid or round cell liposarcoma and pleomorphic liposarcoma.

ALT-WD liposarcomas are locally aggressive rarely metastasizing tumors characterized by ring or giant marker chromosomes on the cytogenetic analysis and by amplification of the 12q13-21 region on Fluorescence In Situ Hybridization (FISH) (MDM2, CDK4 and HMGIC). They account for about 40% iv of liposarcomas with a 5 year Overall survival (OS) around 80%. In a series of WD/DD treated with several regimens response rate was 12.5% OS 15 months and median PFS 3.6 months(95 confidence interval (CI): 3.3-5.9) Mixoid /round cell liposarcoma accounts for 45-50% of all liposarcomas. They tend to metastasize to unusual soft tissue and bone locations. High histologic grade with more than 5% of round cell component is associated with a 5-year OS of 50% approximately. They are characterized by t(23;16)(q13-14;p11) which leads to the fusion of CHOP and TLS genes Pleomorphic liposarcoma accounts for approximately 5-10% of all liposarcomas, characterized by high grade features with frequent and early lung metastasis and cytogenetically by high chromosome counts and complex structural rearrangements.

VEGF is expressed in many STS in which increased expression is associated with higher grade and worse prognosis.

Pazopanib is an oral angiogenesis inhibitor that targets mainly VEGFR, PDGFR and c-kit. Recently the results of a phase II trial of pazopanib in STS have been published. It was a four-cohort 2-stages study. The liposarcoma stratum was closed after the first stage because of a PFS at 12 weeks of 17% (3 out of 17 patients did not progressed after 12 weeks). After central pathologic review, 2 other patients initially classified as other STS were found to have liposarcoma with stable disease at 12 weeks (5/19: 26% PFS12w), thus fulfilling criteria for cohort expansion. Phase II study had been completed and in phase III study patients with liposarcomas were excluded so therefore data on the liposarcoma cohort are inconclusive.

Furthermore the positive results of the phase III study PALETTE have been recently communicated, encouraging this treatment in other sarcomas: progression-free survival (PFS) per independent review was significantly prolonged with pazopanib (median: 4.6 vs 1.5 months; HR=0.31, 95% CI 0.24-0.40; P\<0.0001). The interim analysis for overall survival shows a statistically non-significant improvement of pazopanib vs placebo (median: 11.9 vs 10.4 months, HR=0.83, 95% CI 0.62-1.09).

Soluble factors associated with efficacy and toxicity of pazopanib in these patients had been also reported. Decreases in VEGFR2 and increase in PlGF were both associated with toxicity (HTA and TSH elevation) and poorer prognosis.

Detailed description:

Arms: arm 1: Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.
Interventions: intervention 1: Pazopanib
Intervention descriptions: intervention 1: Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
TITLE: Phase II Clinical Trial of Pazopanib to evaluate the activity and tolerability in
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients with advanced and/or metastatic liposarcoma who have relapsed following
 
 
 
 
 
 
 
 
 
 
standard therapies or for whom no standard therapy exists 
 
SPONSOR PROTOCOL NUMBER: 
GEIS-30 
 
Nº EudraCT: 
2012-002745-38 
 
VERSION: 
H_V03F_2015-02-11 
 
CLINICAL TRIAL SPONSOR:  
 
GRUPO ESPAÑOL DE INVESTIGACIÓN EN SARCOMAS -
 
 
 
 
 
  
GEIS 
 
CLINICAL TRIAL CHIEF INVESTIGATOR: 
 
Dr. Claudia Valverde Morales 
Vall d’Hebron University Hospital 
Passeig Vall d'Hebron 119 - 129, Barcelona 
 
CLINICAL STUDY COORDINATOR IN GERMANY:  
Dr. Bernd Kasper 
University Medical Centre Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
 
TRANSLATIONAL RESEARCH COORDINATOR: 
 
Dr. José Antonio López Guerrero  
Laboratory of Molecular Biology 
Fundación Instituto Valenciano de Oncología 
Prof. Beltrán Báguena 8-11, 46009, Valencia 
 
 
Information included in this protocol is confidential. No person is authorized to make it public without written 
permission of the investigators. This material may be disclosed to and used by study investigators and 
associates as it may be necessary to conduct the clinical study, as well as to patients included in the study, 
Health authorities and Ethics Review Committees. 
 
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PROTOCOL SIGNATURE FORM 
 
Protocol: GEIS-30
Nº EudraCT: 2012-002745-38  
 
Version: ​H_V03F_2015-02-11 
 
 
I have read this protocol and I agree to conduct it in compliance with GCPs and the
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
Helsinki Declaration. 
 
 
 
Sponsor signature 
Chief Investigator Signature 
 
 
 
 
 
 
 
 
 
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PROTOCOL SIGNATURE FORM 
 
Protocol: GEIS-30
Nº EudraCT: 2012-002745-38  
 
Version: H_V03F_2015-02-11 
 
 
Ich habe dieses Protokoll gelesen und stimme zu, die Studie in Übereinstimmung mit allen
 
 
 
 
 
 
 
 
 
  
 
 
 
Festlegungen dieses Protokolls sowie der Deklaration von Helsinki, den ICH GCP
 
 
 
 
 
 
 
 
 
 
 
Guidelines und den Deutschen Gesetzen und Bestimmungen durchzuführen. 
 
 
 
Leiter der klinischen Prüfung 
 
Name 
 
 
Datum
Unterschrift 
 
 
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SIGNATURE PAGE FOR GERMAN SITES 
 
Ich habe dieses Protokoll gelesen und stimme zu, die Studie in Übereinstimmung mit allen
 
 
 
 
 
 
 
 
 
  
 
 
 
Festlegungen dieses Protokolls sowie der Deklaration von Helsinki, den ICH GCP
 
 
 
 
 
 
 
 
 
 
 
Guidelines und den Deutschen Gesetzen und Bestimmungen durchzuführen. 
 
 
Prüfer 
 
Name 
 
 
Datum
Unterschrift 
 
 
 
Stellvertreter des Prüfers 
 
Name 
 
 
Datum
Unterschrift 
 
 
 
Ärztliches Mitglied der Prüfgruppe 
 
Name 
 
 
Datum
Unterschrift 
 
 
 
Ärztliches Mitglied der Prüfgruppe 
 
Name 
 
 
Datum
Unterschrift 
 
 
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1. SUMMARY 
1.1. Type of Request 
A two cohort phase II, open-label, non-randomized, international multi-centre study of an
 
 
 
 
 
 
 
 
 
 
 
 
IMP​ ​licensed but used for new indication. 
 
1.2. Sponsor Data: 
GRUPO ESPAÑOL DE INVESTIGACIÓN EN SARCOMAS - GEIS 
C/Velazquez nº 7, 3ª planta 
28001 – MADRID - Spain.  
 
Contact Data: 
Secretaría Técnica GEIS 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: + 34 93 434 44 12 
Fax: + 34 93 253 11 68 
e-mail: secretaria@grupogeis.org 
 
1.3. Study Title 
Phase II Clinical Trial of Pazopanib to evaluate the activity and tolerability in patients with
  
 
 
 
 
 
 
 
 
 
 
 
 
 
advanced and/or metastatic liposarcoma who have relapsed following standard therapies
 
 
 
 
 
 
 
 
 
 
or for whom no standard therapy exists. 
 
1.4. Sponsor Protocol Number: ​GEIS-30 
 
1.5. Nº EudraCT: ​2012-002745-38 
 
1.6. Chief Investigator 
Dr. Claudia Valverde Morales 
Vall d’Hebron University Hospital 
Passeig Vall d'Hebron 119 - 129, Barcelona. 
 
1.7. Clinical Study Coordinator in Germany 
Dr. Bernd Kasper 
University Medical Centre Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
 
 
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1.8 Translational Research Coordinator  
Dr.  José Antonio López Guerrero  
Laboratory of Molecular Biology 
Fundación Instituto Valenciano de Oncología 
Prof. Beltrán Báguena 8-11, 46009, Valencia 
 
1.9. Monitoring Organization 
MARKETING FARMACEUTICO & INVESTIGACION CLINICA – MFAR S.L. 
Calle Secretari Coloma 64-68, esc.B, entlo. 5ª 
08024 – Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
For German sites: 
COORDINATING CENTER FOR CLINICAL TRIALS 
Karl-von-Frisch-Str. 4 
35043 Marburg 
Germany 
 
1.10. Study Treatment  
Single arm of Pazopanib 800 mg (2x400mg or 4x200 mg) given as a single agent once
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
daily. 
 
Presentation: The investigational product, Pazopanib mono-hydrochloride salt (coded as
 
 
 
 
 
 
 
 
 
GW786034B) is produced as tablets containing Pazopanib mono-hydrochloride salt
 
 
 
 
 
 
 
 
 
equivalent to 400 mg / 200 mg of the free base. Refer to the Pazopanib SPC for
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
information regarding the physical and chemical properties of Pazopanib and a list of
 
 
 
 
 
 
 
 
 
  
 
 
excipients. 
 
Pharmaceutical form:​ Film-coated tablet. 
 
Route of administration:​ oral 
 
1.11. Study phase and design  
A two cohort Phase II, open-label, non-randomized, multi-centre study with 5 centres in
 
 
 
 
 
 
 
 
 
  
 
 
Spain and 5 centres in Germany. Patients will receive oral Pazopanib, 800mg once daily
 
  
 
 
 
 
 
 
 
 
 
 
 
and treatment will continue until disease progression, development of unacceptable
 
 
 
 
 
 
 
 
 
 
toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.  
 
1.12. Primary Objective 
The primary objective of this study is to evaluate the activity of Pazopanib in patients with
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
advanced and/or metastatic liposarcoma by means of progression-free survival (PFS)
 
 
 
 
 
 
 
 
 
 
assessed 12 weeks after start of treatment. (According the RECIST criteria 1.1 and central
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiology review). 
 
 
1.13. Disease under investigation 
Advanced and/or metastatic liposarcoma 
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1.14. Primary endpoint 
The primary efficacy endpoint for this study is progression-free survival (PFS) assessed 12
 
 
 
 
 
 
  
 
 
 
 
 
weeks after start of treatment. (According the RECIST criteria 1.1 and central radiology
 
 
 
 
 
 
 
 
 
 
 
 
 
review). 
 
1.15. Patients to be included 
Patients with advanced and/or metastatic liposarcoma who have relapsed following
 
 
 
 
 
 
 
 
 
 
standard therapies or for whom no standard therapy exists will be included. 
 
1.16. Sample Size 
74 patients (maximum of 37 patients in 2 different cohorts) 
 
1.17. Treatment duration 
Treatment will continue until disease progression, development of unacceptable toxicity,
 
 
 
 
 
 
 
 
 
 
non-compliance, withdrawal of consent by the patient or investigator decision.  
 
1.18. Planned trial periods 
Start date: ​Third quarter 2012.  
First subject first visit (FSFV):​ Fourth quarter 2012.  
Total duration of recruitment period: ​30 months. 
Last subject first visit (LSFV):​ Second quarter 2015. 
Follow-up period: ​12 months. 
End of study date:​ Last patient last visit. Estimated second quarter 2016. 
 
 
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2. INDEX 
 
1. SUMMARY
5 
2. INDEX
8 
3. GENERAL INFORMATION
13 
3.1. Clinical Trial Type
     13 
3.2. Investigational drug description
13 
3.3. Sponsor Data
13 
3.4. Study Monitoring Organization
14 
3.5. Clinical Trial Chief Investigator
14 
3.6. Clinical Study Coordinator in Germany
14 
3.7. Translational Research Coordinator
14 
3.8. Planned trial periods
14 
4. RATIONALE AND OBJECTIVES
15 
4.1 BACKGROUND AND RATIONALE
15 
4.2 Rationale for the Pazopanib Dose
16 
4.3. Study Objectives
17 
4.3.1. Primary Objective:
17 
4.3.2. Secondary Objectives:
17 
4.3.3. Translational Study Objectives
17 
5. STUDY DESIGN
18 
5.1. Development Phase
18 
5.2. Patient Screening Identification
18 
5.3. Central pathological review
18 
5.4. Patient Inclusion
19 
5.5. Treatment description
20 
5.6. Patient Scheduled Visits
21 
5.6.1. Before treatment:
21 
5.6.2. During treatment:
21 
5.6.3. After End of Treatment:
22 
5.7 Response evaluation
22 
5.8. Translational sub-study
22 
5.9. Central Images Review
23 
6. PATIENT SELECTION
24 
6.1. Inclusion Criteria
24 
6.2. Exclusion Criteria
28 
6.3. Patient Withdrawal Criteria
30 
6.3.1. Permanent Discontinuation of Investigational Product
30 
6.3.2. Withdrawal from Study
30 
6.4. Screening and Baseline Failures
31 
7. TREATMENT DESCRIPTION
31 
7.1. Study Medication
31 
7.2. Product Accountability
31 
7.3. Treatment Compliance
32 
7.4. Concomitant Medication
32 
7.4.1. Specific recommendations regarding anticoagulants
33 
7.4.2. Specific recommendations regarding hypoglycemic therapy including insulin 34 
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7.4.3. The Effects of Pazopanib on Other Drugs
34 
7.4.4. The Effects of Other Drugs on Pazopanib
35 
7.5. Treatment of Investigational Product Overdose
35 
7.6. Criteria for regimen modification during the study
36 
7.6.1. Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities36 
7.6.2. Dose Interruptions/Modifications for Hepatotoxicity
40 
7.6.3 Dose Modifications and Management of Diarrhea, Nausea, and Vomiting42 
8. STUDY ASSESSMENTS AND PROCEDURES
46 
8.1. Study Development
46 
8.2 Assessments description:
48 
9. ADVERSE EVENTS
53 
9.1. Definitions
53 
9.2. Reporting of Adverse Events
55 
9.3 SUSAR Expedited reporting by the Sponsor
56 
9.3.1 Terms of SUSAR expedited notification to regulatory authorities
57 
9.3.2 Expedited Reporting, other relevant safety information
57 
9.3.3 Notification to Investigators:
57 
10. STATISTIC CONSIDERATIONS
58 
10.1. Study Endpoints
58 
10.1.1. Primary Efficacy Endpoint
58 
10.1.2. Secondary Endpoints
58 
10.2. Efficacy assessment
59 
10.3. Safety assessment
59 
10.4. Sample Size and Statistical analysis
59 
11. LEGAL AND ETHICS CONSIDERATION
61 
11.1. Ethic Committee
61 
11.2. Authorities
61 
11.3. Informed consent
61 
11.4. Confidentiality
62 
11.5. Insurance Policy
62 
11.6. End of the study
62 
11.7. Early study termination
62 
12. PRACTICAL CONSIDERATIONS
63 
12.1. Diagnostic Criteria for the Study Disease
63 
12.2. Responsibilities according to Good Clinical Practice
63 
12.3. Instructions for e-CRF completion
63 
12.4. Supply of Study Drugs
64 
12.5. Packaging and labelling
64 
12.6. Final report and Publications
64 
12.6.1. Clinical Trial Publication
64 
12.6.2. Translational Research Publication
65 
12.7. Monitoring
65 
12.8. Protocol Amendments
66 
12.9. Data Handling
66 
12.10. Documentation
66 
13. TRANSLATIONAL STUDY
67 
14. REFERENCES:
70 
ANNEX I: Urine Protein Creatinine Ratio (UPC)
72 
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ANNEX II: Determination of Creatinine Clearance (Cl​CR​)
73 
ANNEX III: Laboratory assessment recommendations
74 
ANNEX IV Definition of Responsibilities in Trial Sites
75 
ANNEX V: Declaration of Helsinki, World Medical Association General Assembly
76 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACTH 
Adrenocorticotropic hormone  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated PTT 
AST 
Aspartate aminotransferase 
BP 
Blood pressure  
C24 
Concentration at 24 hr following single-dose 
administration 
CR 
Complete response 
CRF 
Case Report Form 
CrCl 
Creatinine Clearance  
CT 
Computerized tomography 
CYP 
Cytochrome P450 (subtypes 3A, 3A4, 2D6) 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
ECO 
Echocardiography  
ECOG PS 
Eastern Cooperative Oncology Group Performance 
Status 
EIAC 
Enzyme-inducing anticonvulsants 
FDA 
Food and Drug Administration  
Flt-3 
Fms-like tyrosine kinase-3 
FU 
Follow up 
GCP 
Good Clinical Practice 
GISG 
German Interdisciplinary Sarcoma Group 
GSK 
GlaxoSmithKline 
HIF-1a 
Hypoxia-inducible factor-1a 
HRT 
Hormone Replacement Therapy 
IC​50
Half-maximal inhibition 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug  
INR 
International normalized ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics 
Committee 
ITT 
Intent-to-treat 
TKI 
Tyrosine Kinase Inhibitor 
LD 
Longest diameter 
LVEF 
Left Ventricular Ejection Fraction 
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LLN 
Lower Limit of Normal 
MRI 
Magnetic resonance imaging 
msec 
Millisecond(s) 
MTD 
Maximum tolerated dose  
mTOR 
mammalian Target of Rapamycin 
MUGA 
Multi-Unit Gated Analysis 
NCI-CTCAE v4.0 
National Cancer Institute-Common Toxicity Criteria 
for Adverse Events Version 4.0 
OS 
Overall survival 
PD 
Progressive disease  
PDGF 
Platelet-derived growth factor  
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free survival 
PR 
Partial response 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QTc 
Corrected QT interval 
RAP 
Report and analysis plan 
RCC 
Renal cell carcinoma  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event  
SBP 
Systolic blood pressure 
SD 
Stable disease 
SPC 
Summary of Product Characteristic 
STS 
Soft Tissue Sarcoma 
T3 
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VEGFR 
Vascular endothelial growth factor receptor  
μM 
Micromolar 
 
 
 
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3. GENERAL INFORMATION 
STUDY IDENTIFICATION 
 
TITLE: Phase II Clinical Trial of Pazopanib to evaluate the activity and tolerability in
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients with advanced and/or metastatic liposarcoma who have relapsed following
 
 
 
 
 
 
 
 
 
 
standard therapies or for whom no standard therapy exists. 
 
PROTOCOL NUMBER:​ GEIS-30 
 
Nº EudraCT: ​2012-002745-38 
3.1. Clinical Trial Type 
A two cohort phase II, open-label, non-randomized, international multi-centre study of an
 
 
 
 
 
 
 
 
 
 
 
 
IMP​ ​licensed but used for new indication. 
3.2. Investigational drug description 
Single arm (two cohorts) of Pazopanib 800 mg (2x400mg or 4x200 mg) given as a single
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
agent administered once daily. 
 
Presentation: The investigational product, Pazopanib mono-hydrochloride salt (coded as
 
 
 
 
 
 
 
 
 
GW786034B) is produced as tablets containing Pazopanib mono-hydrochloride salt
 
 
 
 
 
 
 
 
 
equivalent to 400 mg / 200 mg of the free base. Refer to the Pazopanib SPC for
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
information regarding the physical and chemical properties of Pazopanib and a list of
 
 
 
 
 
 
 
 
 
  
 
 
excipients. 
 
Pharmaceutical form: Film-coated tablet. Capsule-shaped, white, film-coated tablet with
 
 
 
 
 
 
 
 
 
GS UHL debossed on one side.  
 
Route of administration: ​oral 
3.3. Sponsor Data 
GRUPO ESPAÑOL DE INVESTIGACIÓN EN SARCOMAS - GEIS 
C/Velazquez nº 7, 3ª planta 
28001 – MADRID - Spain.  
 
Contact Data: 
Secretaría Técnica GEIS 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: + 34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: ​investigacion@mfar.net 
3.4. Study Monitoring Organization 
MARKETING FARMACEUTICO & INVESTIGACION CLINICA – MFAR S.L. 
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Calle Secretari Coloma 64-68 esc.B, entlo. 5ª 
08024– Barcelona 
Tel: +34 93 434 44 12/Fax: +34 93 253 11 68 
e-mail: ​investigacion@mfar.net 
 
For German sites: 
COORDINATING CENTER FOR CLINICAL STUDYS 
Karl-von-Frisch-Str. 4 
35043 Marburg 
Germany 
3.5. Clinical Trial Chief Investigator 
Dr. Claudia Valverde Morales 
Vall d’Hebron University Hospital 
Passeig Vall d'Hebron 119-129, Barcelona 
3.6. Clinical Study Coordinator in Germany 
Dr. Bernd Kasper 
University Medical Centre Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
3.7. Translational Research Coordinator  
Dr.  José Antonio López Guerrero  
Laboratory of Molecular Biology 
Fundación Instituto Valenciano de Oncología 
Prof. Beltrán Báguena 8-11, 46009, Valencia 
3.8. Planned trial periods 
Start date: ​Third quarter 2012.  
First subject first visit (FSFV):​ Fourth quarter 2012.  
Total duration of recruitment period: ​30 months. 
Last subject first visit (LSFV):​ Second quarter 2015. 
Follow-up period:​ 12 months. 
End of study date:​ Last patient last visit. Estimated Second quarter 2016. 
 
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4. RATIONALE AND OBJECTIVES 
4.1 BACKGROUND AND RATIONALE 
Soft tissue and bone sarcomas are rare malignant tumors, which encompasses a large
 
 
 
 
 
 
 
 
 
 
  
 
family of more than 50 histologically distinct tumor subtypes, all of which share a putative
 
 
 
 
 
 
 
 
 
 
 
 
  
 
mesenchymal origin. In the case of soft tissue sarcomas (STS) surgical excision is the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mainstay of treatment, but despite curative surgery, around half of patients develop distant
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases and die from disease. Few therapeutic approaches are currently available to
 
 
 
 
 
 
 
 
 
 
 
 
patients with unresectable, locally advanced, or metastatic STS and only anthracyclines,
 
 
 
 
 
 
 
 
 
 
 
ifosfamide and trabectedine have shown activity, with response rates of 20–40% in
 
 
 
 
 
 
 
 
 
 
 
 
previously untreated patients. Recent and ongoing trials have investigated a variety of
 
 
 
 
 
 
 
 
  
 
 
combination chemotherapeutic regimens (variously employing ifosfamide, doxorubicin,
 
 
 
 
 
 
 
gemcitabine, temozolamide, vincristine, cisplatin, and dacarbazine, among others) as well
 
 
 
 
 
 
 
 
 
 
as targeted therapies, which in some cases have yielded improvements in response rate
 
 
 
 
 
 
 
 
 
 
 
 
 
but which have had little impact on survival. No other medical option is currently available,
 
 
 
 
 
 
 
 
 
 
 
  
 
 
and the median survival of patients with soft-tissue sarcoma with non-resectable
 
 
 
 
 
 
 
 
 
 
 
metastases is around 12-15 months, and approximately 8 months after second line
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapy​(1)​. 
Liposarcomas are STS which account for at least 20% of all STS in adults. They can be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
further classified into 3 histologically and biologically different subtypes: well-differentiated
 
 
  
 
 
 
 
 
 
liposarcoma/de-differentiated liposarcoma (ALT-WD), myxoid or round cell liposarcoma
 
 
 
 
 
 
 
 
and pleomorphic liposarcoma.  
ALT-WD liposarcomas are locally aggressive rarely metastasising tumors characterized by
 
 
 
 
 
 
 
 
 
 
ring or giant marker chromosomes on the cytogenetic analysis and by amplification of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12q13-21 region on FISH (MDM2, CDK4 and HMGIC)​(2),(3)​. They account for about 40% ​(4)
 
 
 
 
 
 
 
 
 
 
 
 
  
of liposarcomas with a 5 year OS around 80%. In a series of WD/DD treated with several
 
 
   
 
 
 
 
  
 
 
 
 
 
 
regimens response rate was 12.5% OS 15 months and median PFS 3.6 months(95 CI:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3-5.9)​(5) 
Mixoid /round cell liposarcoma accounts for 45-50% of all liposarcomas. They tend to
 
 
 
 
 
 
 
 
 
 
 
 
 
metastasise to unusual soft tissue and bone locations. High histologic grade with more
 
 
 
 
 
 
 
 
 
 
 
 
 
than 5% of round cell component is associated with a 5-year OS of 50% approx. They are
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
characterized by t(23;16)(q13-14;p11) which leads to the fusion of CHOP and TLS
 
 
 
 
 
 
 
 
 
 
 
 
genes.​(6) 
Pleomorphic
liposarcoma
accounts
for
approximately
5-10%
of
all
liposarcomas,
 
 
 
 
 
 
 
 
 
characterized by high grade features with frequent and early lung metastasis and
 
 
 
 
 
 
 
 
 
 
 
 
cytogenetically by high chromosome counts and complex structural rearrangements. 
VEGF is expressed in many STS in which increased expression is associated with higher
  
 
 
 
 
 
 
 
  
 
 
 
grade and worse prognosis.​ (7) 
Pazopanib is an oral angiogenesis inhibitor that targets mainly VEGFR, PDGFR and c-kit.
  
 
 
 
 
 
 
 
 
 
 
 
Recently the results of a phase II trial (8) of Pazopanib in STS have been published. It was
 
 
 
  
  
  
 
 
 
 
 
 
  
 
a four-cohort 2-stages study. The liposarcoma stratum was closed after the first stage
 
 
 
 
 
 
 
 
 
 
 
 
 
because of a PFS at 12 weeks of 17% (3 out of 17 patients did not progressed after 12
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks). After central pathologic review, 2 other patients initially classified as other STS
 
 
 
 
  
 
 
 
 
 
 
 
were found to have liposarcoma with stable disease at 12 weeks (5/19: 26% PFS12w),
 
 
 
 
 
 
 
 
 
 
 
 
 
 
thus fulfilling criteria for cohort expansion. Phase II study had been completed and in
 
 
 
 
 
 
  
 
 
 
 
 
 
phase III study patients with liposarcomas were excluded so therefore data on the
 
 
 
 
 
 
 
 
 
 
 
 
 
liposarcoma cohort are inconclusive. 
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Furthermore the positive results of the phase III study PALETTE have been recently
 
 
 
 
 
 
 
 
 
 
 
 
 
communicated, encouraging this treatment in other sarcomas: progression-free survival
 
 
 
 
 
 
 
 
 
(PFS) per independent review was significantly prolonged with Pazopanib (median: 4.6 vs
 
 
 
 
 
 
 
 
 
 
 
 
1.6 months; HR=0.31, 95% CI 0.24-0.40; P<0.0001). The interim analysis for overall
 
 
 
 
 
 
 
 
 
 
 
 
survival shows a statistically non-significant improvement of Pazopanib vs placebo
 
 
 
 
 
 
 
 
 
 
(median:  12.5 vs 10.7 months, HR=0.83, 95% CI 0.67 – 1.11 p=0.25) ​(9)​. 
 
Soluble factors associated with efficacy and toxicity of Pazopanib in these patients had
 
 
 
 
 
 
 
 
 
 
 
 
 
been also reported (10)​. Decreases in VEGFR2 and increase in PlGF were both associated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with toxicity (HTA and TSH elevation) and poorer prognosis. 
4.2 Rationale for the Pazopanib Dose 
The Pazopanib dose to be used in this study is 800 mg daily, based on the following
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consideration: 
Pazopanib 800 mg once daily is the recommended monotherapy dose based on clinical
 
 
 
 
 
 
 
 
 
 
 
 
 
and preclinical results.
Once daily doses of 50 mg to 2000 mg Pazopanib were
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigated in the “First Time in Human”, Phase I Study VEG10003. Increases in the
 
 
 
 
 
 
 
  
 
 
 
 
 
Pazopanib dose above 800 mg once daily when administered in the fasted state did not
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
result in a consistent increase in systemic exposure at steady state. Therefore, no further
 
  
 
 
 
 
 
 
 
 
 
 
 
benefit is expected at Pazopanib doses above 800 mg once daily.  
Pharmacodynamic data indicate that Pazopanib, at a monotherapy dose of 800 mg once
 
 
 
 
 
  
 
 
 
 
 
 
daily, results in effects consistent with inhibition of the VEGF receptors it was designed to
 
 
 
 
 
 
 
 
 
 
  
 
 
 
target.
Concentration-effect
relationships
were
observed
between trough plasma
 
 
 
 
 
 
 
 
Pazopanib concentrations and the development of hypertension in Study VEG10003 and
 
 
 
 
 
 
 
 
 
 
 
the percent change from baseline in sVEGFR2 nadir in Study VEG102616.
The trough
 
 
 
 
 
 
 
 
 
 
 
 
 
plasma Pazopanib concentrations associated with one-half the maximal effect (EC50) in
 
 
 
 
 
 
 
 
 
 
 
both concentration-effect relationships were similar (21.3 µg/mL and 15.3 µg/mL) and
 
 
 
 
 
 
 
 
 
 
 
demonstrate that there is a consistent inhibition of VEGF receptor(s) in subjects with
 
 
 
 
 
 
 
 
 
 
 
 
 
cancer when plasma Pazopanib concentrations are maintained above 15 µg/mL.
The
 
 
 
 
 
 
 
 
 
 
 
plasma Pazopanib EC50 values for biologic effects observed in the clinical studies are
 
 
 
 
 
 
 
 
 
 
 
 
 
similar to the plasma concentration of 40 µM (17.5µg/mL) required for optimal inhibition of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VEGFR-2 phosphorylation in mice [GSK Report RH2003/00005/00]. 
Progression Free Survival (PFS) in subjects with renal cell cancer in Study VEG102616
 
 
 
 
 
 
 
 
 
 
 
 
 
was compared between subjects whose trough plasma Pazopanib concentrations (Cmin)
 
 
 
 
 
 
 
 
 
 
at Week 4 were above or below selected threshold values.  The deciles of the observed
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Cmin values were selected as threshold values so that approximately equal numbers of
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects were included in each Cmin interval. Subjects with a Cmin at Week 4 above the
 
 
 
 
 
 
 
 
  
 
 
  
 
 
threshold values had significantly better PFS, compared to the remaining subjects, when
 
 
 
 
 
 
 
 
 
 
 
 
the threshold concentrations steady were 12.6µg/mL, 17.4µg/mL, and 20.6µg/mL. Use of
 
 
 
 
 
 
 
 
 
 
 
thresholds higher than 21µg/mL did not result in a significant improvement in PFS between
 
 
 
 
 
 
   
 
 
 
 
patients
with
Cmin
values
above
and below the threshold.  Patients with Cmin
 
 
 
 
 
 
 
 
 
 
 
 
concentrations above 20.6µg/mL also had significantly better response rate and tumor
 
 
 
 
 
 
 
 
 
 
 
shrinkage than the remaining patients. 
Pazopanib C24 at steady state was greater than 15µg/mL in 93% of subjects who received
 
 
 
 
 
 
 
 
  
 
 
 
 
 
800 mg once daily in Study VEG10003. Individual subjects receiving Pazopanib doses
 
 
 
 
 
 
 
 
 
 
 
 
below 800 mg once daily can achieve plasma concentrations over 15µg/mL, albeit at a
 
 
 
 
 
 
 
 
 
 
 
  
lower frequency compared with what is observed at 800 mg once daily. Therefore, the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pharmacokinetic and pharmacodynamic results across clinical studies demonstrate that
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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Pazopanib 800 mg once daily results in plasma concentrations that provide optimal
 
 
 
 
 
 
 
 
 
 
 
 
biologic effects associated with VEGFR inhibition in the greatest proportion of subjects. 
4.3. Study Objectives 
4.3.1. Primary Objective:  
The primary objective of this study is to evaluate the activity of Pazopanib in patients with
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
advanced and/or metastatic liposarcoma by means of progression-free survival (PFS)
 
 
 
 
 
 
 
 
 
 
assessed 12 weeks after start of treatment. (According the RECIST criteria 1.1 and central
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiology review). 
4.3.2. Secondary Objectives: 
●
Overall progression-free survival (median PFS) 
●
Objective tumor response (confirmed complete response [CR] and partial response
 
 
 
 
 
 
 
 
 
 
[PR] using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) 
●
Time to onset of response 
●
Duration of response 
●
Overall survival (OS) 
●
Clinical benefit rate (CBR) 
●
Growth Modulation Index (GMI). 
●
Safety profile (according CTCAE, version 4.0) 
4.3.3. Translational Study Objectives 
PRIMARY OBJECTIVES: 
●
To evaluate the influence of the angiogenic status of the tumor on the response to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib. 
●
To evaluate the serum profile of serum cytokine markers as indicator of response to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib. 
 
SECONDARY OBJECTIVES: 
●
To evaluate microvessel density (MVD) and p53, MDM2, PTEN and VEGF/PDGF
 
 
 
 
 
 
 
 
 
 
 
pathways by IHQ expression and their correlation with prognosis as well as their
 
 
 
 
 
 
 
 
 
 
 
 
 
role as predictive factors to treatment with Pazopanib (Response, PFS and OS). 
●
To evaluate serum levels of several angiogenic factors/cytoquines using Luminex
 
 
 
 
 
 
 
 
 
 
XMAP Technology at baseline, after the first 3 weeks of treatment, at maximum
 
 
 
 
 
 
  
 
 
 
 
 
response and at progression and their predictive value for survival and response to
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment: VEGF-A, PlGF-1, SDF-1 alpha (CXCL12), TNF alpha, IL-8, IL-6, PDGF
 
 
 
 
 
 
 
 
 
 
 
–beta, HGF, E- Selectine, ICAM1, MMP-9 and FGFb. 
●
To analyse PIK3CA mutations in order to demonstrate if those liposarcomas with
 
 
 
 
 
 
 
  
 
 
 
PIK3CA mutations defines a subgroup of patients with differential response to
 
 
 
 
 
 
 
 
 
 
 
Pazopanib.  
 
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5. STUDY DESIGN 
5.1. Development Phase 
A two cohort Phase II, open-label, non-randomized, multi-center study with 5 centres in
 
 
 
 
 
 
 
 
 
  
 
 
Spain and 5 centres in Germany to evaluate the activity and tolerability of Pazopanib in
 
  
 
 
 
 
 
 
 
 
 
 
 
 
patients with advanced and/or metastatic liposarcoma who have relapsed following
 
 
 
 
 
 
 
 
 
 
standard therapies or for whom no standard therapy exists. 
The drug will be separately investigated in the following liposarcoma subtypes (cohorts): 
 
●
Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) 
●
Myxoid/round cell liposarcoma.  
 
A total of 17 eligible and treated patients will be included (in each stratum) in the first step
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
of the study. If ≤3 successes are observed in a stratum, the trial will be stopped in this
 
 
    
 
 
 
  
 
 
 
 
 
 
 
 
stratum with the conclusion that the drug should not be further investigated in this
 
 
 
 
 
 
 
 
 
 
 
 
 
 
histology. Otherwise, patients will continue to be accrued. Each cohort will independently
 
 
 
 
 
 
 
 
 
 
 
 
recruit a maximum of 37 patients. The statistical analysis will be performed in each
 
 
 
 
 
 
 
 
 
 
 
 
 
 
stratum. 
5.2. Patient Screening Identification 
Informed consent should be obtained prior to start of the specified screening window.
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood
 
 
 
 
 
 
 
 
 
 
 
 
count, imaging study such as bone scan) and obtained prior to signing of informed consent
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
may be utilized for screening or baseline purposes provided these procedures are
 
 
 
 
 
 
 
 
 
 
 
 
conducted as specified in the protocol. Once both clinical and biological samples informed
 
 
 
 
 
 
 
 
 
 
 
 
 
consent forms are signed a trial screening number will be assigned to each patient. Each
 
 
 
  
 
 
 
 
 
 
 
 
 
 
site will receive inside the Site Investigator File a screening log form in which
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pre-determined screening numbers will be assigned. This document should be always at
 
 
 
 
 
 
 
 
 
 
 
 
site under Investigator staff custody. This screening number will identify patients
 
 
 
 
 
 
 
 
 
 
 
throughout the procedures needed to confirm the subjects’ suitability for the trial Protocol
 
 
 
 
 
 
 
 
 
 
 
 
 
(clinical laboratory tests, imaging, central pathological review, etc.).  
An additional document will be provided in the Investigator Site File with detailed Patient
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Identification procedures. 
5.3. Central pathological review 
Once a patient has signed the biological samples consent form, at least one representative
  
 
 
 
 
 
 
 
 
 
 
 
 
formaline fixed paraffin embedded tumour block and H/E (haematoxylin/eosin) slides from
 
 
 
 
 
 
 
 
 
 
 
all the different areas of the tumor will be collected for central pathological review. Patients
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
may be included in the study with H/E slides only, but just if the tumor block is not
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
available (all efforts should be done to send a representative tumor block). Representative
 
 
 
 
 
 
 
  
 
 
 
 
histological sections should be sent for review in those cases without paraffin block,
 
 
 
 
 
 
 
 
 
 
 
 
 
including H/E and other necessary stains. The diagnostic report, including macroscopic
 
 
 
 
 
 
 
 
 
 
 
description of the specimen should be shipped together with the samples in all cases. First
 
 
 
 
 
 
 
 
 
 
  
 
 
 
diagnosis sample or another more recent available sample obtained during the routine
 
 
 
 
 
 
 
 
 
 
 
 
care previous to study entry will be acceptable. Tumour biopsy at study entry will NOT be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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compulsory but recommended if clinically acceptable (ex. superficial or easily accessible
 
 
  
 
 
 
 
 
 
 
locations). All the samples from Spain and Germany will be sent by courier to the central
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory and diagnosis will be available in approximately one week. The central
 
 
 
 
 
 
 
 
 
 
 
 
pathological review is a pre-requisite for entering the trial. The study treatment should not
 
   
 
 
 
 
 
 
 
 
 
 
be initiated unless the diagnosis is confirmed by means of the central pathological review. 
 
All the slides will be returned to the patient site with a formal report as per specific form
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
after pathological central review. The paraffin blocks will be sent first to the translational
 
 
 
 
 
 
 
 
 
 
 
 
 
 
research coordinator. All remaining samples will also be returned after the end of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
project. 
 
Central Review of diagnosis will be carried out by: 
Dr. Cleofé Romagosa 
Vall d'Hebron University Hospital 
Pathology Department 
Pg Vall d'Hebron 119-129 
08035 Barcelona 
Spain 
 
For sending the biological samples, please contact to: 
 
A central review report will be generated as per specific form and will be replied to sites. 
For sending the biological samples, please contact to: 
 
MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
 
All samples will be shipped codified as is specified in the detailed tumour collection and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
shipment procedures. 
 
An additional document will be provided in the Investigator Site File with detailed tumour
 
 
 
 
 
 
 
 
 
 
 
 
 
 
collection and shipment procedures. 
5.4. Patient Inclusion 
After confirming that the patient is suitable for inclusion in this trial (inclusion/exclusion
 
 
 
 
 
 
 
 
 
 
 
 
 
criteria), a patient trial number will be centrally assigned to each subject. 
The procedure for patient inclusion is as follows: 
 
●
Complete and sign the patient inclusion forms (the patient registration forms should
 
 
 
 
 
 
 
 
 
 
 
 
be signed by a clinician identified at signature list and delegation of responsibilities
 
 
  
 
 
 
 
 
 
 
 
 
log. 
●
Please, send completed and signed patient inclusion form to: 
 
GEIS–30_H_V03F_2015-02-11 
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MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
FAX (+ 34 93 253 11 68) or e-mail to ​investigacion@mfar.net 
 
 
●
MFAR, S.L​ will proceed with patient inclusion procedure, and  
●
Will reply site, sending the confirmation of patient inclusion form, both by fax and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
email. The confirmation of patient inclusion will contain the patient trial number. 
●
The treatment with Pazopanib should be started ​only if site has received the
 
 
 
 
 
 
 
  
 
 
 
 
confirmation of inclusion forms. 
 
The patient trial number will identify patients throughout the participation in the study. 
 
An additional document will be provided in the Investigator Site File with detailed Patient
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion procedures. 
5.5. Treatment description  
The treatment with Pazopanib should be started ​only if site has received the confirmation
 
 
 
 
 
 
 
  
 
 
 
 
 
of inclusion forms as per section 5.4 of this protocol. 
Pazopanib 800 mg (2x400mg or 4 x 200 mg) per day, once a day, should be taken orally
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
without food at least one hour before or two hours after a meal until disease progression,
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
the development of unacceptable toxicity, non-compliance, withdrawal of consent by the
 
 
 
 
 
 
 
 
 
 
 
patient, or investigator decision.  
Pazopanib should be stored in a secure area under the appropriate physical conditions for
 
 
 
 
  
 
 
 
 
 
 
 
 
the product. Access to and administration of the investigational product will be limited to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the investigator and authorized site staff. Pazopanib does not require any special storage
 
 
 
 
 
 
 
 
 
 
 
 
 
conditions. Investigational product (Pazopanib) should begin within 7 days of inclusion
 
 
 
 
 
 
  
 
 
 
(longer delays must be discussed with Study Chair). 
 
For Pazopanib dose modifications, please, see in section 7.6 of this protocol. 
 
Stock of Pazopanib will be centrally managed by ​MFAR S.L​, in case of any issue
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regarding Pazopanib, please contact to: 
 
MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
5.6. Patient Scheduled Visits 
For more information, please, see in Table 5: Table of Assessments (section 8 of this 
protocol). 
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5.6.1. Before treatment: 
Informed consent must be obtained prior to start of the specified screening window.
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood
 
 
 
 
 
 
 
 
 
 
 
 
count, imaging study such as bone scan) and obtained prior to signing of informed consent
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
may be utilized for screening or baseline purposes provided these procedures are
 
 
 
 
 
 
 
 
 
 
 
 
conducted as specified in the protocol. 
Screening: To determine patient eligibility, within 14 days prior treatment start, it should be
 
 
 
 
 
 
 
 
 
 
  
 
 
performed the following assessments: consent form signature, inclusion/exclusion criteria,
 
 
 
 
 
 
 
 
 
medical history, physical exam (with Blood pressure assessment and vital and cancer
 
 
 
 
 
 
 
 
 
 
 
 
signs and symptoms), ECOG, concomitant medication, clinical laboratory test, ECG, LVEF
 
 
 
 
 
 
 
 
 
 
 
(MUGA ECO), Baseline imaging CT/MRI, tumor specimen collection, serum collection. 
5.6.2. During treatment: 
In general, physical exam with BP, concomitant medication, clinical laboratory test and
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status, and adverse event collection (diarrhoea, liver toxicity, etc.), should be
 
 
 
 
 
 
 
 
 
 
 
 
performed in each schedule visit. 
First 12weeks of treatment: 
Week 0 (day 1): Physical exam (with Blood pressure assessment), ECOG, concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, treatment control and dispensing. 
Week 1 (day 8): Physical exam (with Blood pressure assessment), ECOG, concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests and adverse events. 
Week 3 (day 22): Physical exam (with Blood pressure assessment), ECOG concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, adverse events and serum collection at the end of 3
 
 
 
 
 
 
 
 
 
 
 
 
  
weeks (day 22 of treatment), treatment control and dispensing. 
Week 5 (day 36): Physical exam (with Blood pressure assessment), ECOG, concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, adverse events, treatment control and dispensing. 
Week 7 (day 50): Physical exam (with Blood pressure assessment), ECOG, concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, ECG, Imaging (CT scan /MRI), adverse events,
 
 
 
 
 
 
 
 
 
 
 
treatment control and dispensing. 
Week 9 (day 64): Physical exam (with Blood pressure assessment), ECOG, concomitant
  
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, adverse events and treatment control and dispensing. 
Week 12 (day 85): Physical exam (with Blood pressure assessment), ECOG, concomitant
 
 
 
 
 
 
 
 
 
 
 
 
medication, clinical laboratory tests, ECG, LVEF determination, Imaging (CT scan
 
 
 
 
 
 
 
 
 
 
/MRI),.adverse events, treatment control and dispensing. 
From week 12 up to the End of Treatment Visit: 
Every 4 weeks thereafter: Physical exam (with Blood pressure assessment), ECOG,
 
 
 
 
 
 
 
 
 
 
 
concomitant medication, clinical laboratory tests and adverse events. Treatment control
 
 
 
 
 
 
 
 
 
 
and dispensing 
Every 8 weeks thereafter: ECG and Imaging (CT scan /MRI). 
LVEF determination: (MUGA/ECO) will be performed at baseline and every 12 weeks +/-2
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks (3 months) thereafter or more frequently if clinically indicated. 
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Serum collection: Within 72 hours after radiological response is documented. 
5.6.3. After End of Treatment: 
End of treatment Visit (to be performed 28 days after end of treatment): Physical exam
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(with Blood pressure assessment and vital and cancer signs and symptoms), clinical
 
 
 
 
 
 
 
 
 
 
 
 
laboratory test, ECG, adverse events. 
After discontinuation of protocol treatment in patients who have not progressed, will still be
 
 
 
 
  
 
 
 
 
 
 
 
 
re-evaluated by imaging every 8 weeks, unless they have started a new anti-cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy. 
After progression disease: follow up for survival, patient status (alive/dead/lost to follow up)
 
 
 
 
 
 
 
 
 
 
 
 
 
and new anti-cancer therapy. 
5.7 Response evaluation  
Informed consent must be obtained prior to start of the specified screening window.
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood
 
 
 
 
 
 
 
 
 
 
 
 
count, imaging study such as bone scan) and obtained prior to signing of informed consent
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
may be utilized for screening or baseline purposes provided these procedures are
 
 
 
 
 
 
 
 
 
 
 
 
conducted as specified in the protocol. 
 
Response evaluation will be done by means of RECIST version 1.1 criteria.  
 
Imaging Studies: CT Scan or MRI will be used for response evaluation. Disease should be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
captured and target/non-target identified at baseline, CT scan or MRI as appropriate.
 
 
 
 
 
 
 
 
 
 
 
 
Subsequently, imaging studies required to investigate known disease should be performed
 
 
 
 
 
 
 
 
 
 
 
on week 7, on week 12 and every 8 weeks thereafter. Imaging methods will be employed
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
consistently during the course of each patient’s evaluation during the study. After
 
 
 
 
 
 
 
 
 
 
 
 
discontinuation of protocol treatment, patients who have not progressed will still be
 
 
 
 
 
 
 
 
 
 
 
 
re-evaluated every 8 weeks, unless they have started a new anti-cancer therapy. 
5.8. Translational sub-study 
For those patients that have consented for the participation in the translational sub-study,
 
 
 
 
 
 
 
 
 
 
 
 
 
the biological samples will be collected as follows: 
●
Paraffin-embedded samples from original tumor and if clinically acceptable (ex.
 
 
 
 
 
  
 
 
 
superficial or easily accessible locations), tumour biopsy at study entry. 
●
Serum from peripheral blood will be performed (4 per subject): 
1. Within 72 hours prior starting the treatment (basal). 
2. Within 72 hours after the first 3 weeks of treatment (Day 22). 
3. Within 72 hours after radiological response is documented. 
4. Within 72 hours after progressive disease is documented. 
Translational sub-study will be carried out by: 
 
Dr. José Antonio López Guerrero 
Fundación Instituto Valenciano de Oncología 
GEIS–30_H_V03F_2015-02-11 
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Laboratory of Molecular Biology 
C/Prof. Beltrán Báguena, 8-11 
46009 Valencia 
Spain. 
 
All samples will be shipped codified as is specified in the detailed tumour collection and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
shipment procedures. For more information regarding translational sub-study, please see
 
 
 
 
 
 
 
 
 
 
section 13 of this protocol. 
 
For sending the biological samples, please contact to: 
 
MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
 
An additional document will be provided in the Investigator Site File with detailed biological
 
 
 
 
 
  
 
 
 
 
 
 
 
sample collection and shipment procedures. 
5.9. Central Images Review 
All images assessments will be central reviewed through on-line platform by: 
Dr. Jordi Andreu 
Radiology Department 
Pg Vall d'Hebron 119-129 
08035 Barcelona 
Spain 
It is strongly recommended to upload the baseline MRI/CT scan before patient inclusion, if
  
 
 
 
 
 
 
 
 
 
 
  
it is not possible, it should be done as soon as possible after patient inclusion.  
All images assessments, performed during the clinical trial, should be uploaded to the
 
 
 
 
 
 
 
 
 
 
 
 
 
specific platform as soon as possible.  
All scans generated should be exportable in electronic format (DICOM) to enable secure
 
 
 
 
 
 
 
 
 
 
 
 
 
and rapid electronic transmission to the designated central imaging laboratory. 
All scans will be identified ​only ​by the specific codification detailed in the radiologic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
guidelines. 
A central review report will be generated as per specific form. 
For any issue regarding central images review, please contact to: 
 
 
MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
GEIS–30_H_V03F_2015-02-11 
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Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
 
 
An additional document will be provided in the Investigator Site File with detailed central
 
 
 
 
 
 
 
 
 
 
 
 
 
 
images review loading information. 
6. PATIENT SELECTION 
TYPE OF PATIENTS:  
Patients with high or intermediate grade malignant liposarcoma with metastatic or locally
 
 
 
 
 
 
 
 
 
 
 
 
advanced disease that fulfil all eligibility criteria will be included. 
6.1. Inclusion Criteria 
A subject will be considered eligible for inclusion in this study if all the following criteria are
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
met: 
 
1. Subjects
must
provide
written
informed
consent
prior
to
performance
of
 
 
 
 
 
 
 
 
 
 
study-specific procedures or assessments and must be willing to comply with
 
 
 
 
 
 
 
 
 
 
 
treatment and follow-up. 
●
Informed consent must be obtained prior to start of the specified screening
 
 
 
 
 
 
 
 
 
 
 
 
window. 
●
Procedures conducted as part of the subject’s routine clinical management
 
 
 
 
 
 
 
 
 
 
(e.g., blood count, imaging study such as bone scan) and obtained prior to
 
 
 
 
 
 
 
 
 
 
 
 
 
signing of informed consent may be utilized for screening or baseline
 
 
 
 
 
 
 
 
 
 
 
purposes provided these procedures are conducted as specified in the
 
 
 
 
 
 
 
 
 
 
protocol. 
2. Age ≥ 18 years or legal age of consent if greater than 18 years 
3. Histological
confirmed
diagnosis
of
high
or
intermediate
grade
malignant
 
 
 
 
 
 
 
 
 
liposarcoma with metastatic or locally advanced disease. Formaline fixed paraffin
 
 
 
 
 
 
 
 
 
 
embedded tumour block and/or representative H/E (haematoxylin/eosin) slides
 
 
 
 
 
 
 
 
must be available for central pathologic review to classify tumors in the 2 eligible
 
 
 
 
 
 
 
 
 
 
 
  
 
subtypes:  
●
Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) 
●
Myxoid/round cell liposarcoma  
4. Patient must have documentation of disease progression within 6 months prior to
 
 
 
 
 
 
 
  
 
 
 
study entry. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
6. Measurable disease by RECIST v1.1 criteria. At least one measurable lesion
 
 
 
 
 
 
 
 
 
 
 
located outside of a previously irradiated area. If the only measurable lesion is in a
 
 
  
 
 
  
 
 
 
  
  
previously irradiated area, RECIST progression should be documented after
 
 
 
 
 
 
 
 
 
radiotherapy, in the previous 6 months before study entry. 
GEIS–30_H_V03F_2015-02-11 
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7. The patient should not be considered eligible for surgery or radical radiotherapy.
 
 
 
 
 
 
 
 
 
 
 
 
e.g. Patients to whom surgery/radiotherapy cannot be performed with a curative
 
 
 
 
 
 
 
 
  
 
intent due to the extension of the disease. In the case of radiotherapy, it may also
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
be limited due to a previous treatment with radiotherapy in the same area. 
8. The patient must have either been considered ineligible for systemic chemotherapy
 
 
 
 
 
 
 
 
 
 
 
or received at least one previous regimen for relapsed, refractory or metastatic
 
 
 
 
 
 
 
 
 
 
 
 
disease. A maximum of three previous lines for advanced/metastatic disease are
 
 
 
 
 
 
 
 
 
 
 
allowed. 
Patients not eligible for systemic chemotherapy: 
●
Because of age, a biological condition or patient-refusal 
●
Generally, patients that received anthracyclines in the adjuvant setting are
 
 
 
 
 
 
 
 
 
 
not eligible for first line therapy with this agent for advanced disease. 
●
Patients with a solitary kidney or >60 years old are usually not the best
 
 
 
 
 
 
 
 
 
 
 
 
 
 
candidates for treatment with regular doses of ifosfamide.  
9. Tumour
tissue
must
be
provided
for
all
subjects
for
biomarker
analysis
 
 
 
 
 
 
 
 
 
 
 
before/during treatment with investigational product.  
10.The patient should be able to swallow and retain study drug 
11.Adequate organ system function as defined in Table 1 
 
 
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Table 1: Definitions for Adequate Organ Function 
 
System 
Laboratory Values 
Hematology 
Absolute
neutrophil
count
 
 
 
(ANC) 
≥ 1.5 X 10​9​/L 
Haemoglobi​n  
≥ 9 g/dL (5.6 mmol/L) 
Platelets 
≥ 100 X 10​9​/L 
Prothrombin
time
(PT)
or
 
 
 
 
international
normalized
 
 
ratio (INR)​b  
≤ 1.2 X ULN 
Activated
partial
 
 
thromboplastin time  (aPTT) 
≤ 1.2 X ULN 
Hepatic 
Total bilirubin 
≤ 1.5 X ULN  
Alanine
amino transferase
 
 
 
(ALT)
and
Aspartate
 
 
 
aminotransferase (AST)​c  
≤ 2.5 X ULN 
Renal 
Serum creatinine 
≤ 1.5 mg/dL (133 µmol/L) 
Or,
if
>1.5 mg/dL:
 
 
 
Calculated
creatinine
 
 
clearance (Cl​CR​) (reference
 
 
 
appropriate appendix) 
≥ 30 mL/min to ≥ 50 mL/min  
Urine Protein to Creatinine
 
 
 
 
Ratio
(UPC;
appropriate
 
 
 
appendix)​d  
<1 
Or, 24-hour urine protein 
<1g 
a.Subjects may not have had a transfusion within 7 days of screening
 
 
 
 
 
 
 
 
 
 
 
assessment. 
b.Subjects receiving anticoagulant therapy are eligible if their INR is stable
 
 
 
 
 
  
 
  
 
and
within
the
recommended
range
for
the
desired
level
of
 
 
 
 
 
 
 
 
 
 
anticoagulation. 
c. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper
 
  
 
 
 
 
  
 
 
limit of normal) are not permitted.  
d.If UPC ≥1, then a 24-hour urine protein must be assessed.
Subjects
 
  
 
  
 
 
 
 
 
 
 
must have a 24-hour urine protein value <1 g to be eligible. Use of urine
 
  
 
 
 
 
 
 
 
 
 
 
 
dipstick for baseline renal function assessment is not acceptable. 
 
12.. A female is eligible to enter and participate in this study if she is of: 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
 
 
 
 
 
 
 
 
including any female who has had: 
GEIS–30_H_V03F_2015-02-11 
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●
A hysterectomy 
●
A bilateral oophorectomy (ovariectomy) 
●
A bilateral tubal ligation 
●
Is post-menopausal 
Female subjects not using hormone replacement therapy (HRT) must have
 
 
 
 
 
 
 
 
 
 
experienced total cessation of menses for ≥1 year and be greater than 45 years in
 
 
 
 
 
   
 
 
 
 
 
 
  
age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value
 
 
 
 
 
  
 
 
 
 
 
>40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).  
Female subjects using HRT must have experienced total cessation of menses for ≥
 
 
 
 
 
 
 
 
 
 
 
  
1 year and be greater than 45 years of age OR have had documented evidence of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
menopause based on FSH and estradiol concentrations prior to initiation of HRT 
Childbearing potential, including any female who has had a negative serum
 
 
 
 
 
 
 
 
 
 
 
pregnancy test within 2 weeks prior to the first dose of study treatment, preferably
 
 
  
 
 
 
 
 
 
 
 
 
 
as close to the first dose as possible, and agrees to use adequate contraception.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The acceptable contraceptive methods, when used consistently and in accordance
 
 
 
 
 
 
 
 
 
 
with both the product label and the instructions of the physician, are as follows: 
●
Complete abstinence from sexual intercourse for 14 days before exposure to
 
 
 
 
 
 
 
 
 
 
 
investigational product, through the dosing period, and for at least 21 days
 
 
 
 
 
 
 
 
 
 
 
 
after the last dose of investigational product 
●
Oral contraceptive, either combined or progestogen alone 
●
Injectable progestogen 
●
Implants of levonorgestrel 
●
Estrogenic vaginal ring  
●
Percutaneous contraceptive patches  
●
Intrauterine device (IUD) or intrauterine system (IUS) with a documented
 
 
 
 
 
 
 
  
 
failure rate of less than 1% per year 
●
Male partner sterilization (vasectomy with documentation of azoospermia)
 
 
 
 
 
 
 
 
prior to the female subject's entry into the study, and this male is the sole
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
partner for that subject  
●
Double barrier method: condom and an occlusive cap (diaphragm or
 
 
 
 
 
 
 
 
 
 
cervical/vault
caps)
with
a
vaginal
spermicidal
agent
 
 
 
 
 
 
 
(foam/gel/film/cream/suppository) 
Female subjects who are lactating should discontinue nursing prior to the first dose
 
 
 
 
 
 
 
 
 
 
 
 
 
of study drug and should refrain from nursing throughout the treatment period and
 
 
 
 
 
 
 
 
 
 
 
 
 
for 14 days following the last dose of study drug 
 
13.LVEF above the lower limit of normal for the institution, based on ECHO or MUGA. 
Deviations from inclusion criteria are not allowed because deviations can potentially
 
 
 
 
 
 
 
 
 
 
 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject
 
 
 
 
 
 
 
 
 
 
 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
GEIS–30_H_V03F_2015-02-11 
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6.2. Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
 
1. Prior history of malignancies other than liposarcoma. 
subjects who have had another malignancy and have been disease-free for 3 years,
 
 
 
 
 
 
 
 
 
 
  
 
or 
subjects with a history of completely resected non-melanomatous skin
 
 
 
 
 
 
 
 
 
carcinoma or successfully treated in situ carcinoma are eligible.  
2. Clinical evidence of central nervous system (CNS) metastases or leptomeningeal
 
 
 
 
 
 
 
 
 
 
carcinomatosis,
except
for
individuals
who
have
previously-treated
CNS
 
 
 
 
 
 
 
 
metastases, are asymptomatic, and have had no requirement for steroids or
 
 
 
 
 
 
 
 
 
 
 
anti-seizure medication for 6 months prior to first dose of study drug. Screening with
 
 
  
 
 
 
 
 
 
 
 
 
 
CNS imaging studies (computed tomography [CT] or magnetic resonance imaging
 
 
 
 
 
 
 
 
 
 
[MRI]) is required only if clinically indicated or if the subject has a history of CNS
 
 
 
  
 
 
  
 
 
  
 
 
 
metastases. 
3. Clinically significant gastrointestinal abnormalities that may increase the risk for
 
 
 
 
 
 
 
 
 
 
gastrointestinal bleeding including, but not limited to: 
●
Active peptic ulcer disease 
●
Known intraluminal metastatic lesion/s with risk of bleeding 
●
Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn’s disease), or
 
 
 
 
 
 
 
 
 
other gastrointestinal conditions with increased risk of perforation  
●
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
 
 
 
 
 
 
 
 
abscess within 28 days prior to beginning study treatment. 
4. Clinically significant gastrointestinal abnormalities that may affect absorption of
 
 
 
 
 
 
 
 
 
investigational product including, but not limited to: 
●
Malabsorption syndrome  
●
Major resection of the stomach or small bowel. 
5. Corrected QT interval (QTc) > 480 msecs  
6. History of any one or more of the following cardiovascular conditions within the past
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 months: 
●
Cardiac angioplasty or stenting 
●
Myocardial infarction 
●
Unstable angina 
●
Coronary artery bypass graft surgery 
●
Symptomatic peripheral vascular disease 
●
Class III or IV congestive heart failure, as defined by the New York Heart
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Association (NYHA) 
7. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140
 
 
 
 
 
 
 
 
 
 
 
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. 
GEIS–30_H_V03F_2015-02-11 
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Initiation or adjustment of antihypertensive medication(s) is permitted prior to
 
 
 
 
 
  
 
 
 
study entry. Following antihypertensive medication initiation or adjustment,
 
 
 
 
 
 
 
 
blood pressure (BP) must be re-assessed three times at approximately
 
 
 
 
 
 
 
 
 
 
2-minute
intervals.
At
least
24
hours
must
have
elapsed
between
 
 
 
 
 
 
 
 
 
 
anti-hypertensive medication initiation or adjustment and BP measurement.
 
 
 
 
 
 
 
 
These three values should be averaged to obtain the mean diastolic blood
 
 
 
 
 
 
 
 
 
 
 
 
pressure and the mean systolic blood pressure. The mean SBP / DBP ratio
 
 
 
 
 
 
 
 
 
  
 
 
must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by
 
 
 
 
 
 
 
  
 
  
 
 
Safety Review Team) in order for a subject to be eligible for the study. 
8. History of cerebrovascular accident including transient ischemic attack (TIA),
 
 
 
 
 
 
 
 
 
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
 
 
 
 
 
 
 
 
 
 
  
months. 
Subjects
with
recent
DVT
who
have
been
treated
with
therapeutic
 
 
 
 
 
 
 
 
 
 
anti-coagulating agents 
for at least 6 weeks are eligible 
9. Major surgery or trauma within 28 days prior to first dose of investigational product
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and/or presence of any non-healing wound, fracture, or ulcer (procedures such as
 
 
 
 
 
 
 
 
 
 
 
 
catheter placement not considered to be major surgery). 
10.Evidence of active bleeding or bleeding diathesis.  
11.Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
 
 
 
 
 
 
 
 
 
that increase the risk of pulmonary hemorrhage. 
Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels)
 
 
 
 
 
 
 
 
 
are excluded; however, the presence of a tumor that is touching, but not
 
 
 
 
 
  
 
 
 
 
 
 
infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly
 
 
 
 
 
 
 
 
 
 
 
recommended to evaluate such lesions). 
12.Recent hemoptysis (≥½ teaspoon of red blood within 8 weeks before first dose of
 
 
 
 
 
 
 
 
 
 
 
 
 
study drug). 
13.Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
 
 
 
 
 
 
 
 
 
 
 
could interfere with subject’s safety, provision of informed consent, or compliance to
 
 
 
 
 
 
 
 
 
 
 
 
study procedures.  
14.Unable or unwilling to discontinue use of prohibited medications listed in section 7.4
 
 
 
 
 
 
 
 
 
  
 
 
of this protocol or at least 14 days or five half-lives of a drug (whichever is longer)
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
prior to the first dose of study drug and for the duration of the study. 
15.Treatment with any of the following anti-cancer therapies:  
●
radiation therapy, surgery or tumor embolization within 14 days prior to the
 
 
 
 
 
 
 
 
 
 
 
 
first dose of Pazopanib 
●
chemotherapy, immunotherapy, biologic therapy, investigational therapy or
 
 
 
 
 
 
 
hormonal therapy within 14 days or five half-lives of a drug (whichever is
 
 
 
 
 
 
 
 
  
 
 
 
longer) prior to the first dose of Pazopanib 
16.Administration of any non-oncologic investigational drug within 30 days or 5
 
 
 
 
 
 
 
 
 
 
 
half-lives whichever is longer prior to receiving the first dose of study treatment 
17.Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
 
 
 
 
 
 
 
 
 
  
 
  
progressing in severity, except alopecia. 
GEIS–30_H_V03F_2015-02-11 
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Deviations from exclusion criteria are not allowed because they can potentially jeopardize
 
 
 
 
 
 
 
 
 
 
 
 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore,
 
 
 
 
 
 
 
 
 
 
 
 
adherence to the criteria as specified in the protocol is essential. 
6.3. Patient Withdrawal Criteria 
6.3.1. Permanent Discontinuation of Investigational Product 
Subjects will receive investigational product until any of the following occur: 
●
Subject experiences disease progression according to RECIST V 1.1  
●
Subject experiences unacceptable toxicities or an adverse experience that would, in
 
 
 
 
 
 
 
 
 
  
the judgement of the investigator, make continued administration of the study
 
 
 
 
 
 
 
 
 
 
 
regimen an unacceptable risk.  
●
Subject is considered by the investigator or the sponsor to be significantly
 
 
 
 
 
 
 
 
 
 
 
 
non-compliant with the requirements of the protocol 
●
A more than 3 weeks delay in treatment administration 
●
Study is closed or terminated 
●
Subject withdraws consent for study participation 
The reason for discontinuing investigational product must be clearly recorded on the case
 
 
 
 
 
 
 
 
 
 
 
 
 
report forms (CRF).  
A temporary interruption in study medication due to an AE is not considered to be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
permanent discontinuation from investigational product. 
6.3.2. Withdrawal from Study 
Subjects will be encouraged to complete the study; however, they may voluntarily
 
 
 
 
 
 
 
 
 
 
 
 
withdraw at any time. The investigator may also, at his/her discretion, withdraw the subject
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from participating in this study at any time, or the sponsor may discontinue the study. 
Reasons for early withdrawal from the study should be documented in the CRF as:  
●
Study closed/terminated 
●
Subject lost to follow-up 
●
Investigator’s decision 
●
Subject withdrew consent 
●
Major protocol violations 
●
Death 
 
Date of withdrawal from the study, with reason for withdrawal, will be recorded on the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRF.
In the case of death, a death certificate should be obtained if possible, with the
 
 
 
 
 
  
 
 
 
 
  
 
 
 
cause of death evaluated and documented. 
 Patients withdrawn the trial for any reason, cannot enter again. 
6.4. Screening and Baseline Failures 
A subject is considered to be a screening/baseline failure if the subject signs the informed
 
  
 
 
  
 
  
 
 
 
 
 
consent, but withdraws before study randomization. All potential subjects who are
 
 
 
 
 
 
 
 
 
 
 
screened for enrolment in this study including screening/baseline failures will be listed on
 
 
 
 
 
 
 
 
 
 
 
 
 
the Subject Screening Log/Identification List but will not be entered in the study database.
 
 
 
 
 
 
 
 
 
  
 
 
 
Reasons for exclusion will be recorded for potential subjects who do not enter the study. 
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7. TREATMENT DESCRIPTION 
7.1. Study Medication 
Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with a dual
  
 
 
 
 
 
 
 
 
 
 
 
  
 
activity both as an antiagiogenic and also and anti-tumoral agent. 
The investigational product, Pazopanib monohydrochloride salt is produced as tablets
 
 
 
 
 
 
 
 
 
 
containing Pazopanib monohydrochloride salt equivalent to 200 mg or 400 mg of the free
 
 
 
 
 
 
 
 
 
 
 
 
 
base.
Refer to the Pazopanib SPC for information regarding the physical and chemical
 
 
 
 
 
 
 
 
 
 
 
 
 
properties of Pazopanib and a list of excipients.  
Investigational product must be stored in a secure area under the appropriate physical
 
 
 
 
 
  
 
 
 
 
 
 
conditions for the product (Pazopanib does not require any special storage conditions).
 
 
 
 
 
 
 
 
 
 
 
 
Access to and administration of the investigational product will be limited to the
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator and authorized site staff. Investigational product must be dispensed or
 
 
 
 
 
 
 
 
 
 
 
administered only to subjects enrolled in the study and in accordance with the protocol. 
Investigational product (Pazopanib) should begin within ​7 days of inclusion (longer delays
 
 
 
 
 
  
 
 
 
 
 
must be discussed with Study Chair by email: ​investigacion@mfar.net​). 
Pazopanib 800 mg (2x400mg or 4x200 mg) per day (once a day) should be taken orally
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
without food at least 1 hour before or at least 2 hours after a meal. The time of day for
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
administration of Pazopanib should be relatively constant, but does not need to be
 
 
 
 
 
 
 
 
 
 
 
 
 
recorded on the CRF.
If a subject misses a dose, the subject should take the dose as
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
soon as possible, but not less than 12 hours before the next dose is due. If the next dose
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
is due in less than 12 hours, the subject should skip the missed dose and take the next
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose as scheduled. 
Pazopanib will be provided to sites by the Sponsor trough ​GSK​. The contents of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational
product
label
will
be
in
accordance with all applicable regulatory
 
 
 
 
 
 
 
 
 
 
 
requirements.  
7.2. Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, or
 
 
 
 
 
 
 
 
 
 
 
 
head of the medical institution (where applicable) must document the amount of
 
 
 
 
 
 
 
 
 
 
 
 
investigational product dispensed and/or administered to study subjects, the amount
 
 
 
 
 
 
 
 
 
 
returned by study subjects, and the amount received from and returned to Sponsor, when
 
 
 
 
 
 
 
 
 
 
 
 
 
 
applicable. Product accountability records must be maintained throughout the course of
 
 
 
 
 
 
 
 
 
 
 
the study. 
7.3. Treatment Compliance 
A record of the number of Pazopanib tablets dispensed to and returned by each subject
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
must be maintained and reconciled with the CRF. 
After completion of the study, all unused study drug will be inventoried and either
 
 
 
 
 
 
 
 
 
 
 
 
 
 
packaged for return shipment to Sponsor or destroyed at the site.  
Copies of all forms documenting receipt of study drug by the study site and return of study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
drug (if applicable), together with drug accountability records, will be retained according to
 
 
 
 
 
 
 
 
 
 
 
 
 
the local regulations governing record retention. 
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7.4. Concomitant Medication 
All subjects will be asked to provide a complete list of prescription and over-the-counter
 
 
 
 
 
 
  
 
 
 
 
 
 
medications that have been taken within the 4 weeks prior to Screening. The investigator
 
 
 
 
 
 
  
 
 
 
 
 
 
must be informed as soon as possible about any new medication(s) taken from the time of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening until the completion of the post-treatment follow-up visit.  
All concomitant medications taken during the study will be recorded in the electronic case
 
 
 
 
 
 
 
 
 
 
 
 
 
 
report form (e-CRF) with indication, dose information, and dates of administration. 
 
If future changes are made to the list of permitted/prohibited medications, formal
 
 
 
 
 
 
 
 
 
 
 
 
documentation will be provided and stored in the study file. Any such changes will be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
communicated to the investigative sites in the form of a letter. 
 
Permitted medications 
Patients should receive full supportive care during the study, including transfusion of blood
 
 
 
 
 
 
 
 
 
 
 
 
 
and
blood
products,
and
treatment
with antibiotics, analgesics, erythropoietin, or
 
 
 
 
 
 
 
 
 
 
bisphosphonates, when appropriate. Anti-emetics (such as prochlorperazine, lorazepam,
 
 
 
 
 
 
 
 
ondansetron or other 5-HT antagonists) may be administered prophylactically in the event
 
 
 
 
 
 
 
 
  
 
 
of nausea. Anti-diarrheals, such as loperamide, may be administered as needed in the
 
 
 
 
 
 
 
 
 
 
 
 
 
event of diarrhea. Although acetaminophen at doses of ≤2 g/day is permitted, it should be
 
 
 
 
 
 
 
   
  
  
 
 
used with caution in subjects with impaired liver function.  
 
Use with cautions 
Concomitant use of Pazopanib with certain medications (substrates of CYP3A4, CYP2C8,
 
 
 
 
 
 
 
 
 
 
 
and CYP2D6) with a narrow therapeutic window should be undertaken with CAUTION due
 
 
  
 
 
 
 
 
 
 
 
 
to the potential for alterations in the pharmacological effects of these medications or an
 
 
 
 
 
 
 
 
 
 
 
 
 
 
increased risk for serious or life threatening adverse events associated with such
 
 
 
 
 
 
 
 
 
 
 
 
medications (see below) secondary to the inhibition of specific CYP enzymes by
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib.
In addition, the potential for drug interaction with such medications, although
 
 
 
 
 
 
 
 
 
 
 
 
diminished, may persist after the last dose of Pazopanib due to its long half-life (i.e., mean
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30.9 hours); therefore, continue to exercise CAUTION for at least 7 days and up to 15
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
days after the last dose of Pazopanib when administering these medications. These
 
 
 
 
 
 
 
 
 
 
 
 
medications include (but are not limited to): 
●
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine
 
 
 
 
 
 
(potential
increased
risk
for
developing
ergot
toxicity
that includes severe
 
 
 
 
 
 
 
 
 
 
vasospasm leading to peripheral as well as cerebral ischemia) 
●
Neuroleptics: pimozide (potential increased risk for QT interval prolongation,
 
 
 
 
 
 
 
 
 
ventricular arrhythmia, and sudden death) 
●
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine,
 
 
 
 
 
 
 
propafenone (potential increased risk for QT interval prolongation and Torsade de
 
 
 
 
 
 
 
 
 
 
 
Pointes) 
●
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for
 
 
 
 
 
 
 
 
 
nephrotoxicity and neurotoxicity) 
●
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine 
 
Substances that induce or inhibit CYP3A4 may alter the pharmacological effects of
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib and should be used with CAUTION.  
  
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Medications
that
inhibit
CYP3A4
may
result
in
increased
plasma
Pazopanib
 
 
 
 
 
 
 
 
 
 
concentrations. Co-administration of strong CYP3A4 inhibitors is prohibited (see Section
 
 
 
 
 
 
 
 
 
 
on Prohibited Medications); therefore selection of an alternate concomitant medication with
 
 
 
 
 
 
 
 
 
 
 
no or minimal potential to inhibit CYP3A4 is recommended.  
CYP3A4 inducers may decrease plasma Pazopanib concentrations. Selection of an
 
 
 
 
 
 
 
 
 
 
alternate concomitant medication with no or minimal enzyme induction potential is
 
 
 
 
 
 
 
 
 
 
 
recommended.  
●
Drugs that induce CYP3A4 and may decrease Pazopanib plasma concentrations
 
 
 
 
 
 
 
 
 
 
include (but are not limited to): 
●
Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10
 
 
 
 
 
 
 
 
 
mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
●
Anticonvulsants: phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
●
HIV antivirals: efavirenz, nevirapine 
●
Antibiotics: rifampin (rifampicin), rifabutin, rifapentene 
●
Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone 
 
Prohibited medications 
 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or
 
 
 
 
 
 
 
 
 
 
 
hormonal (other than leuprolide or other GnRH agonists)] while on treatment in this study.  
Medications
that
inhibit
CYP3A4
may
result
in
increased
plasma
Pazopanib
 
 
 
 
 
 
 
 
 
 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED
 
 
 
 
 
 
 
 
 
beginning 14 days prior to the first dose of study drug until discontinuation from the study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Strong CYP3A4 inhibitors include (but are not limited to): 
●
Antibiotics: clarithromycin, telithromycin, troleandomycin 
●
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, lopinavir) 
●
Antifungals:  itraconzaole, ketoconazole, voriconazole 
●
Antidepressants:  nefazodone 
7.4.1. Specific recommendations regarding anticoagulants 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib has no effect on the metabolism of S-warfarin. Hemorrhagic events, however,
 
 
 
 
 
 
 
 
 
 
 
 
have been reported in clinical studies with Pazopanib; therefore, Pazopanib should be
 
 
 
 
 
 
 
 
 
 
 
 
used with caution in subjects with increased risk of severe bleeding or who are receiving
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight
 
 
 
 
 
 
 
 
 
 
 
heparin, unfractionated heparin).
Subjects taking concomitant anticoagulant therapy
 
 
 
 
 
 
 
 
should be monitored regularly for changes in relevant coagulation parameters as clinically
 
 
 
 
 
 
 
 
 
 
 
 
indicated, as well as for any clinical bleeding episodes. 
7.4.2. Specific recommendations regarding hypoglycemic therapy 
including insulin 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that
 
 
 
 
 
 
 
 
 
 
 
 
there will be no clinically relevant pharmacokinetic interaction between Pazopanib and
 
 
 
 
 
 
 
 
 
 
 
hypoglycemic agents.
Transient decreases in serum glucose (mainly Grade 1 and 2,
 
 
 
 
 
 
 
 
  
 
 
rarely Grade 3) have been observed in clinical studies with Pazopanib.
In addition,
 
 
 
 
 
 
 
 
 
 
 
 
 
decreases in blood sugar have been recently reported in subjects treated with another
 
 
 
 
 
 
 
 
 
 
 
 
 
small molecule tyrosine kinase inhibitor, sunitinib ​(11) (Billemont, 2008). Such changes may
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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require an adjustment in the dose of hypoglycemic and/or insulin therapy. Subjects should
 
 
  
 
 
 
 
 
 
 
 
 
be advised to report symptoms of hypoglycemia (e.g., confusion, visual disturbances,
 
 
 
 
 
 
 
 
 
 
 
palpitations, sweating). Serum glucose should be tested during treatment with Pazopanib
 
 
 
 
 
 
 
 
 
 
 
as outlined in the protocol and as clinically indicated. 
7.4.3. The Effects of Pazopanib on Other Drugs 
In vitro data indicate that Pazopanib is a potential inhibitor for CYP3A4, CYP2C8,
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.
Pregnane X
 
 
 
 
 
 
 
 
  
receptor transient transfection assay suggested some potential for human CYP3A4
 
 
 
 
 
 
 
 
 
 
induction at high concentrations. Results from drug-drug interaction studies conducted in
 
 
 
 
 
 
 
 
 
 
 
subjects with cancer suggest that Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and
 
 
 
 
 
   
 
 
 
 
 
 
CYP2D6 in vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metabolism.
Therefore,
concomitant
use
of
Pazopanib
with certain medications
 
 
 
 
 
 
 
 
 
(substrates of CYP3A4, CYP2C8, and CYP2D6) with a narrow therapeutic window should
 
 
 
 
 
 
  
 
 
 
 
be undertaken with ​CAUTION due to the potential for alterations in the pharmacological
 
 
 
 
 
 
 
 
 
 
 
 
 
effects of these medications or an increased risk for serious or life threatening adverse
 
 
 
 
 
 
 
 
 
 
 
 
 
 
events associated with such medications (see below) secondary to the inhibition of specific
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP enzymes by Pazopanib.
In addition, the potential for drug interaction with such
 
 
 
 
 
 
 
 
 
 
 
 
 
medications, although diminished, may persist after the last dose of Pazopanib due to its
 
 
 
 
 
 
 
 
 
 
 
 
 
 
long half-life (i.e., mean 30.9 hours); therefore, continue to exercise ​CAUTION for at least
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 days and up to 15 days after the last dose of Pazopanib when administering these
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
medications.  These medications include (but are not limited to): 
●
Ergot derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
 
 
 
 
 
 
(potential
increased
risk
for
developing
ergot
toxicity
that includes severe
 
 
 
 
 
 
 
 
 
 
vasospasm leading to peripheral as well as cerebral ischemia) 
●
Neuroleptics: pimozide (potential increased risk for QT interval prolongation,
 
 
 
 
 
 
 
 
 
ventricular arrhythmia, and sudden death) 
●
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine,
 
 
 
 
 
 
 
propafenone (potential increased risk for QT interval prolongation and Torsade de
 
 
 
 
 
 
 
 
 
 
 
Pointes) 
●
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for
 
 
 
 
 
 
 
 
 
nephrotoxicity and neurotoxicity) 
●
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
7.4.4. The Effects of Other Drugs on Pazopanib 
Results from in vitro studies suggest that the oxidative metabolism of Pazopanib in human
 
 
 
 
 
 
 
 
 
 
 
  
 
liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2
 
  
 
 
 
 
 
 
 
 
 
and CYP2C8.
Furthermore, in vitro data suggest that Pazopanib is a substrate for
 
 
 
 
 
 
 
 
 
 
 
 
 
p-glycoprotein.
Substances that induce or inhibit CYP3A4 may alter the pharmacological
 
 
 
 
 
 
 
 
 
 
 
effects of Pazopanib and should be used with​ CAUTION.   
Medications
that
inhibit
CYP3A4
may
result
in
increased
plasma
Pazopanib
 
 
 
 
 
 
 
 
 
 
concentrations.
Co-administration of strong CYP3A4 inhibitors is prohibited (see Section
 
 
 
 
 
  
 
 
 
on Prohibited Medications); therefore selection of an alternate concomitant medication with
 
 
 
 
 
 
 
 
 
 
 
no or minimal potential to inhibit CYP3A4 is recommended.  
CYP3A4 inducers may decrease plasma Pazopanib concentrations.
Selection of an
 
 
 
 
 
 
 
 
 
 
alternate concomitant medication with no or minimal enzyme induction potential is
 
 
 
 
 
 
 
 
 
 
 
recommended.
Drugs that induce CYP3A4 and may decrease Pazopanib plasma
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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concentrations include (but are not limited to): 
●
Glucocorticoids:
cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10
 
 
 
 
 
 
 
 
 
mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
●
Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
●
HIV antivirals:  efavirenz, nevirapine 
●
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
●
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone 
7.5. Treatment of Investigational Product Overdose 
No maximum tolerated dose (MTD) was reached in dose escalation studies of Pazopanib
 
 
 
 
 
 
 
 
 
 
 
 
 
administered as a single agent at doses of up to 2000 mg/day. Pazopanib exposure at
 
  
 
 
 
 
 
 
 
 
 
 
 
 
higher doses appeared to reach a plateau level at a dose of 800 mg daily. 
In the event of overdose (defined as administration of more than the protocol-specified
 
 
 
 
 
 
 
 
 
 
 
 
 
dose), the investigator should contact ​MFAR S.L. and additional monitoring of the subject
 
 
 
 
 
 
 
 
 
 
 
 
 
for AEs/SAEs and laboratory abnormalities should be considered. Decisions regarding
 
 
 
 
 
 
 
 
 
 
dose interruptions or modifications will be made by the investigator in consultation with the
 
 
 
 
 
 
 
 
 
  
 
 
 
GEIS Study Chair based on the clinical evaluation of the subject. Information regarding the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
quantity of the excess dose should be documented in the CRF. 
 
 
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7.6. Criteria for regimen modification during the study 
7.6.1. Dose Interruptions/Modifications for Specific, Non-liver 
Related, Toxicities 
As a general rule, if dose reduction of IP is necessary, the dose should be reduced
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
stepwise by 200 mg at each step, and the subject should be monitored for approximately
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 to 14 days at each dose level. If toxicity does not abate during this monitoring time, the
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
IP may need to be interrupted and/or the dose further decreased with continued monitoring
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for an additional 10-14 days at each dose level, and so on.  
If the toxicity has abated with reduction of the dose and dose re-escalation is considered
 
 
 
 
 
 
 
 
 
 
 
 
  
 
safe by the investigator, the IP dose can then be increased step-wise back to the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pre-event dose (in 200 mg increments, after monitoring for 10-14 days at each dose level
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to ensure that toxicity did not recur or worsen).  
If a subject’s treatment has been interrupted for more than 21 days, the Investigator must
  
 
 
 
 
 
 
 
 
 
 
 
 
 
contact the Trial Chief Investigator by email ​(​investigacion@mfar.net​) to review the
 
 
 
 
 
 
 
 
 
 
 
subject’s condition in order to resume the treatment.  
Recommendations for investigational product dose interruptions/modifications in case of
 
 
 
 
 
 
 
 
 
specific treatment-emergent AEs are provided in the following Table 
 
Table 2: Dose Modification Algorithms for Potential Treatment-Related Adverse 
Events 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(A). Asymptomatic and 
persistent SBP of ≥ 140 and 
<170 mmHg, or DBP ≥ 90 and 
<110 mmHg, or a clinically 
significant increase in DBP of 
20 mmHg (but still below 110 
mmHg). 
Step 1. Continue investigational product (IP) at the current dose.  
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled blood pressure (BP). If BP is not 
well-controlled within 2 weeks, consider referral to a specialist and go 
to scenario (B). 
(B). Asymptomatic SBP ≥170 
mmHg, or DBP≥110 mmHg, or 
failure to achieve 
well-controlled BP within 2 
weeks in scenario (A).  
Step 1.Consider reducing or interrupting IP, as clinically indicated. 
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.  
Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 mg 
if IP was interrupted. 
(C). Symptomatic hypertension 
or recurring SBP ≥170 mmHg, 
or DBP≥110 mmHg, despite 
modification of antihypertensive 
medication(s) 
Step 1. Interrupt IP  
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.  Referral to a specialist for 
further evaluation and follow-up is also recommended. 
Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 
mg. 
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(D). Refractory hypertension 
unresponsive to above 
interventions. 
Discontinue IP and continue follow-up per protocol. 
Prolongation of QTc Interval: ​If the QTc is prolonged, the ECG should be manually read to ensure 
accuracy of the reading.  The values below refer to manually-read ECGs.  
 
QTc ≥ 480 < 500 msec 
Continue IP; monitor as clinically indicated. 
QTc ≥ 500 msec 
Discontinue IP and continue follow-up per protocol. 
Proteinuria 
UPC <3 
Continue Pazopanib at the current dose; monitor as clinically 
indicated 
UPC ≥3 or 24-h urine protein ≥ 
3g 
Step 1. Interrupt IP. 
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is <3 
or 24-hr urine protein is <3 grams.  Then restart Pazopanib 
dose-reduced by 200 mg. 
Step 3.  If UPC ≥3 or 24-h urine protein ≥ 3g recurs, repeat steps 1 
and 2. 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the Pazopanib 
dose can no longer be reduced, discontinue Pazopanib and 
continue follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
For hemoptysis, interrupt Pazopanib and contact Chief Study 
Physician to discuss whether further treatment with Pazopanib is 
appropriate. 
For other Grade I haemorrhage/bleeding events, continue Pazopanib 
at the current dose; monitor as clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue IP and continue follow-up per protocol. Otherwise, 
interrupt IP until the AE resolved to ≤ Grade 1.  
Step 2. Restart IP; consider reducing dose and monitor as clinically 
indicated.  
Grade 3 or 4, or  
Recurrent ≥ Grade 2 event after 
dose interruption/reduction. 
Discontinue IP and continue with follow-up per protocol.  
  
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue IP at the current dose; monitor as clinically indicated 
Grade 3  
 
Step 1. Interrupt IP.  
Step 2. Initiate and monitor anticoagulation as clinically indicated.  
Step 3. Resume IP at reduced dose only if all of the following criteria
 
 
 
 
 
 
 
  
 
 
 
 
 
are met:  
●
The subject must have been treated with anticoagulant at the
 
 
 
 
 
 
 
 
 
 
desired level of anticoagulation for at least one week. 
●
No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic
 
  
  
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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events have occurred while on anticoagulation treatment. 
Subject
should
be
monitored
as
clinically
indicated
during
 
 
 
 
 
 
 
 
anticoagulation treatment and after resuming study treatment. When
 
 
 
 
 
 
 
 
treating with warfarin, international normalized ratio (INR) should be
 
 
 
 
 
 
 
 
 
monitored within three to five days after any change in IP dosing (eg,
 
 
 
 
 
 
 
 
 
 
 
 
 
re-initiating, escalating/de-escalating, or discontinuing IP), and then at
 
 
 
 
 
 
 
 
least weekly until the INR is stable. The dose of warfarin (or its
 
 
 
 
 
 
 
 
 
 
 
 
 
derivatives) may need to be adjusted to maintain the desired level of
 
 
 
 
 
 
 
 
 
 
 
 
anticoagulation 
Grade 4 and/or PE 
Discontinue IP and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
Any Grade 
Discontinue IP and continue follow-up per protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue IP with current dose; monitor as clinically indicated.  
Grade 3 or 4 
Step 1. Interrupt IP until toxicity resolves to ≤ Grade 2. 
Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically 
indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia, discontinue IP and follow-up per protocol. 
Anemia:​  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or 
bleeding as noted above. 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or 
dermatitis without pain 
(erythema, oedema, 
hyperkeratosis) 
Continue IP at present dose 
 Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily 
living (ADLs) (peeling, blisters, 
oedema, bleed, hyperkeratosis) 
1.
Hold IP  
2.
Treat as clinically appropriate 
3.
Upon resolution to Level 1 or better restart  IP with a dose 
reduction to 400 mg 
4.
If recurrent consider a further dose reduction to 200mg or 
discontinuation 
Grade 3 
Severe skin changes with pain 
and limiting self care ADLs 
 
Discontinue IP 
Other Clinically Significant Adverse Events​b  
Grade 1 
Continue IP; monitor as clinically indicated. 
Grade 2 or 3, if clinically 
significant  
Step 1. Interrupt IP until toxicity resolves to ≤ Grade 1. 
Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically 
indicated.  
Grade 4 
Discontinue IP and continue follow-up per protocol.  
●
Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
●
AEs are graded according to NCI Common Terminology Criteria for Adverse Events 
GEIS–30_H_V03F_2015-02-11 
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v4.0 (NCI CTCAE v4)  
      Abbreviations: BP, blood pressure; IP, investigational product. 
 
 
 
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7.6.2. Dose Interruptions/Modifications for Hepatotoxicity 
 
 
Patients over 60 years of age have an increased risk of ALT > 3 x ULN. 
 
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations and
 
 
 
 
 
 
 
 
 
 
 
 
 
should be undertaken with caution and close monitoring. 
 
Recommendations
for
IP
dose
interruptions/modifications
in
case
of
liver-related
 
 
 
 
 
 
 
 
 
treatment-emergent AEs are provided in Table 3. As a general rule, since many subjects
 
 
 
 
 
 
 
  
 
 
 
 
 
are taking multiple concurrent medications, it is critical to: 
 
(a) do a thorough evaluation of the subject’s concurrent medications (and ensure all
 
  
 
 
 
 
 
 
 
 
 
 
are 
recorded in the eCRF), and 
(b) identify and discontinue those with known hepatotoxicity and replace with a non-
 
 
 
 
 
 
 
 
 
 
  
hepatotoxic equivalent for the same indication if necessary.  
 
Record alcohol use on the liver event alcohol intake form in the eCRF. Liver dysfunction
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
must be fully evaluated even if clinical signs and symptoms indicate progression of liver
 
 
 
 
  
 
 
 
 
 
 
 
 
tumor lesions.
Imaging studies must be obtained to document potential progression of
 
 
 
 
 
 
 
 
 
 
 
 
malignancy. 
 
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Table 3: Guidelines for Management of Treatment Emergent Hepatotoxicity 
 
Event 
Dose Modification Algorithms 
(A). ALT of ≤3.0 x
 
 
  
  
ULN 
Continue Pazopanib at current dose with full panel LFT (a) monitored as per protocol. 
(B). ALT >3.0 x ULN
 
 
  
 
to
≤8.0
x
ULN
 
 
 
 
without
bilirubin
 
 
elevation (defined as
 
 
 
total
bilirubin
(b)
 
 
 
<2.0 x ULN or direct
  
 
 
 
bilirubin ≤35%) and
 
 
 
without 
hypersensitivity 
symptoms
(e.g.,
 
 
fever, rash)  
Liver Event Monitoring Criteria: 
(1) Continue Pazopanib at current dose levels.  
(2) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs​a
 
 
 
 
 
 
 
 
 
 
 
 
 
weekly or more frequently if clinically indicated until ALT/AST is reduced to Grade 1. 
(C). ALT >8.0 x ULN
 
 
  
 
without
bilirubin
 
 
elevation (defined as
 
 
 
total bilirubin​b <2.0 x
 
 
  
ULN
or
direct
 
 
 
bilirubin ≤35%) and
 
 
 
without 
hypersensitivity 
symptoms
(e.g.,
 
 
fever, rash) 
1​st​ occurrence – Liver Event Interruption Criteria: 
(1) Interrupt Pazopanib until toxicity resolves to ≤Grade 1 or baseline. Report the
 
 
 
 
 
 
  
 
 
 
 
 
event to Sponsor as an SAE ​within 24 hours of learning of its occurrence. Make
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
every reasonable attempt to have subjects return to the clinic within 24 to 72 hours
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for repeat liver chemistries and liver event follow up assessments. 
(2) Liver imaging and other laboratory investigations should be considered as
 
 
 
 
 
 
 
 
 
 
 
clinically appropriate. 
(3) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs​a
 
 
 
 
 
 
 
 
 
 
 
 
 
weekly or more frequently if clinically indicated until ALT/AST is reduced to
 
 
 
 
 
 
 
 
 
 
 
 
Grade 1.  
(4) If the subject is benefiting from the study treatment, contact Study
Chief
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician for possible re-challenge.
Re-treatment may be considered if ALL
 
 
 
 
 
 
 
  
 
following criteria are met:  
- ALT/AST reduced to Grade 1 
- Total bilirubin <1.5 x ULN or direct bilirubin ≤ 35% 
- No hypersensitivity signs or symptoms 
- Subject is benefiting from therapy.  
(5) Reintroduce Pazopanib, if warranted, at lower dose. 
Recurrence – Liver Event Stopping Criteria: 
If aminotransferase levels > 3xULN recur, discontinue Pazopanib permanently and
 
 
  
 
 
 
 
 
 
monitor subject closely for clinical signs and symptoms; perform full panel LFTs a
 
 
 
 
 
 
 
 
 
 
 
  
weekly or more frequently if clinically indicated until ALT/AST is reduced to Grade 1.  
(D).
ALT
>3.0
x
 
 
 
 
 
ULN
​with
 
 
concomitant 
elevation in bilirubin
 
 
 
(b) (defined as total
 
 
 
 
bilirubin
≥
2.0
x
 
 
 
 
ULN;
with
direct
 
 
 
bilirubin
>35%)
or
 
 
 
with hypersensitivity
 
 
symptoms
(e.g.,
 
 
fever, rash).  
Liver Event Stopping Criteria: 
(1) Discontinue Pazopanib immediately, report the event to Sponsor as an SAE
 
 
 
 
 
 
 
 
 
 
 
 
within 24 hours of learning of its occurrence. Make every reasonable attempt to
 
 
 
 
 
 
 
 
 
 
 
 
 
have subjects return to the clinic within 24 hours for repeat liver chemistries and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
liver event follow up assessments. 
(2)
Consult
a
gastroenterologist
/
hepatologist,
and
perform
the
following
 
 
 
 
 
 
 
 
 
 
assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-Barr virus
 
 
 
 
 
 
 
 
 
 
 
 
 
(IgM antibody, heterophile antibody, or monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney
 
 
 
 
 
 
 
 
 
 
microsomal antibodies. 
- Serum creatinine phosphokinase for possible muscle injury caused LFT elevation 
- Liver imaging 
-Consider toxicological blood screen for possible contributing chemical/medical
 
 
 
 
 
 
 
 
entities  
(3) Monitor subject closely for clinical signs and symptoms; record the appearance or
 
 
 
 
 
 
 
 
 
 
 
 
 
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worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue,
 
 
 
 
 
 
 
 
 
 
 
nausea,
vomiting,
right
upper
quadrant
pain or tenderness, fever rash or
 
 
 
 
 
 
 
 
 
 
 
eosinophilia as relevant on the AE report form. Perform full panel LFTs​a weekly or
 
 
 
 
 
 
 
 
 
 
 
 
 
 
more frequently if clinically indicated until LFTs are reduced to Grade 1.  
For
isolated
total
 
 
 
bilirubin(b) elevation
 
 
without
concurrent
 
 
ALT
increases
 
 
(defined as ALT <3
 
 
 
 
X ULN). 
 
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other
 
 
 
 
 
 
 
 
 
 
 
signs/symptoms of liver injury) does not require dose modification. Pazopanib
 
 
 
 
 
 
 
 
 
 
inhibits
UGT1A1
and
OATP1B1,
which
can
cause
elevation
of
indirect
 
 
 
 
 
 
 
 
 
 
(unconjugated) bilirubin in the absence of liver injury. 
(2)
If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of
 
 
 
 
  
 
 
 
 
 
 
 
 
 
bilirubin elevation should be performed. If bilirubin is >35% direct (conjugated),
 
 
 
 
  
  
 
 
 
further evaluation for underlying cause of cholestasis should be performed. 
(a) Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation tests should be performed as clinically indicated. 
(b) Serum bilirubin fractionation should be performed if testing is available.
If testing is
 
 
 
 
 
 
  
 
 
 
 
 
 
unavailable and a subject meets the criterion of total bilirubin >1.5 x ULN, then the event
 
  
 
 
 
 
 
 
 
  
 
 
 
 
should be promptly reported as an SAE. 
 
Abbreviations: ​ALT alanine aminotransferase; ​AST aspartate aminotransferase; ​eCRF
 
 
 
 
 
 
 
 
electronic case report form; ​IP investigational product; ​LFT liver function tests; ​SAE
 
 
 
 
 
 
 
 
 
 
 
 
serious adverse event; ​ULN​ upper limit of normal 
7.6.3 Dose Modifications and Management of Diarrhea, Nausea, 
and Vomiting 
These general guidelines are provided to facilitate subject care in the event of diarrhea,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
thereby avoiding serious complications.
Guidelines such as these should never replace
 
 
 
 
 
 
 
 
 
 
 
sound clinical judgment.
Experience thus far suggests that use of monotherapy
 
 
 
 
 
 
 
 
 
 
 
Pazopanib is associated with an increased incidence of diarrhea, primarily of Grade 1 or 2.
  
 
 
 
 
 
 
 
 
 
  
 
 
In rare cases, diarrhea can be debilitating and potentially life threatening, with dehydration,
 
 
 
 
 
 
 
 
 
 
 
 
 
renal insufficiency, and electrolyte imbalances. 
Standardized and universal guidelines have been developed by an American Society of
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Oncology panel for treating chemotherapy-induced diarrhea.​ (12) 
Early identification and intervention is critical for the optimal management of diarrhea. A
 
 
 
 
 
 
 
 
 
 
 
 
 
subject’s baseline bowel patterns should be established so that changes in patterns while
 
 
 
 
 
 
 
 
 
 
 
 
 
on treatment can be identified. An assessment of frequency, consistency, and duration of
 
 
 
 
 
 
 
 
 
 
 
 
 
diarrhea, as well as knowledge of other symptoms such as fever, cramping, abdominal
 
 
 
 
 
 
 
 
 
 
 
 
 
pain, nausea, vomiting, dizziness and thirst should be taken at baseline, permitting
 
 
 
 
 
 
 
 
 
 
 
 
identification of patients at high risk of diarrhea. Patients should be educated on signs and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms of diarrhea with instructions to report any changes in bowel patterns to the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study site physician. 
 
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below. 
 
Table 4: NCI CTCAE Version 4.0 criteria for defining diarrhea  
Toxicit
y 
Grade 
Diarrhea  
(includes diarrhea of small bowel or colonic origin and/or ostomy diarrhea) 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline 
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2 
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline 
3 
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; severe 
increase in ostomy output compared to baseline; limiting self-care activities of daily 
living 
4 
Life threatening consequences, urgent intervention indicated 
5 
Death 
 
Uncomplicated diarrhea is considered mild to moderate and is defined as CTCAE Grade 1
 
  
 
 
 
 
  
 
 
 
  
to 2 with no complicating signs or symptoms. 
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with
 
  
 
 
 
 
 
  
  
 
  
  
 
one or more of the following signs or symptoms: severe cramping, ≥Grade 2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia,
 
 
 
 
 
 
  
  
 
obvious bleeding, dehydration. 
 
Management Guidelines 
Uncomplicated diarrhea of CTCAE Grade 1 or 2​: 
 
●
Hydration: have subject drink 8 to 10 large glasses (approximately 2 litres) of clear
 
 
 
  
 
 
 
 
  
 
 
 
non-caffeinated liquids a day (e.g., broth or electrolyte-containing sports drinks).  
●
If Grade 2 diarrhea, consider dose reduction of investigational products. 
●
Dietary modifications:
have subject stop all lactose-containing products and eat
 
 
 
 
 
 
 
 
 
 
frequent, small meals 
●
Pharmacologic intervention using loperamide: 
●
Begin loperamide at initial dose of 4 mg followed by 2 mg every 4 hours or
 
 
 
 
 
  
 
 
  
 
  
 
 
after every unformed stool. The recommended maximum daily dose of
 
 
 
 
 
 
 
 
 
 
loperamide is 16 mg/day. 
●
Continuation of loperamide is suggested until diarrhea-free for 12 hours. 
●
If mild to moderate diarrhea persists for more than 24 hours, administer
 
 
 
 
 
 
 
 
 
 
 
 
loperamide 2 mg every 2 hours and pursue evaluation for other treatable
 
 
 
  
 
 
 
 
 
 
 
causes. 
●
If mild to moderate diarrhea persists after 48 hours total treatment with
 
 
 
 
 
 
 
 
 
 
 
 
loperamide, discontinue study drug(s) and consider initiation of second-line
 
 
 
 
 
 
 
 
 
agents (lomotil, octreotide). 
 
 
Complicated diarrhea of CTCAE Grade 3 or 4 diarrhea or Grade 1 or 2 with
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
complicating features requires aggressive management: 
 
●
Subject must call study site physician immediately in response to any event of
 
 
 
 
 
 
 
 
 
 
 
 
 
severe diarrhea with or without complications as listed above.  
●
Hospitalization may be required for subjects most at risk for life-threatening
 
 
 
 
 
 
 
 
 
 
 
complications. 
●
Interrupt investigational products until symptoms resolve; consider reintroducing at
 
 
 
 
 
 
 
 
 
a reduced dose (discuss with Chief Trial Investigator or designee). 
●
If loperamide has not been initiated, begin loperamide usage immediately at an
 
 
 
 
 
 
 
 
 
 
 
 
initial dose of 4 mg followed by 2 mg every 2 hours or after every unformed stool.
 
 
  
 
 
  
 
  
 
 
 
 
 
 
The recommended maximum daily dose of loperamide is 16 mg/day. 
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●
If no improvement in severity after 24-hours of maximal loperamide dosing, subject
 
 
 
 
 
 
 
 
 
 
 
 
must visit study site and be evaluated: 
●
For dehydration, use intravenous fluids as appropriate.  
●
Antibiotic therapy should be considered in patients, who present with signs and
 
 
 
 
 
 
 
 
 
 
 
 
symptoms of bacterial diarrhea such as fever, bloody diarrhea, and presence of
 
 
 
 
 
 
 
 
 
 
 
 
fecal leukocytes. Investigators should have a low threshold to start such treatment
 
 
 
 
  
 
 
 
 
 
 
in patients with Grade 3 or Grade 4 neutropenia.  
●
Before initiation of antimicrobial therapy, stool cultures should be obtained. When
 
 
 
 
 
 
 
 
 
 
 
bacterial etiology for diarrhea is suspected, study-treatment and anti-motility agents
 
 
 
  
 
 
 
 
 
(loperamide or others) should be held. 
●
Intervention should be continued until diarrhea free for 24 hours. 
 
Alternative
Pharmacologic
Intervention
for
Uncomplicated
and
Complicated
 
 
 
 
 
 
 
Diarrhea 
 
●
Lomotil
(dephenoxylate
2.5
mg
+
atropine
0.025
mg) can be used. The
 
 
 
 
 
 
 
 
 
 
 
 
recommended dose is 2 tablets 4 times daily. When diarrhea is under control, a
 
 
  
  
 
 
 
 
 
 
  
dose reduction should be attempted. 
 
Nausea and Vomiting 
 
Every attempt should be made to control nausea and vomiting in subjects who have
 
 
 
 
 
 
 
 
 
 
 
 
 
 
emesis and are unable to retain Pazopanib. 
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be
 
 
 
  
 
 
 
 
 
 
 
treated with standard anti-nausea/anti-emetic therapy as necessary. 
If a subject vomits after taking study medication, the subject should be instructed not to
  
 
 
 
 
 
 
 
 
 
 
 
 
 
take a replacement dose on that same day. The subject should resume taking Pazopanib
  
 
 
 
 
 
 
 
 
 
 
 
 
at the next scheduled dose on the following day.
If vomiting persists, then the subject
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should contact their physician. To prevent or treat nausea and vomiting standard
 
 
 
 
 
 
 
 
 
 
 
 
medications are recommended.
Depending upon approved medications in your region,
 
 
 
 
 
 
 
 
 
 
these may include: 5-HT​3 receptor antagonist (granisetron, ondansetron, dolasetron
 
 
 
 
 
 
 
 
 
mesylate); NK-1 receptor antagonists such as aprepitant, metoclopramide, phenothiazine
 
 
 
 
 
 
 
 
 
(prochlorperazine);
corticosteroids,
(dexamethasone,
prednisone);
and
cannibinoids
 
 
 
 
 
 
(dronabinol). 
 
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8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Study Development 
Screening test for inclusion (lab tests and imaging) should have been performed ≤14 days
 
 
 
 
 
 
 
 
 
 
 
  
 
 
before first dose administration. 
 
Table 5: ​summarizes the assessments to be performed throughout the study as well as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
their schedule. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE Of ASSESSMENT 
 
 
Before 
Treatment 
During Treatment 
After treatment  
 
Screening  
(within 14 
days prior 
treatment 
start) 
Week
0 
 
W1 
 
W3 
W5 
 
W7 
 
W9 
W 
12 
Every  
4 
weeks 
(after 
w12) 
Every  
8 
week
s 
Every  
12 
 
week
s 
28 
days 
after 
end 
of 
treat
ment  
Before 
PD, 
every 8 
weeks 
until PD  
After PD 
every 12 
weeks 
Day 
1 
Day 
 8 
Day 
22 
Day 
36 
Day 
50 
Day 
64 
Day 
85 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Excl
usion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam​a ​(with 
vital and 
cancer signs 
and 
symptoms)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Clinical 
Laboratory 
Tests​ b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
ECG​d 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
LVEF 
(MUGA/ECO) 
X​** 
 
 
 
 
 
 
X 
 
 
X 
 
 
Efficacy 
Assessment 
(Imaging/MRI)
* 
X​** 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
Adverse 
Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Tumor 
specimen 
collection ​1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
collection ​2 
X 
 
 
X 
 
 
x​2 
Treatment 
control and 
dispensing 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Tumor assessment should be repeated in week 7 and week 12
 
 
 
 
 
 
  
 
 
 
and every 8 weeks thereafter until documented progression for
 
 
 
 
 
 
 
 
 
patients with CR, PR, or SD and/or for
patients who have
 
 
 
 
 
 
 
 
 
 
 
discontinued study therapy due to toxicity or reasons other than
 
 
 
 
 
 
 
 
 
 
progressive disease, unless they have started a new anti-cancer
 
 
 
 
 
  
 
 
therapy. 
**Both tumor assessment before treatment and LVEF can be done
 
 
 
 
 
 
 
 
 
 
up to 28 days prior the start of the treatment. 
1​ Tumor sample will be collected before treatment. 
2​Serum will be collected as described: 
1.
Within 72 hours prior starting the treatment (basal).  
2.
Within 72 hours after first 3 weeks of treatment (day 22). 
3.
Within
72
hours
after
radiological
response
is
 
 
 
 
 
 
 
documented. 
4.
Within 72 hours after progressive disease is documented. 
a ​Monitoring of BP: A measurement of BP should be taken the day of the visit +/- 3
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
days.  
b ​Hematology Profile and Chemistry Profile (including liver Function) in every visit 
c ​Thyroid function test (T4 and TSH):basal and every 12 weeks. 
d ​ECG: Baseline, week 7 and 12 and every 8 weeks thereafter. 
Unless otherwise indicated, during treatment the marge for visits / explorations is
 
 
 
 
 
 
 
 
  
  
+/- 4 days and after completion of treatment +/- 7 days 
 
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8.2 Assessments description: 
1. Informed Consent: ​Written permission will be given by each patient prior to undergoing
 
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol-specific evaluations and prior to receiving treatment. The patient should sign 2
 
 
 
 
 
 
 
 
 
 
  
separate informed consents: one for the clinical trial and another for the biological
 
 
 
 
 
 
 
 
 
 
 
 
 
samples. 
2. Inclusion/Exclusion criteria: Will be reviewed by each patient prior to undergoing
 
 
 
 
 
 
 
 
 
 
 
 
protocol-specific evaluations and prior to receiving treatment. 
3.
Medical
History:
Past
or
current
medical conditions and treatments, current
 
 
 
 
 
 
 
 
 
 
 
medications, medications taken within 30 days of randomization, date of diagnosis, prior
 
 
 
 
 
 
 
 
 
 
 
 
cancer therapy and surgery, pathological confirmation of malignancy, and staging of
 
 
 
 
 
 
 
 
 
 
 
liposarcoma at the time of diagnosis and study entry. Any pre-existing toxicity (eg, Grade 1
 
 
 
 
 
 
 
 
 
 
 
 
 
  
fatigue) should be documented and recorded at this time. 
4. Physical Exam:  
4.1 Pre-treatment (Screening): ​Evaluation by body system, height, weight, body
 
 
 
 
 
 
 
 
 
 
surface area (BSA) and measurement of vital signs (blood pressure and body
 
 
 
 
 
 
 
 
 
 
 
 
temperature). 
4.2 During treatment and follow up visits: ​Evaluation by body system, weight,
 
 
 
 
 
 
 
 
 
 
 
 
body surface area (BSA) and verification of patient blood pressure measurements,
 
 
 
 
 
 
 
 
 
 
 
every treatment visit before study drug administration and at every visit and
 
 
 
 
 
 
 
 
 
 
 
 
follow-up visit. 
5. ECOG Performance Status (PS): ​PS will be assessed at screening, at day 1 before
 
 
 
 
 
 
 
 
 
 
 
 
  
 
the study drug is administered, and in week 1, 3, 5, 7, 9 and week 12. Thereafter, every
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
treatment visit before the study drug is administered (4 weeks). 
If subjects discontinue study treatment without disease progression (e.g., withdrawal of
 
 
 
 
 
 
 
 
 
 
 
study treatment due to unacceptable toxicity), continue the assessments of ECOG PS in
 
 
 
 
 
 
 
 
 
 
 
 
 
accordance with the disease assessments until subjects experience disease progression. 
6. Concomitant Medication: The use of any natural/ herbal products or others “folk
 
 
 
 
 
 
 
 
 
 
 
 
 
remedies” should be discouraged but use of these products, as well as use of vitamins or
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
nutritional supplements and all others concomitant medications must be recorded in the
 
 
 
 
 
 
 
 
 
 
 
 
Case Report Form (CRF). Any medications, with the exception noted in the section
 
 
 
 
 
 
 
 
 
 
 
 
 
(additional details), which are considered necessary for patient´s welfare, and which it is
 
 
 
 
 
 
 
 
 
 
   
believed will not interfere with the study medication, may be given at the discretion of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator, providing the medication, doses, dates and reasons for administration in the
 
 
 
 
 
 
 
 
 
 
 
 
CRF. 
7. Adverse Events: ​The CTC-AE version 4.0 will be used to evaluate the clinical safety of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the treatment in this study. Subjects will be assessed for AEs at each clinical visit and as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
necessary throughout the study.  
8. Clinical Laboratory Tests: 
8.1 Hematology Profile: includes a complete blood count with differential and
 
 
 
 
 
 
 
 
 
 
 
platelet count. 
8.2 Coagulation Profile: ​includes INR, prothrombin time, and PTT. 
8.3 Chemistry Profile: includes total protein, albumin, blood urea nitrogen,
 
 
 
 
 
 
 
 
 
 
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creatinine, AST, ALT, alkaline phosphatase, total bilirubin, phosphorus, sodium,
 
 
 
 
 
 
 
 
 
potassium,
calcium,
chloride,
magnesium,
amylase,
lipase,
and
lactate
 
 
 
 
 
 
 
 
dehydrogenase. 
8.4 Urinalysis: ​routine analysis (UPC) or dipstick measurements and, if clinically
 
 
 
 
 
 
 
 
  
 
indicated, microscopic analysis. If dipstick or routine urinalysis (UPC) indicates
 
 
 
 
 
 
 
 
 
 
proteinuria ≥2+, a 24-hour urine collection (to assess protein) must be obtained.
  
  
 
 
 
 
 
 
 
 
 
Use of urine dipstick for baseline​ ​renal function assessment is not acceptable. 
8.5 Pregnancy Test (for Women of Child-bearing Potential): ​serum or urine
 
 
 
 
 
 
 
 
 
 
 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta human
 
 
 
 
 
 
 
 
 
 
 
 
chorionic gonadatropin [β-HCG]) within 7 days prior to randomization. Thereafter,
 
 
 
  
 
 
 
 
 
the serum pregnancy test only needs to be repeated if clinically indicated or as
 
 
 
 
 
 
 
 
  
 
 
 
 
required by local regulation 
8.6 Thyroid function test: TSH monitoring; if abnormal, free T4 testing: basal and
 
 
 
 
 
  
 
 
 
 
 
 
every 12 weeks thereafter. 
Hematology Profile, Coagulation Profile and Chemistry Profile (including liver
 
 
 
 
 
 
 
 
 
function) will be assessed at screening, at day 1 before the study drug is
 
 
 
 
 
 
 
 
 
 
 
 
 
 
administered, in weeks 1, 3, 5, 7, 9 and week 12. Thereafter, every treatment visit
 
 
 
 
 
 
  
 
 
 
 
 
 
 
before the study drug is administered (every 4 weeks). 
 
9. Electrocardiogram (ECG): ​A baseline electrocardiogram (ECG) value is to be obtained
 
 
  
 
 
 
  
 
 
 
within 14 days prior to randomization. ECG should be done in week 7 and week 12 and
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
every 8 weeks thereafter. Another determination will be performed at end of treatment visit
  
 
 
 
 
 
 
 
 
 
 
 
 
(28 days after end of treatment). 
10. LVEF determination: (MUGA/ECO) will be performed at baseline and every 12 weeks
 
 
 
 
 
 
 
 
 
 
 
 
 
thereafter or more frequently if clinically indicated. A MUGA scan is the preferred method
 
 
 
  
 
  
 
  
 
 
 
for left ventricular ejection fraction (LVEF) measurement. If a MUGA scan cannot be
 
 
 
 
 
 
 
 
 
 
 
 
 
performed, an echocardiogram should be done. The same type of LVEF assessment must
 
 
 
 
 
 
 
 
 
 
 
 
 
be performed at baseline and at all subsequent points in the study 
A MUGA scan should be performed sooner if a subject develops signs and symptoms of
 
 
 
 
 
 
   
 
 
 
 
 
 
congestive heart failure (ie, shortness of breath during mild exertion or when lying down,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
feeling very tired, cough (especially at night), swelling of the feet and/or ankles). 
11. Tumor specimen collection: ​Tumor specimen will be collected during the screening
 
 
 
 
 
 
 
 
 
 
 
 
period for central pathological review. First diagnosis sample or another more recent
 
 
 
 
 
 
 
 
 
 
 
 
available sample obtained during the routine care previous to study entry will be
 
 
 
 
 
 
 
 
 
 
 
 
 
acceptable. Tumor biopsy at study entry will NOT be compulsory but recommended if
 
 
 
 
 
 
 
 
 
 
 
  
clinically acceptable (ex. superficial or easily accessible locations) 
12. Serum from peripheral blood: Serum will be collected from the patient considering
 
 
 
 
 
 
 
 
 
 
 
 
 
the following scheme: 
1. Within 72 hours prior starting the treatment (basal).  
2. Within 72 hours after the first 3 weeks of treatment (day 22). 
3. Within 72 hours after radiological response is documented. 
4. Within 72 hours after progressive disease is documented 
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Serum specimens will be kept at each centre and sent at the end of the study to a central
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
laboratory for translational studies. 
13. Efficacy Assessment (imaging): ​TC or MRI as appropriate. Disease should be
 
 
 
 
 
 
 
 
 
 
 
 
captured and target/non-target identified at baseline. All the baseline disease assessments
 
 
 
 
 
 
 
 
 
 
 
should be completed within 28 days prior to the date of inclusion in the trial. Subsequently,
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
imaging studies required to investigate known disease should be repeated in week 7 and
 
 
 
 
 
 
 
 
 
 
 
  
 
week 12 and every 8 weeks thereafter. Imaging methods will be employed consistently
 
 
 
  
 
 
 
 
 
 
 
 
during the course of each patient’s evaluation during the study. After discontinuation of
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol treatment, patients who have not progressed will still be re-evaluated every 8
 
 
 
 
 
 
 
 
 
 
 
  
weeks, unless they have started a new anti-cancer therapy. 
 
Table 6: Acceptable Imaging Assessment Methods and Technical Requirements 
 
Anatomic region 
Preferred / 
Alternative 
methods 
Technique requirements 
Mandated 
Strongly recommended 
Chest, abdomen 
and pelvis:  
 
Note: ​ ​Scan must 
cover lung apices 
to diaphragm, 
diaphragm 
through entire 
liver and to below 
the pubic 
symphysis.  
CT – preferred 
for chest, 
abdomen and 
pelvis 
 
●
Slice thickness: ≤7.5 
mm (reconstruction 
interval equal to slice 
thickness, i.e. no gap) 
although ≤5mm is 
strongly 
recommended  
●
Use intravenous (i.v.) 
contrast for 
abdomen/pelvis 
unless 
contraindicated. 
●
Multi-slice CT 
●
Slice thickness: ≤5mm (reconstruction 
interval) 
●
Iodine contrast: 100-150 ml (300 mg 
Iodine/ml) at 2–3 ml/second 
●
Oral contrast: use institutional standard 
MRI – 
alternative for 
abdomen and 
pelvis 
[use CT for 
chest coverage] 
●Use 1.0T and above 
scanner 
●Use gadolinium based 
i.v. contrast (dose = 
0.1mmol/kg) unless 
contraindicated 
●Include both T1 and 
T2-weighted 
sequences with 
T1-weighted both pre 
and post-contrast. 
●
1.5T or 3.0T scanner, phased-array coil 
●
5-8mm scanning 
●
T2-weighted FSE with fat suppression 
pre-contrast. 
●
T1W (2D or 3D) pre and post contrast with fat 
suppression. 
Brain  
MRI - preferred 
●Use of 1.0T and above 
scanner 
●Use gadolinium based 
i.v. contrast (dose = 
0.1mmol/kg) unless 
contraindicated 
●1.5T or 3.0T scanner with head coil 
●T1 weighted (pre and post contrast) and T2 
weighted (pre contrast) axial scans.  
●Further details as per institutional standard. 
CT - alternative 
●Use i.v. contrast unless 
contraindicated  
●Per institutional standard  
Bone 
●
Bone scintigraphy is preferred, although PET (18F-fluoride NaF or FDG) and 99m
 
 
 
 
 
 
 
 
 
 
 
 
Technetium SPECT is acceptable as an alternative.  
●
Hotspots indicative of metastases must be investigated with X-ray, CT or MRI.  
●All scans generated should be exportable in electronic format (DICOM) to enable secure and 
rapid electronic transmission to the designated central imaging laboratory. 
●The same modality for a given anatomical coverage and the same scanning procedure (most 
 
 
 
 
 
 
 
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importantly: reconstruction slice thickness, anatomic coverage, use of i.v contrast) should be 
consistent between baseline and all subsequent follow up scanning. If possible, the same 
scanner or an equivalent scanner should be used throughout the study. 
 
 
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Table 7: Disease Assessment Scope and Schedules 
Anatomic 
Region & 
Assessment 
Modality​1, 2 
Baseline​3 
Following First Dose​4  
Chest, abdominal 
and pelvic CT or 
MRI 
To be performed on all 
subjects. 
To be performed on all subjects in week 7 and week 
12 every 8 weeks thereafter. 
Head CT or MRI 
Screening with CNS 
imaging studies (computed 
tomography [CT] or 
magnetic resonance 
imaging [MRI]) is required 
only if clinically indicated or 
if the subject has a history 
of CNS metastases. ​Note: 
subjects with a positive 
scan must be excluded from 
the study with the exception 
of those subjects meeting 
criteria in footnote 5 ​5   
To be performed only as clinically indicated. 
Bone Scan 
To be performed only as 
clinically indicated 
1) To be performed only as clinically indicated (i.e. 
subject is symptomatic with bone pain).  
 
●
The following information must be documented: date of assessment, diagnostic technology
 
 
 
 
 
 
 
 
 
 
 
used for each anatomic region (e.g. chest spiral CT), description of the type and site of a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
lesion (e.g. liver mass). 
●
The same method, technique should be used to characterize each identified lesion at
 
 
 
 
 
 
 
 
 
 
 
 
 
baseline and subsequent disease assessments.  
●
All the baseline disease assessments should be completed within 28 days prior to the date
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of inclusion in the trial. 
●
Disease assessments should be performed at the indicated frequency following the first
 
 
 
 
 
 
 
 
 
 
 
 
dose until documented disease progression, death or upon initiating another anti-cancer
 
 
 
 
 
 
 
 
 
 
 
treatment, whichever occurs first.  
●
Subjects with CNS metastases at baseline will be excluded from the study with the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
exception of those subjects who have previously-treated CNS metastases (surgery ±
 
 
 
 
 
 
 
 
 
 
 
radiotherapy, radiosurgery, or gamma knife) and meet both of the following criteria: a) are
 
 
 
 
 
 
 
 
 
 
 
 
 
 
asymptomatic and b) have no requirement for steroids or EIACs.  
 
 
 
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14. Treatment control and dispensing:  
●
Treatment control: A record of the number of Pazopanib tablets taken and
 
 
 
 
 
 
 
 
 
 
 
 
returned by each subject should be recorded in patient's medical record and
 
 
 
 
 
 
 
 
 
 
 
 
register in the CRF. 
●
Treatment dispensing: At Pharmacy Service. Adequate number of Pazopanib
 
 
 
 
 
 
 
 
 
tablets for 3 weeks of treatment during the first 12 weeks and for 4 weeks of
 
  
 
 
 
 
 
 
 
 
 
  
 
 
treatment thereafter, should be dispensed. 
15. Survival: ​patient status (alive/dead/lost to follow up) and new anti-cancer therapy. All
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects should be followed until death, if possible. The date of death and cause of death
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
should be evaluated and documented in the eCRF. 
9. ADVERSE EVENTS 
ICH GCP requires that both investigators and sponsors follow specific procedures when
 
 
 
 
 
 
 
 
 
 
 
 
reporting adverse events/reactions in clinical trials. These procedures are described in this
 
 
 
 
 
 
 
 
 
  
 
section of the protocol.  
Any event involving adverse drug reactions, illnesses with onset during the study or
 
 
 
 
 
 
 
 
 
 
 
 
 
exacerbations of pre-existing illnesses should be recorded. 
In addition, clinically significant changes in physical examination findings and abnormal
 
 
 
 
 
 
 
 
 
 
 
objective test findings (e.g., x-ray, ECG) should also be recorded as AE. The criteria for
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
determining whether an abnormal objective test finding should be reported as an AE are
 
 
 
 
 
 
 
 
 
 
 
 
 
 
as follows: 
●
test result is associated with clinically significant symptoms, and/or 
●
test result leads to a change in study dosing or discontinuation from the study,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
significant additional concomitant drug treatment or other therapy, and/or 
●
test result leads to any of the outcomes included in the definition of a SAE, and/or 
●
test result is considered to be an AE by the investigator. 
9.1. Definitions 
The definitions from ICH GCP apply in this trial protocol.  
 
Adverse event (AE) 
An adverse event is any untoward medical occurrence in a patient or clinical investigation
 
 
  
 
 
 
 
  
 
 
 
 
subject which does not necessarily have a causal relationship with the study treatment.  
 
Adverse reaction (AR)  
All untoward and unintended responses to an investigational medicinal product related to
 
 
 
 
 
 
 
 
 
 
 
 
any dose administered. 
 
Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR): 
 
Any untoward medical occurrence or effect that at any dose: 
●
results in death (is fatal), 
●
is life-threatening, 
●
requires or prolongs inpatient hospitalization, 
●
results in persistent or significant disability or incapacity, 
●
is a congenital anomaly or birth defect, or 
GEIS–30_H_V03F_2015-02-11 
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●
is medically significant. 
 
Medical and scientific judgement should be exercised in deciding whether urgent reporting
 
 
 
 
 
 
  
 
 
 
 
is appropriate in other situations such an important medical events that may not be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immediately life-threatening or result in hospitalization but may jeopardize the patient or
 
 
 
 
 
 
 
 
 
 
 
 
may require intervention to prevent one of the outcomes listed in the above definition. 
Any suspected transmission of an infectious agent through the medication is also
 
 
 
 
 
 
 
 
 
 
 
 
considered a SAE. 
 
Additionally, for the purpose of this study it will be consider as SAEs, all
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hepatotoxicities as follows: 
 
1) ALT >3.0 x ULN with concomitant elevation in bilirubin (defined as total bilirubin ≥
 
 
  
 
 
 
 
 
 
 
 
 
  
2.0 x ULN, with direct bilirubin >35%) or with hypersensitivity symptoms (e.g., fever,
  
 
 
 
 
 
 
 
 
 
 
 
rash) – bilirubin fractionation should be performed if testing available 
 
2) ALT >8.0 x ULN without bilirubin elevation (defined as total bilirubin <2.0 x ULN or
 
 
  
 
 
 
 
 
 
 
 
  
 
 
direct bilirubin ≤35%) and without hypersensitivity symptoms (e.g., fever, rash) –
 
  
 
 
 
 
 
 
 
  
bilirubin fractionation should be performed if testing available 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
A SUSAR is a SAR that is classified as ‘unexpected’ i.e. a serious adverse reaction, the
 
 
  
 
 
 
 
 
 
  
 
 
 
 
nature and severity of which is not consistent with the information about the medicinal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
product in question set out in the summary of product characteristics for that product.  
 
Last version of Summary of Product Characteristic available in EMEA website, will be the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
reference document to establish the AE expectedness for Pazopanib. 
 
Life Threatening Event  
It is any event in which the subject was at risk of death at the time of the event; it does not
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
refer to an event which hypothetically might have caused death if it were more severe. 
 
Hospitalization / Prolongation of Hospitalization 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs or
 
 
 
 
 
 
 
 
 
 
 
worsens during the course of a patient’s participation in a clinical study must be reported
 
 
 
 
  
 
 
  
 
 
 
 
 
as a serious adverse event. Prolongation of hospitalization is defined as any extension of
  
 
 
 
 
 
  
 
 
 
 
 
an inpatient hospitalization beyond the stay anticipated/required for the initial admission,
 
 
 
 
 
 
 
 
 
 
 
as determined by the investigator or treating physician. 
 
 
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Hospitalizations that do not meet criteria for serious adverse event reporting are:  
a)
Reasons
described
in
protocol
(e.g.,
drug
administration,
protocol-required
 
 
 
 
 
 
 
 
 
investigations). Hospitalizations or prolonged hospitalization for a complication of therapy
 
 
 
 
 
  
 
 
 
administration or procedures will be reported as Serious Adverse Event. 
b) Hospitalization or prolonged hospitalization for technical, practical or social reasons, in
 
 
 
 
 
 
 
 
 
 
 
 
absence of an adverse event. 
c) Pre-planned hospitalizations (i.e., planned before study entry). Any surgery or
 
 
 
 
 
 
 
 
 
 
 
procedure planned before study entry must be documented on the case report form. 
 
Unexpected Adverse Reaction 
An unexpected adverse reaction, the nature or severity of which is not consistent with the
 
 
 
 
 
 
 
 
 
  
 
 
 
 
applicable product information. 
 
Last version of Summary of Product Characteristic available in EMEA website, will
 
 
 
 
 
 
 
 
 
 
 
 
be the reference document to establish the AE expectedness for Pazopanib. 
 
Associated with the use of the drug 
An adverse event is considered associated with the use of the drug if the causality
 
 
 
 
 
 
 
 
 
 
 
  
 
 
assessment is related to study drug or is unknown according to definitions listed below 
 
Causality Assessment 
The investigator must provide an assessment of causality of each study drug, including
 
 
 
 
 
 
 
 
 
 
 
 
 
products in combination and comparators, according to the following criteria: 
Y
There is a reasonable chance that the study drug(s) caused the SAE. 
N
There is not a reasonable chance that the study drug(s) caused the SAE and other
  
  
 
 
 
 
 
 
 
 
 
 
 
causes are more 
likely.  
UK
Unknown. It should only be used in special situations where the investigator has
  
 
 
 
 
 
 
 
 
 
 
 
insufficient 
information (e.g. the patient was not attended in his/her centre) and when
 
 
 
 
 
 
 
 
 
 
 
 
none of the above options can be utilized. 
9.2. Reporting of Adverse Events 
The sponsor will collect AEs up to 30 days after administration of the last dose of study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
drug. 
All adverse events must be recorded using medical terminology in the source document
 
 
 
 
 
 
 
 
 
 
 
 
 
and the CRF. Investigators must assess the severity (grade) of the event following
 
 
 
 
 
 
 
 
 
 
 
 
 
NCI-CTCAE V 4.0 Criteria and assign a relationship to study therapy and pursue and
 
 
 
 
 
  
 
 
 
 
 
 
 
obtain information adequate both to determine the outcome and to assess whether it
 
 
 
 
 
 
 
 
 
 
 
  
meets the criteria for classification as a SAE requiring immediate notification. The
 
 
 
 
 
 
 
 
 
 
 
 
investigator must provide any information as requested by sponsor in addition to that on
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the CRF. 
Any serious adverse events which occur from patient informed consent signature, during
 
 
 
 
 
 
 
 
 
 
 
 
the clinical study or within 30 days of receiving the last dose of study medication, whether
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
or not related to the study drug, must be reported by the investigator. In addition, any
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs which occur as a result of protocol specific diagnostic procedures or interventions
 
 
 
  
 
 
 
 
 
 
 
 
must also be reported.
Beyond this period of time, only those SAEs suspected to be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
related to the study drug will be reported. 
All SAEs suspected to be related to study treatment should be followed after the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment/study withdrawal until the event or its symptoms have resolved or stabilized at a
 
 
 
 
 
 
 
 
 
 
 
 
  
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grade acceptable to the Investigator, Chief investigator and/or Sponsor.  
Site investigation staff should notify the sponsor, all the pregnancies of female subjects
 
 
 
 
 
 
 
 
 
 
 
 
 
and female partners of male subject that occurred during the clinical trial within 24 hours
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from becoming aware. Site investigation staff, should also communicate the outcome of
 
 
 
 
 
 
 
 
 
 
 
 
the pregnancy within 24 hours since the awareness. 
The cause of death of a deceased patient in a clinical trial, whether the case of an
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expected event or associated with the investigational agent, is considered an SAE and
 
 
 
 
 
 
 
 
 
 
 
 
 
therefore must be communicate using the SAE form. The autopsy report should be sent to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor identified only with the patient inclusion number. 
 
For the purpose of this study it will be consider as SAEs, all hepatotoxicities as
 
 
 
 
 
  
 
 
 
 
 
 
 
 
follows: 
 
1) ALT >3.0 x ULN with concomitant elevation in bilirubin (defined as total bilirubin ≥
 
 
  
 
 
 
 
 
 
 
 
 
  
2.0 x ULN, with direct bilirubin >35%) or with hypersensitivity symptoms (e.g., fever,
  
 
 
 
 
 
 
 
 
 
 
 
rash) – bilirubin fractionation should be performed if testing available 
 
2) ALT >8.0 x ULN without bilirubin elevation (defined as total bilirubin <2.0 x ULN or
 
 
  
 
 
 
 
 
 
 
 
  
 
 
direct bilirubin ≤35%) and without hypersensitivity symptoms (e.g., fever, rash) –
 
  
 
 
 
 
 
 
 
  
bilirubin fractionation should be performed if testing available 
 
 
All serious adverse events must be reported by fax within 24h to 
MFAR, S.L. 
by fax  (+ 34 93 253 11 68) or e-mail to ​investigacion@mfar.net 
 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the
 
 
 
 
  
 
 
 
 
 
 
 
 
adverse events in question. Where applicable, information from relevant hospital case
 
 
 
 
 
 
 
 
 
 
 
records and autopsy reports should be included. Follow-up information should be
 
 
 
 
 
 
 
 
 
 
 
forwarded to MFAR S.L. within 24 hours. 
All SAEs suspected to be related to study drug must be followed up after the time of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy discontinuation until the event or its consequences resolve or stabilize at an
 
 
 
 
 
 
 
 
 
 
 
 
 
acceptable level for the investigator, the Trial Chief Investigator and/or Sponsor. 
9.3 SUSAR Expedited reporting by the Sponsor 
The Sponsor will be responsible for the reporting of SUSARs to regulatory authorities. The
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor will follow the procedure detailed in current version of the document "Detailed
 
 
 
 
 
 
 
 
 
 
 
 
 
guidance on the collection, verification and presentation of adverse reaction reports arising
 
 
 
 
 
 
 
 
 
 
 
 
from clinical trials on medicinal products for human use“ available at EMEA website. 
All suspected unexpected serious adverse reactions (SUSAR) will be reported in
 
 
 
 
 
 
 
 
 
 
 
accordance with current regulations on clinical trials in Europe, to the competent authority
 
 
 
 
 
 
 
 
 
 
 
 
 
and EC and Investigators within the time and procedure established by the “Detailed
 
 
 
 
 
 
 
 
 
 
 
 
 
guidance on the collection, verification and presentation of adverse reaction reports arising
 
 
 
 
 
 
 
 
 
 
 
 
from clinical trials on medicinal products for human use” and following any local
 
 
 
 
 
 
 
 
 
 
 
 
 
regulations. 
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9.3.1 Terms of SUSAR expedited notification to regulatory 
authorities 
The maximum period for reporting shall be 15 calendar days from first knowledge by the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sponsor of the suspected adverse reaction. When the suspected serious unexpected
 
 
 
 
 
 
 
 
 
 
 
adverse reaction is fatal or life-threatening, the sponsor shall notify within a maximum of 7
 
  
 
 
 
 
 
 
 
  
 
  
calendar days from first knowledge by the sponsor of the case. This information must be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
completed as far as possible within eight additional calendar days. This information should
 
 
 
 
 
 
 
 
 
 
 
 
 
include an assessment of the importance and implication of the findings, including relevant
 
 
 
 
 
 
 
 
 
 
 
 
 
previous experience with the same or similar medication. 
9.3.2 Expedited Reporting, other relevant safety information 
The sponsor shall notify (as soon as possible and no later than 15 days) any information
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
which would alter the risk / benefit of the investigational drug, or to determine changes in
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
dosage schedule or conduct of trial, for example: 
●
A qualitative change or an increase in the percentage of occurrence of the SAR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expected, it is considered clinically significant. 
●
The SUSAR occurring after completion of a clinical trial reported by the investigator
 
 
 
 
 
  
 
 
 
 
 
 
to the sponsor. 
New information concerning the conduct of the trial or investigational drug development
 
 
 
 
 
 
 
 
 
 
 
 
and likely to affect the safety of subjects, including: 
●
Serious adverse events that may be associated with the test procedures and can
 
 
 
 
 
 
 
 
 
 
 
 
 
modify the performance thereof. 
●
A significant risk to subjects such as lack of efficacy of an investigational drug used
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to treat a life threatening illness. 
●
Relevant safety new findings from animal studies (as formation of cancer). 
●
Any premature termination or temporary closure of a clinical trial with the same
 
 
 
 
 
 
  
 
 
 
 
 
investigational drug for safety reasons, made in another country and by the same
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor. 
●
The Severe Adverse Reaction related solely to non IMP considered relevant (as
 
 
 
 
 
 
 
 
 
 
 
 
they are not subject to the general rules for expedited reporting of individual cases
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of SUSAR). 
Furthermore, if relevant information is obtained, it will be notified as soon as possible. 
9.3.3 Notification to Investigators: 
The Sponsor shall report the Investigators any information that may affect the safety of trial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects, as soon as possible. 
In addition, the Sponsor shall inform the researchers of the safety issues that impact the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
conduct
of clinical trials or product development, including development program
 
 
 
 
 
 
 
 
 
 
interruption or changes to safety-related protocol issues. 
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10. STATISTICAL CONSIDERATIONS 
10.1. Study Endpoints 
10.1.1. Primary Efficacy Endpoint 
The primary end-point of the study is progression free survival 12 weeks after start of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy, measured as a binary variable. This will be based on the disease evaluation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
performed 12 weeks after start of treatment with central radiology review. Patients who are
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alive and progression free at this time will be considered as successes. Patients who have
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progressed or are dead at this time will be considered as failure. Patients with an unknown
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression status will be considered as failure. The diagnosis of progression should be
 
 
 
 
 
 
 
 
 
 
 
 
 
based on tumor measurements, according to the RECIST 1.1 criteria. 
10.1.2. Secondary Endpoints 
Overall progression free survival (median PFS) 
Overall progression free survival will be computed from the date of start of treatment to the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
first documented date of progression or the date of death, whatever the cause. Patients
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alive and free from progression at the time of the analysis will be censored at the date of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
last follow-up.  
 
Objective tumor response  
Objective tumor response, measured according to the RECIST 1.1 criteria, will be used as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
secondary end-point in this trial. 
 
Response criteria are essentially based on a set of measurable lesions identified at
 
 
 
 
 
 
 
 
 
 
 
 
 
baseline as target lesions, and followed until disease progression.  
 
Time to onset of response 
It will be computed from the date of start of treatment to the time of first documented
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response. 
 
Duration of response 
It will be computed from time of attaining response to the time of first documented
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression or death. 
 
Overall survival (OS) 
It will be computed from the date of start of treatment to the date of death, whatever the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cause. Patients alive or lost for follow-up at the time of the analysis will be censored at the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
date of last follow-up. 
 
Clinical benefit rate  
Patients who achieve CR, PR, or SD for 6 months or more and an improvement of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms will be considered as having derived clinical benefit. 
 
Growth Modulation Index (GMI) 
GMI is the ratio between time to progression (TTP) with pazopanib (TTPp) divided by the
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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TTPp-1 with the previous line of therapy. 
 
Safety profile (according CTCAE, version 4.0) 
 
The safety and tolerability of Pazopanib will be determined by means of type, incidence,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
severity, timing, seriousness, and relatedness; of reported AEs, physical examinations,
 
 
 
 
 
 
 
 
 
 
and laboratory tests. Toxicity will be graded and tabulated by the NCI-CTCAE v 4.0.  
10.2. Efficacy assessment  
Disease should be captured and target/non-target identified at baseline by CT or MRI as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
appropriate. Subsequently, imaging studies required to investigate known disease should
 
 
 
 
 
 
 
 
 
 
be performed on week 6/7, on week 12 and every 8 weeks thereafter. Imaging methods
 
 
 
 
 
 
 
 
 
  
 
 
 
 
will be employed consistently during the course of each patient’s evaluation during the
 
 
 
 
 
 
 
 
 
 
 
 
 
study. After discontinuation of protocol treatment, patients who have not progressed will
 
 
 
 
 
 
 
 
 
 
 
 
still be re-evaluated every 8 weeks, unless they have started a new anti-cancer therapy,
 
 
 
  
 
 
 
 
  
 
 
 
withdrawal of consent or death, whichever occur first. ​10.2.1. Efficacy assessment
 
 
 
 
 
 
 
 
 
 
 
populations: 
Intent to treat (ITT) analysis: Efficacy analysis will be carried out in the ITT population. All
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients participating in the study will be included in the analysis of efficacy. 
Per Protocol (PP) analysis: Efficacy analysis will be carried out in per protocol population.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All patients participating in the study and received at least 3 weeks of treatment with
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Pazopanib with no major protocol deviations will be included in the analysis of efficacy. 
10.3. Safety assessment  
Any patient included in the study receiving at least a single dose of study medication will
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
be evaluable for the toxicity analysis. 
Safety profile will be characterized by treatment-emergent Adverse Events (TEAE), vital
 
 
 
 
 
 
 
 
 
 
 
signs and laboratory abnormalities. Assessment of adverse events will include type,
 
 
 
 
 
 
 
 
 
 
 
incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology
 
 
 
 
 
 
 
 
 
 
 
Criteria for Adverse Events [CTCAE], Version 4.0), timing, seriousness, and relatedness;
 
 
 
 
 
 
 
 
 
 
 
and laboratory abnormalities. Baseline tumor-related signs and symptoms will be recorded
 
 
 
 
 
 
 
 
 
 
 
as adverse events during the trial if they worsen in severity or increase in frequency. 
In each study visit all adverse events will be registered according to NCI-CTC version 4.0 
10.4. Sample Size and Statistical analysis 
The drug will be separately investigated in the following liposarcoma subtypes: 
●
Well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT-WD) 
●
Myxoid/round cell liposarcoma.  
The Simon two-stage design will be separately applied in each stratum. A total of 17
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients will be included in each stratum for the first step of the trial. For the second step,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 (up to 37) additional patients will enter in each stratum provided the results of the first
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
step were positive. A total of 37 patients could enter the study in each stratum.  
Success will be defined as documented disease stabilization or response after at least 12
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks of therapy.  
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The following design characteristics and decision rules apply separately to each stratum.
 
 
 
 
 
 
 
 
 
 
 
 
The Simon optimal one sample two stages testing procedure (optimal design) will be used
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with the following hypotheses:  
●
Success in 20% of the cases or less in one of the strata will be considered as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
unacceptable, and would not warrant further investigation (null hypothesis). Therefore,
 
 
 
 
 
 
 
 
 
 
the value of P0 will be taken as 20%.  
●
Success in 40% of the cases or more in one of the strata will be considered as an
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
acceptable result warranting further investigation of the drug in this histology
 
 
 
 
 
 
 
 
 
 
 
(alternative hypothesis). Therefore, the value of P1 will be taken as 40%.  
These two reference values are based on a retrospective analysis of the EORTC STBSG
 
 
 
 
 
 
  
 
 
 
 
 
 
database of patients treated with 2nd line therapy​ (13)​.  
Under those hypotheses, a total of 37 eligible and treated patients will need to be recruited
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
in each stratum and followed for at least 12 weeks. The size of the type I and type II errors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
is 10% (alpha=beta=0.1).  
A total of 17 eligible and treated patients will be included (in each stratum) in the first step
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
of the study.  
1.
If ≤3 successes are observed in a stratum, the trial will be stopped in this stratum
   
 
 
 
  
 
 
 
 
 
 
 
 
 
with the conclusion that the drug should not be further investigated in this histology.  
2.
Else, patients will continue to be accrued until 37 eligible patients have been
 
 
 
 
 
 
 
 
 
 
 
 
 
recruited and have started therapy. If 11 or more successes are observed in those
 
 
 
 
  
 
 
 
 
 
 
 
 
37 patients, we will conclude that the results of this trial warrant further investigation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in this histology.  
In addition, sequential tests for each cohort combined with overall futility test will be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
performed after the first stage accrual is achieved, as described by LeBlanc et al​(14)​. This
 
 
 
 
 
  
 
 
 
 
 
 
 
 
procedure allows for stopping a subgroup for futility keeping error rates. 
PFS and OS will be calculated from the date of treatment initiation and will be estimated by
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the Kaplan-Meier method in each stratum. Due to the rarity of the disease, patients will be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
allowed to get in the study while the first stage analysis is being performed unless
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
otherwise advised by safety or futility sequential test for each cohort. 
 
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11. LEGAL AND ETHICS CONSIDERATION 
11.1. Ethic Committee 
This study will be conducted in accordance with the ethical principles that have their origin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in the Declaration of Helsinki adopted by the 18​th World Medical Association General
 
 
 
 
 
 
 
 
 
 
 
 
 
Assembly, Helsinki, Finland. 
The study will be carried out in conformity with the requirements of the “Declaration of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Helsinki” adopted by the 18​th World Medical Association General Assembly held in
 
 
 
 
 
 
 
 
 
 
 
 
Helsinki, Finland, June 1964 and revised by the 29th World Medical Association General
 
 
 
 
 
 
 
 
 
 
 
 
 
Assembly held in October 1975 in Tokyo, the 35​th World Medical Association General
 
 
 
 
 
 
 
 
 
 
 
 
 
Assembly held in Venice in October 1983, the 41​st World Medical Association General
 
 
 
 
 
 
 
 
 
 
 
 
 
Assembly celebrated in Hong Kong in 1989, the 48​th World Medical Association General
 
 
 
 
 
 
 
 
 
 
 
 
 
Assembly held in Somerset West, South Africa in October 1996, the 52​nd World Medical
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Association General Assembly celebrated in Edinburgh, Scotland in October 2000, the 59​th
 
 
 
  
 
  
 
 
 
 
World Medical Association General Assembly held in Seoul, Korea, October 2008 (Annex
 
 
 
 
 
 
 
 
 
 
 
 
XII); the Good Clinical Practice (GCP) norms issued by the working group on the Efficacy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of
Medicinal
Substances
of
the European Union (1990) (CPMP/ICH/135/95) and
 
 
 
 
 
 
 
 
 
 
applicable regulatory requirements and laws on the country where the Trial is taking place. 
According to Directive 95/46 of the European parliament and 2001/20 /EC by which the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
requirements to perform a clinical trial are established, the information obtained in the
 
 
  
 
 
 
 
 
 
 
 
 
course of the clinical trial, will only be able to be used by the clinical trial sponsor to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluate the results according to the mentioned regulation. 
11.2. Authorities 
The study protocol and/or related documents will be submitted to regulatory authorities
 
 
 
 
 
 
 
 
 
 
 
 
before commencement of the clinical trial, as national authorities on the country where the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
trial is taking place require. 
11.3. Informed consent 
The patient should sign 2 separate informed consents: one for the clinical trial and another
 
 
 
  
 
 
 
 
 
 
 
 
 
 
for biological samples studies. 
The clinician will have to explain the nature, objectives and possible consequences of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical trial in a manner that is understandable by the patient. 
The patient must give his/her consent before being admitted into the study and before
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biological samples are taken. 
The study subject will provide his/her consent, signing by duplicate the appropriate model.
 
 
 
 
 
 
 
 
 
 
 
 
 
For this purpose, each model must carry the signature of investigator and patient. The
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator will retain one copy of the original of each patient’s signed consent form.  
The investigator will not start any investigation related with the study until the consent has
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
been obtained.  
The informed consent form used in this study, and any changes made during the course of
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
the study, must be prospectively approved by the Ethics Committee.  
11.4. Confidentiality 
In order to warrant the confidentiality of study data according to Directive 95/46 of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
European parliament and 2001/20/EC, personal and clinical data can only be accessed by
 
 
 
 
 
 
 
 
 
 
 
 
 
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the Sponsor of the study or its designated staff, for monitoring/auditing purposes, the
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator and team of collaborators, the Ethics Committee of the investigational site, or
 
 
 
 
 
 
 
 
 
 
 
 
 
the one overseeing the centre, and pertinent Health Authorities. 
The investigator should facilitate access to the source documents and data for monitoring
 
 
 
 
 
 
 
 
 
 
 
 
 
and auditing purposes. 
The content of the case report forms (CRF), as well as the documents generated during
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the study will be protected from non permitted uses by persons not involved in the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigation, and will therefore be considered strictly confidential and not revealed to third
 
 
 
 
 
 
 
 
 
 
 
 
 
parties, except those specified in the previous paragraphs. 
11.5. Insurance Policy 
The insurance or indemnity in accordance with pertinent regulatory requirements will be
 
 
 
 
 
 
 
 
 
 
 
 
provided. 
All patients in this study are insured through the Insurance Company HDI International with
 
  
 
 
 
 
 
 
 
 
 
 
 
an insurance policy that satisfies the conditions stipulated by the RD 223/2004 in Spain. 
11.6. End of the study 
The study will be considered closed from a normative point of view after data on primary
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
and secondary variables are sufficiently prepared for its initial publication.  
11.7. Early study termination 
This study can be terminated prematurely if in the opinion of the sponsor there is a
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
reasonable and sufficient cause. The investigator will receive a written notification in which
 
 
 
 
 
 
 
  
 
  
 
the sponsor motivates the interruption of the study. Reasons that justify are as follows, but
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
not limited to: 
●
Finding of unforeseen, considerable or unacceptable risks for the patients. 
●
Impossibility to include an acceptable number of patients. 
●
Insufficient compliance with protocol requisites. 
●
Plans to modify halt or discontinue the development of study drug. 
●
In case of early termination of the study, all the study material (blank or totally or
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
partially filled out CRF, study drugs, etc) must be returned to GEIS. 
 
 
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12. PRACTICAL CONSIDERATIONS 
12.1. Diagnostic Criteria for the Study Disease 
Patients included on this trial should have histological confirmed diagnosis of high or
 
 
 
 
 
 
 
 
 
 
 
 
 
intermediate grade malignant liposarcoma with metastatic or locally advanced disease.
 
 
 
 
 
 
 
 
 
 
Patient must have documentation of disease progression within 6 months prior to study
 
 
 
 
 
 
 
  
 
 
 
 
entry documented as progressive by CT scan or MRI. Prior scans will be used to classify
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the patient as having progressive disease at baseline according to RECIST 1.1 criteria. 
Paraffin embedded tumour blocks/slides will be collected for all patients for a central
 
 
 
 
 
 
 
 
 
 
 
 
 
pathological review. First diagnosis sample or another more recent available sample
 
 
 
 
 
 
 
 
 
 
 
obtained during the routine care previous to study entry will be acceptable. Tumour biopsy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at study entry will NOT be compulsory but recommended if clinically acceptable (ex.
 
 
 
 
 
 
 
 
  
 
 
 
superficial or easily accessible locations). The central pathological review is a pre-requisite
 
 
 
 
 
 
 
 
   
 
for entering the trial; the study treatment should not be initiated unless the diagnosis is
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
confirmed by means of the central pathological review.  
12.2. Responsibilities according to Good Clinical Practice 
Investigator Responsibilities 
Responsibilities of the principal investigator of each participating centre include: 
●
To sign the study protocol. 
●
To know in depth all study drugs characteristics. 
●
To obtain informed consent of subjects before inclusion in the trial. 
●
To ensure that adequate medical care is provided to a subject for any adverse
 
 
 
 
 
 
 
 
  
 
 
 
 
events, including clinically significant laboratory valued, related to the trial. 
●
Collect, register and notify data in a correct way. 
●
To notify immediately to the sponsor all SAE and unexpected adverse events. 
●
To take responsibility that all people involved in the trial will respect the
 
 
 
 
 
 
 
 
 
 
 
 
 
confidentiality of any information about the study subjects. 
●
To keep the Ethics Committee regularly informed on the facts of the study. 
●
To take responsibility on the elaboration of the final study report, providing his/her
 
 
 
 
 
 
 
 
 
 
 
 
 
agreement and signature. 
For German Investigator Responsibilities see also Annex VII 
12.3. Instructions for e-CRF completion 
The data will be recorded GCP-compliantly by means of the electronic documentation
 
 
 
 
 
 
 
 
 
 
 
 
system (electronic CRFs) at the study centre. 
The application is designed to be entirely server-based. All stages in the processing, with
 
  
 
 
 
 
 
 
 
 
 
 
 
the exception of the actual data entry and display, are performed centrally on a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
web/database server. In particular, data storage will be undertaken exclusively centrally.
 
 
 
 
 
 
 
 
 
 
 
The server is housed at "Centro de Proceso de Datos de InterHost en Madrid, calle
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albasanz, 71" 
For data entry and print-outs, the system is based fully on the so-called "web interface",
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i.e. entry forms and reports are displayed on the client computer as HTML pages (Hyper
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Text Markup Language = standard page description language on the Internet) within a
 
 
  
 
 
 
 
 
 
 
  
Web browser. No user-specific software is necessary to operate the system on the
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator’s client computer. There is the possibility of direct access to the raw data by
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
means of ODBC for further processing of the data. 
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The data are checked for correctness by ranks and validity and consistency checks.
 
 
 
 
 
 
 
 
 
 
 
 
 
Implausible or missing data can be corrected or supplemented following discussion with
 
 
 
 
 
 
 
 
 
 
 
 
the investigator. The correction documents are stored (audit trail). 
Other than the investigator, only expressly authorised persons trained for the study may
 
 
 
 
 
 
 
 
 
 
 
 
 
complete the e-CRF.  
All data in the e-CRF should be able to be documented in measurement records or by
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
entry in patient records.  
12.4. Supply of Study Drugs 
Pazopanib will be supplied by the Sponsor. 
12.5. Packaging and labelling  
The study drugs labels will contain all the information to comply with standing regulatory
 
 
 
 
 
 
 
 
 
 
 
 
 
 
requirements. 
12.6. Final report and Publications 
12.6.1. Clinical Trial Publication 
The final publication of the trial results will be written by the Chief Investigator on the basis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of the final analysis performed at the ​Institut de Recerca del Hospital Universitari Vall
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d'Hebrón, Barcelona (Vall d' Hebrón Universtary Hospital Research Institute, Barcelona).  
A draft manuscript will be submitted by the Chief Investigator, other co-authors (including
 
 
 
 
 
 
 
 
 
 
 
 
 
the Clinical Study Coordinator in Germany) and ​GlaxoSmithKline for review no later than
 
 
 
 
 
 
 
 
 
 
 
 
 
six months after receiving the Data Center report (final analysis). After revision by the Data
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Center, other co- authors (including the Clinical Study Coordinator in Germany) and
 
 
 
 
 
 
 
 
 
 
 
 
GlaxoSmithKline​, the manuscript will be sent to a major scientific journal. Results obtained
 
 
 
 
 
 
  
 
 
 
 
 
in the different strata may be separately published. 
Regarding authorship, institutional entry of 5% of evaluable patients in the study results in
 
 
 
 
 
 
 
 
 
 
 
 
  
qualification for one authorship (two names for 20% entry, up to the number of authors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
allowed by the journal). The reference pathologist, radiologist and statistician, who have
 
 
 
 
 
 
 
 
 
 
 
 
contributed to the trial, will be included in the authorship of the final manuscript.  
The sequence of the authors in publication will be: Chief investigator (first), subsequent
 
 
 
 
 
 
 
 
 
 
 
 
 
authors according to the number of patients, Clinical Study Coordinator in Germany (last). 
The title of all manuscripts will include ​“GEIS and GISG”​, and all manuscripts will include
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
an
appropriate
acknowledgement
section,
mentioning
all
investigators
who
have
 
 
 
 
 
 
 
 
 
contributed to the trial, the data centre staff involved in the study, as well as supporting
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
bodies (Sponsor's Partner, etc...).  
All publications (papers, abstracts, presentations...) including data from the present trial
 
 
 
 
 
 
 
 
 
 
 
will be submitted for review to all co-authors prior to submission. They will also be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
submitted to ​GlaxoSmithKline allowing a period of at least 30 days for review (at least 5
 
 
 
  
 
 
 
 
 
 
 
 
 
  
working days for abstracts). They will not include either ​GSK confidential information other
 
 
 
 
 
 
 
 
 
 
 
 
 
than the study results or personal data on any patient, such as name or initials. 
The Chief Investigator and the Clinical Study Coordinator in Germany must approve all
 
 
 
 
 
 
 
 
 
 
 
 
 
publications, abstracts and presentations of data pertaining to patients included in this
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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study. 
This is applicable to any individual patient registered/randomized in the trial, or any
 
 
 
 
 
 
 
 
 
 
 
 
 
subgroup of these.  
Such a publication cannot include any analysis of any of the study end-points unless the
  
 
 
 
 
 
 
 
 
 
 
 
 
 
final results of the trial have already been published by the​ ​Chief Investigator. 
12.6.2. Translational Research Publication 
Results of the translational research project will be published in major scientific journals,
 
 
 
 
 
 
 
 
 
 
 
 
 
after the publication of the main results of the clinical study. 
The first author will be the Translational Study Coordinator. All centres that have
 
 
 
 
 
 
 
 
 
 
 
 
 
contributed to at least 5% of the analysed material will be represented in the publication by
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
one co-author; centres that have contributed to at least 15% of the analysed material will
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be represented by two co-authors; this(these) author(s) will be selected by each centre
 
 
 
 
 
 
 
 
 
 
 
 
 
internally (pathologist, molecular biologist, clinician...). All centres that have provided
 
 
 
 
 
 
 
 
 
 
material for the analysis will be acknowledged. The list of authors will also include the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chief Investigator and the Clinical Study Coordinator in Germany. 
The clinical trial will be registered in "clinicaltrials.gov", database of National Institute of
 
 
 
 
 
 
 
 
 
 
 
 
 
Health of United States of America. 
12.7. Monitoring 
The study will be monitored by regular site visits, telephone calls and periodic inspection of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the CRF with enough frequency to ascertain the following: 
 
●
Investigational Products (IPs): storage conditions, that the supplies are sufficient
 
 
 
 
 
 
 
 
 
 
throughout the trial. 
●
Rate of patient inclusion. 
●
Compliance with approved protocol and all approved amendment, if any. 
●
That the investigator receives all documents and all trial supplies needed to conduct
 
 
 
 
 
 
 
 
 
 
 
 
 
the trial properly and to comply with the applicable regulatory regulations. 
●
That the investigator and trial staff is adequately informed about the trial. 
●
Integrity and accuracy of data (as per monitoring plan): 
▪
Consent Informed (version, signature and date) 
▪
Eligibility criteria 
▪
Baseline tests 
▪
SAE and SAE reporting 
▪
Primary endpoint 
▪
Biological Samples storage and collection 
▪
Stock reconciliation in pharmacy. 
●
CRFs completion and adverse events collection. 
●
Reporting of protocol deviations according GCPs and the applicable regulatory local
 
 
 
 
 
 
 
 
 
 
 
requirements. Taking appropriate action to prevent recurrence to the detected
 
 
 
 
 
 
 
 
 
 
deviations. 
 
Monitoring visits will be done by study monitors. It is understood that these monitors will
 
 
 
 
 
 
 
  
 
 
 
 
 
 
have access to the clinical records after asking the investigator. Adequate time for these
 
 
 
 
 
 
 
 
 
 
 
 
 
 
visits should be allocated by the Investigator. The Investigator will also ensure that the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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monitor is given direct access to the documents. 
12.8. Protocol Amendments 
Supplements and changes to the protocol can be performed exclusively by the Sponsor,
 
 
 
 
 
 
 
 
 
 
 
 
 
who must submit them to the Ethics Committee and the local Regulatory Authority protocol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
amendments. 
 
12.8.1 Amendment 1 
The 1st amendment modify the schedule in the monitoring of plasma hepatotoxicity and
 
 
 
 
 
 
 
 
 
 
 
 
 
therefore in the schedule of visits. It does not increase the number of visits. These
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
modifications are implemented in Protocol version 2.0 April 8, 2013. 
 
12.8.1 Amendment 4 
New safety information about pazopanib is included in the protocol version 3.0 February
 
 
 
 
 
 
 
 
 
 
 
 
 
11, 2015. 
12.9. Data Handling 
All data (personal, clinical, economic, derived from biologic material) obtained from
 
 
 
 
 
 
 
 
 
 
 
patients will be handled according to the Directive 95/46/EC of the European Parliament
 
 
 
 
 
 
 
 
 
 
 
 
 
and of the Council of 24 October 1995 on the protection of individuals with regard to the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
processing of personal data. According to such legislation, patients will be able to exert
 
 
 
 
 
 
 
 
 
 
 
 
 
 
their rights to access, modification, opposition and cancellation of their data, for which the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical trial physician must be addressed. The content of the CRFs, as well as the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documents generated during the study will be considered strictly confidential and not
 
 
 
 
 
 
 
 
 
 
 
 
revealed to third parties. 
12.10. Documentation 
The Investigator/Institution should maintain trial documents according to ICH Topic E6
 
 
 
 
 
 
 
 
 
 
 
Section 8, and as required by pertinent regulatory requirements. 
Essential documents should be stored according to ICG GCP guidelines or for a longer
 
 
 
 
 
 
 
 
 
 
 
  
 
period of time, if required by pertinent regulations. 
The original patient data (clinical record) must be kept archived for the time stipulated by
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the study centre regulations. This period should not be less than 15 years. 
 
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13. TRANSLATIONAL STUDY 
PRIMARY OBJECTIVES: 
●
To evaluate the influence of the angiogenic status of the tumor on the response to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib. 
●
To evaluate the serum profile of serum cytokine markers as indicator of response to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib. 
 
SECONDARY OBJECTIVES: 
●
To evaluate microvessel density (MVD) and p53, MDM2, PTEN and VEGF/PDGF
 
 
 
 
 
 
 
 
 
 
 
pathways by IHQ expression and their correlation with prognosis as well as their
 
 
 
 
 
 
 
 
 
 
 
 
 
role as predictive factors to treatment with Pazopanib (Response, PFS and OS). 
●
To evaluate serum levels of several angiogenic factors/cytoquines using Luminex
 
 
 
 
 
 
 
 
 
 
XMAP Technology at baseline, after the first 3 weeks of treatment, at maximum
 
 
 
 
 
 
  
 
 
 
 
 
response and at progression and their predictive value for survival and response to
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment: VEGF-A, PlGF-1, SDF-1 alpha (CXCL12), TNF alpha, IL-8, IL-6, PDGF
 
 
 
 
 
 
 
 
 
 
 
–beta, HGF, E- Selectine, ICAM1, MMP-9 and FGFb. 
●
To analyse PIK3CA mutations in order to demonstrate if those liposarcomas with
 
 
 
 
 
 
 
  
 
 
 
PIK3CA mutations defines a subgroup of patients with differential response to
 
 
 
 
 
 
 
 
 
 
 
Pazopanib.  
 
 
STUDY OF BIOMARKERS: 
 
Paraffin-embedded samples from 74 original tumors and if clinically acceptable (ex.
 
 
 
 
 
 
 
 
 
 
 
superficial or easily accessible locations), tumour biopsy at study entry will be collected
 
 
 
 
 
 
 
 
 
 
 
 
 
and the following analysis will be carried out: 
●
Microvessel density on full sections of the tissue. 
●
Immunohistochemical profile of angiogenic markers and p53, MDM2 and PTEN. 
●
Quantitative RT-PCR of a panel of angiogenic markers. 
 
Serum from peripheral blood will be performed (4 per subject): 
1. Within 72 hours prior starting the treatment (basal). 
2. Within 72 hours after the first 3 weeks of treatment. 
3. Within 72 hours after radiological response is documented. 
4. Within 72 hours after progressive disease is documented. 
 
Methodology: 
a) Microvessel density and immunohistochemistry: Full sections of paraffin-embedded
 
 
 
 
 
 
 
 
 
material will be stained with anti-CD34 or anti-CD31 and evaluated using a light
 
 
 
 
 
 
 
 
 
 
 
 
 
microscope and specific software for measuring microvessesls with no muscular walls. 
Tissue microarrays (TMA) will be constructed containing at least two cores (1.0 mm in
 
 
 
 
 
 
 
 
 
 
 
 
 
 
diameter) from each tissue sample. 
At least the following antibodies will be tested: VEGF, PDGF, VEGFR-1 (flt-1), VEGFR-2
 
 
 
 
 
 
 
 
 
 
 
 
 
(flk-1/KDR), PDGFR-alfa, PDGFR-beta, HIF-1, TSP-1, VE-cadherin, p53, MDM2 and
 
 
 
 
 
 
 
 
 
PTEN.  
Additional tests could be considered depending of new findings or evidences in the field of
 
 
 
 
 
 
 
 
 
 
  
 
 
 
tumor angiogenesis. 
GEIS–30_H_V03F_2015-02-11 
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b) RT-PCR Low density arrays for the expression of angiogenic factors: We will perform an
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA extraction from paraffin embedded material and an RT-PCR low density expression
 
 
 
 
 
 
 
 
 
 
 
 
array containing 94 angiogenesis-related genes will be analysed. These arrays include
 
 
 
 
 
 
 
 
 
 
 
known angiogenesis growth factors like VEGF, and known matrix derived inhibitors such
 
 
 
 
 
 
 
 
 
 
 
 
as endostatin. Additionally, the panel contains markers and targets for angiogenesis and
 
 
 
 
 
 
 
 
 
 
 
 
lymphangiogenesis. 
List of genes included: 
- Angiogenic growth factors (28): ANG, ANGPT1, ANGPT2, ANGPT4, CSF3, CTGF,
 
 
 
 
 
 
 
 
 
 
 
CXCL12, ECGF1, EDIL3, EPHB2, FGF1, FGF2, FGF4, FST, GRN, HGF, IL8, LEP, MDK,
 
 
 
 
 
 
 
 
 
 
 
 
 
PDGFB, PROK1, PTN, TGFA, TGFB1, TNF, VEGF, VEGFB, VEGFC. 
- Angiogenesis inhibitors (37): ADAMTS1, ANGPTL1, BAI1, CHGA, COL15A1, COL18A1,
 
 
 
 
 
 
 
 
 
 
COL4A1, COL4A2, COL4A3, CXCL10, CXCL2, F2, FBLN5, FGA, FLT1, FN1, HSPG2,
 
 
 
 
 
 
 
 
 
 
 
IFNB1, IFNG, IL12A, ITGA4, LECT1, PF4, PLG, PRL, SEMA3F, SERPINB5, SERPINC1,
 
 
 
 
 
 
 
 
 
 
 
SERPINF1, THBS1, THBS2, TIMP2, TIMP3, TNFSF15, TNMD, TNNI1, VASH1. 
- Angiogenesis markers (10): AMOT, ANGPTL2, ANGPTL3, ANGPTL4, CEACAM1,
 
 
 
 
 
 
 
 
 
HEY1, ITGAV, PECAM1, PGK1, XLKD1. 
- Angiogenesis targets (13): EDG1, ENPP2, FLT3, FLT4, ITGB3, KDR, KIT, NRP1, NRP2,
 
 
 
 
 
 
 
 
 
 
 
 
 
PDGFRA, PDGFRB, TEK, TIE1 
- Lymphangiogenesis markers (5): CD44, CDH5, FIGF, FOXC2, PROX1  
- Controls (2): 18S, GAPDH 
 
c) Serum cytokine markers: The Luminex technology will be employed for the analysis of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12
cytokines
[VEGF-A,
PlGF-1,
SDF-1
alpha
(CXCL12),
TNF
alpha,
IL-8,
IL-6,
 
 
 
 
 
 
 
 
 
 
 
PDGF–beta, HGF, E-Selectine, ICAM1, MMP-9 and FGFb]. 
 
d) Analysis of PIK3CA mutations: DNA extraction, amplification of exons 4, 7, 9 and 20 of
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
PIK3CA by PCR and direct sequencing will be performed. 
 
The proposed biomarker study includes analysis of tumor tissue at diagnosis and serum
 
 
 
 
 
 
 
 
 
 
 
 
 
cytokines and growth factors at different phases within the treatment schedule. In the case
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of serum, the kinetic profile of each biomarker will be considered (decreased, constant,
 
 
 
 
 
 
 
 
 
 
 
 
 
increased). All analysed parameters will be correlated with: Progression-free survival
 
 
 
 
 
 
 
 
 
 
(PFS) assessed 12 weeks after start of treatment (According the RECIST criteria 1.1);
 
 
 
 
 
 
 
 
 
 
 
 
 
median PFS; objective tumor response; overall survival and histopathological parameters. 
For the statistical analysis, we will use binary variables reflecting the positivity status of the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
measures (yes or no; presence/absence). Association with histopathological parameters,
 
 
 
 
 
 
 
 
 
and objective tumor response, all categorical, will be also assessed using a chi-square test
 
 
 
 
 
 
 
 
 
 
  
 
 
to determine homogeneity or linear trend for ordinal variables. The significance level will
 
 
 
 
 
 
 
 
 
 
 
 
 
be set at 5%. To study the impact of the histological, immunohistochemical and molecular
 
 
 
 
 
 
 
 
 
 
 
 
 
 
factors on progression-free survival (PFS) and overall survival (OS), the Kaplan-Meier
 
 
 
 
 
 
 
 
 
 
 
proportional risk test (log rank) will be used. Evidence of the relative risk for each patient
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will be also provided by means of a Cox proportional hazards model using stepwise
 
 
 
 
 
 
 
 
 
 
 
 
 
 
selection to identify the independent predictors of poor outcome. 
We do not plan to use multivariate analysis to analyse biomarkers. Standard pre-post
 
 
 
 
 
 
 
 
 
 
 
 
 
univariate tests will be used instead. 
For the kinetic profile of the serum biomarkers, each variable will be considered as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
continuous. A correlation between the growth factor or cytokine levels with the different
 
 
 
 
 
 
 
 
 
 
 
 
 
points of the treatment schedule will be considered and the slope value will be used in
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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order to distinguish those cases with no change, negative or positive trend. The threshold
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will be calculated after considering the behaviour of the whole series. 
The slope value will be considered from baseline and using the nonparametric Wilcoxon
 
 
 
 
 
 
 
 
 
 
 
 
 
signed-rank test. However other analysis will be undertaken depending of the behaviour of
 
 
 
 
 
 
 
 
 
 
 
 
 
the measures.  
 
For sending the biological samples, please contact to: 
 
MARKETING FARMACÉUTICO & INVESTIGACIÓN CLÍNICA, S.L. 
Secretari Coloma, 64-68, esc. B, entlo. 5ª 
08024 Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
 
An additional document will be provided in the Investigator Site File with detailed biological
 
 
 
 
 
  
 
 
 
 
 
 
 
sample collection and shipment procedures. 
 
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14. REFERENCES: 
 
1. Minchom A, Jones RL, Fisher C et al. Clinical Benefit of Second-Line Palliative
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy in Advanced Soft-Tissue Sarcoma. Sarcoma, vol. 2010, Article ID
 
 
 
 
 
 
 
 
 
 
264360, 8 pages, 2010. doi:10.1155/2010/264360. 
2. Mandahl N et al. Nonramdom pattern of telomeric associations in atypical
 
 
 
 
 
 
 
 
 
 
 
lipomatous tumors with ring and giant marker chromosomes.
Cancer Genet
 
 
 
 
 
 
 
 
 
 
Cytogenet 1998; 103:25. 
3. Meis-Kindblom
JM
et
al.
Cytogenetic
and
molecular
genetic
analyses
of
 
 
 
 
 
 
 
 
 
 
liposarcoma and its soft tissue simulators: recognition of new variants and
 
 
 
 
 
 
 
 
 
 
 
differential diagnosis. Virchows Arch 2001; 439:141. 
4. Jones RL, Fisher C, Al-Muderis et al. Differential sensitivity of liposarcoma subtypes
 
 
 
 
 
 
 
 
 
 
 
 
to chemotherapy. Eur J Cancer. Dec 2005; 41(18):2853-60. 
5. Toulmonde
M,
Italiano
A,
Penel
N
et
al.
Advanced
 
 
 
 
 
 
 
 
 
well-differentiated/dedifferentiated
liposarcomas:
Role
of
chemotherapy
and
 
 
 
 
 
 
survival. J Clin Oncol 29: 2011 (suppl; abstr 10071). Data actualized in poster
  
 
 
 
 
 
 
 
 
 
 
 
presentation. 
6. Antonescu
Cr
et
al.
Specificity
of
TLS-CHOP
rearrangement
for classic
 
 
 
 
 
 
 
 
 
 
myxoid/round cell liposarcoma: absence in predominantly myxoid well-differentiated
 
 
 
  
 
 
 
liposarcoma. J Mol Diagn 2000; 2: 132. 
7. Pakos EE et al. Expression of vascular endothelial growth factor and its receptor,
 
 
 
 
 
 
 
 
 
 
 
 
 
KDR/Flk-1 in soft tissue sarcomas. Anbticancer Res 2005; 25: 3596. 
8. Sleijfer S et al. Pazopanib, a multikinase angiogénesis inhibitor, in patients with
 
 
 
 
  
 
 
 
 
 
 
relapsed or refractory advanced Soft Tissue Sarcoma: A phase II study from the
 
 
 
 
 
 
  
  
 
 
 
EORTC- Soft Tissue and Bone Sarcoma Group (EORTC62043). JCO 2009; 27(19):
 
 
 
 
 
 
 
 
 
 
 
3126. 
9. Van Der Graaf W, Blay JY, Chawla SP et al. Pazopanib for metastatic soft-tissue
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sarcoma (PALETTE): A randomized, double-blind, placebo-controlled phase III trial.
 
  
 
 
 
 
 
 
The Lancet 2012; 379 (9829): 1879. 
10.Sleijfer S et al. Soluble factors associated with efficacy and toxicity of Pazopanib in
  
 
 
 
 
 
 
 
 
 
 
  
advanced soft tissue sarcoma patients: An EORTC-STBSG. JCO 28;/ s, 2010 ( abst
 
 
 
 
 
 
 
 
  
  
 
10040). 
11.Billemont B, Medioni J, Tailade L, Helley D, Meric JB, Rixe O, Oudard S, Blood
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib.
 
 
 
 
 
 
 
 
 
 
 
 
British Journal of Cancer.  2008: 99, 1380-1382 
12.Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et
 
 
 
 
 
 
 
 
 
 
 
 
 
al., Recommended Guidelines for the Treatment of Cancer-Inducted Diarrhea.
J
 
 
 
 
 
 
 
 
 
 
Clin Oncol. 2004, 22; 2918-26. 
13.Van Glabbeke M, Verweij J, Judson I et al. Progression-free rate as the principal
 
 
 
 
 
  
 
 
 
 
 
 
 
end-point for phase II trials in soft-tissue sarcomas. European Journal of Cancer 38
 
 
  
 
 
 
 
 
 
 
 
 
(2002) 543–549. 
14.LeBlanc M, Rankin C and Crowley J. Multiple Histology Phase II Trials.Clin Cancer
 
 
  
 
 
 
 
 
  
 
 
GEIS–30_H_V03F_2015-02-11 
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Res 2009; 15: 4256-4262.  
 
 
 
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ANNEX I: Urine Protein Creatinine Ratio (UPC) 
 
Clinical meaning of UPC 
 
There is a good correlation between the ratio of protein concentration to creatinine
 
 
 
 
 
 
 
 
 
 
 
 
 
concentration in a random urine sample and the amount of protein excreted over 24 hours.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine excretion is fairly constant throughout the day regardless of changes in urine
 
 
 
 
 
 
 
 
 
 
 
 
 
flow rate. 
Normal protein excretion is <150 mg/24 hours and is similar for men and women. 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day. 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day. 
 
Calculating UPC 
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).  
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.  
Example:​  Patient has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.  
UPC ratio= (90 mg/dL) / (30 mg/dL) =  3  
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
24-hour period. 
 
Units for UPC ratio 
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the
 
 
 
 
 
 
 
 
 
 
 
 
 
same units (mg/dL, g/L, or μmol/L). If, for example, protein concentration is expressed in
 
 
 
 
 
 
 
 
 
 
  
 
 
mg/dL and creatinine concentration is expressed in µmol/L, conversion of one of the
 
 
 
 
 
 
 
 
 
 
 
 
 
concentration values is required.  Conversion factors are:  
 
From  
To  
Conversion Factor  
Conventional Units: mg/dL 
SI Units: µmol/L 
Multiply by 88.4 
SI Units: µmol/L 
Conventional Units: 
mg/dL 
Divide 88.4  
 
  
References: 
Xin G, Wang M, Jian L, Xu F, Wang H. Protein-to-creatinine ratio in spot urine samples as
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
a predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39.  
NKF: NKF KDOQI Guidelines [Internet]. National Kidney Foundation; nd. KDOQI Clinical
 
 
 
 
 
 
 
 
 
 
 
Practice
Guidelines
for
Chronic
Kidney
Disease:
Evaluation,
Classification,
and
 
 
 
 
 
 
 
 
 
Stratification.
Available
from
 
 
 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm 
 
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ANNEX II: Determination of Creatinine Clearance (Cl​CR​) 
Estimation of creatinine clearance using Cockroft and Gault method:  
 
Cl​CR ​for males (mL/min) =
[140 - age (years)] X [weight (kg)] 
                        (72) X [Serum creatinine (mg/dL)] 
Cl​CR​ for females (mL/min) =
(0.85) X [140 - age (years)] X [weight (kg)] 
                 (72) X [Serum creatinine (mg/dL)] 
For SI units: 
Cl​CR​ for males (mL/min) = 
[140 - age (years)] X [weight(kg)] X (1.23) 
                     [Serum creatinine (µmol/L)] 
Cl​CR​ for females (mL/min) = 
[140 - age(years)] X [weight(kg)] X (1.05) 
          [Serum creatinine (µmol/L)] 
 
Calculation of creatinine clearance based on 24-hour urinary creatinine excretion 
and concurrent serum creatinine levels: 
Cl​CR​ = ​C​U​·V 
            C​CR 
Here, C​U is the concentration of creatinine in the urine (mg/dL or µmol/L, for SI units), V is
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
the urine volume (in mL per minute of urine produced during the collection period), C​CR is
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
the serum creatinine concentration (mg/dL or µmol/L, for SI units), and Cl​CR is the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
creatinine clearance in mL per minute. 
 
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ANNEX III: Laboratory assessment recommendations 
Clinical Laboratory Assessments 
Laboratory assessments should be performed as indicated in the Time and Events Table
 
 
 
 
 
 
 
 
 
 
 
 
 
(table 5).
These assessments may be carried out within 3 days before the actual visit to
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
allow flexibility in scheduling. Assessments may be performed more frequently if clinically
 
 
 
 
 
 
 
 
 
  
 
indicated.
Correction of electrolytes (most importantly, potassium, magnesium and
 
 
 
 
 
 
 
 
 
calcium) to within normal ranges should take place prior to study entry and during study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
conduct as clinically indicated. 
 
All laboratory tests with values that become abnormal and clinically significant while the
 
 
 
 
 
 
 
 
 
 
 
 
 
subject is participating in the study or within 28 days after the last dose of study drug
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should be repeated until the values return to normal or baseline.  
Results for all unscheduled clinical laboratory assessments (.e.g., hematology, TSH/T4,
 
 
 
 
 
 
 
 
 
 
coagulation parameters) should be recorded on an unscheduled laboratory form in the
 
 
 
 
 
 
 
 
 
 
 
 
eCRF. 
Table 6 shows the clinical laboratory assessments that should be reported. 
 
Table 6: Clinical Laboratory Assessments 
 
Clinical Chemistry 
Renal function 
Urea, ​Creatinine 
Liver function test (LFT)
 
 
 
 
Panel  
Albumin,
Alkaline phosphatase,
Alanine aminotransferase (ALT),
 
 
 
 
 
 
Aspartate aminotransferase (AST) and Bilirubin (total)​b 
Electrolytes and others 
Calcium,
Potassium,
Sodium,
Magnesium,
Inorganic
phosphate,
 
 
 
 
 
 
Glucose, and Lactate Dehydrogenase (LDH) 
Hematology 
Hematocrit, Hemoglobin, White Blood Cell Count, Red Blood Cell
 
 
 
 
 
 
 
 
 
Count, Neutrophils, and Platelets 
Coagulation Tests 
Activated partial thromboplastin (aPTT) and International Normalization
 
 
 
 
 
 
 
Ratio (INR)​c 
Urinalysis for Proteinuria 
UPC​d 
Thyroid Function Test 
TSH​e 
 
a) Estimated creatinine clearance should be calculated using the Cockroft and Gault
 
 
 
 
 
 
 
 
 
 
 
 
method (Annex III).
Alternatively, creatinine clearance can be measured directly by
 
 
 
 
 
 
 
 
 
 
 
24-hour urine collection.  
b) A direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 X
  
 
 
 
 
 
  
 
 
 
  
 
 
  
upper limit of normal (ULN). See Section 7.6.2 for stopping criteria and dose modification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
guidelines for treatment-emergent liver function abnormality. 
c) Coagulation tests may also be performed in response to an AE/SAE of bleeding and as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinically indicated.  
d) UPC should be evaluated as described in Annex II or by 24-hour urine protein. If UPC ≥
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
3 or if urine protein is ≥3g, then the dose modification table guidelines should be followed
 
  
 
   
 
 
 
 
 
 
 
 
 
 
(Section 7.6.1).  
e) Unscheduled thyroid function tests [TSH and thyroxine (free T4)] should be performed if
 
 
 
 
 
 
 
 
 
 
 
 
  
clinically indicated (e.g., if a subject develops signs and symptoms suggestive of
 
 
 
 
 
 
 
 
 
 
 
 
hypothyroidism). 
 
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ANNEX IV​ ​Definition of Responsibilities in Trial Sites 
Only valid for German sites 
 
 
Am 26. Oktober 2012 trat das Zweite Arzneimittelrechtsänderungsgesetz in Kraft. Infolge 
dessen gelten neue Anforderungen hinsichtlich Prüfer, Stellvertreter, Prüfstelle und 
Prüfgruppe 
 
 
§ 4 (25) AMG (​Prüfer​) 
●
Prüfer ist in der Regel ein für die Durchführung der klinischen Prüfung bei
 
 
 
 
 
 
 
 
 
 
 
 
 
Menschen
in
einer
Prüfstelle
verantwortlicher
Arzt
oder
in
begründeten
 
 
 
 
 
 
 
 
 
Ausnahmefällen
eine
andere
Person,
deren
Beruf
auf
Grund
seiner
 
 
 
 
 
 
 
 
 
wissenschaftlichen Anforderungen und der seine Ausübung voraussetzenden
 
 
 
 
 
 
 
Erfahrungen in der Patientenbetreuung für die Durchführung von Forschungen am
 
 
 
 
 
 
 
 
 
 
Menschen qualifiziert. 
●Wird eine klinische Prüfung in einer Prüfstelle von einer Gruppe von Personen
 
 
 
 
 
 
 
 
 
 
 
 
durchgeführt, ​so ist der Prüfer der für die Durchführung ​verantwortliche Leiter
 
 
 
 
 
 
 
 
 
 
 
dieser Gruppe​. 
●Wird eine Prüfung in mehreren Prüfstellen durchgeführt, wird ​vom Sponsor ein Prüfer
 
 
 
 
 
 
 
 
 
 
 
 
als Leiter der klinischen Prüfung benannt​. 
§ 40 (1a) AMG (​Stellvertreter, Prüfgruppe​) 
●
Der ​Prüfer bestimmt angemessen qualifizierte Mitglieder der Prüfgruppe​. 
●Er hat sie ​anzuleiten und zu ​überwachen ​sowie ihnen die für ihre Tätigkeit im
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rahmen der Durchführung der klinischen Prüfung erforderlichen Informationen​,
 
 
 
 
 
 
 
 
insbesondere den Prüfplan und die Prüferinformation, ​zur Verfügung zu stellen​. 
●Der Prüfer hat ​mindestens einen Stellvertreter mit vergleichbarer Qualifikation zu
 
 
 
 
 
 
 
 
 
 
benennen​. 
§ 40(2) AMG (​Aufklärung der Patienten​) 
●
Die
betroffene
Person
ist
durch
einen
Prüfer,
der
Arzt
oder
bei
 
 
 
 
 
 
 
 
 
 
 
zahnmedizinischer Prüfung Zahnarzt ist, ​oder durch ein Mitglied der Prüfgruppe,
 
 
 
 
 
 
 
 
 
 
das Arzt, oder, bei zahnmedizinischer Prüfung, Zahnarzt ​ist​, über Wesen,
 
 
 
 
 
 
 
 
 
 
Bedeutung, Risiken und Tragweite der klinischen Prüfung sowie über ihr Recht
 
 
 
 
 
 
 
 
 
 
 
aufzuklären, […] 
●
Der betroffenen Person ist ferner Gelegenheit zu einem ​Beratungsgespräch mit
 
 
 
 
 
 
 
 
 
 
Prüfer oder Mitglied der Prüfgruppe, das Arzt ​oder Zahnarzt ​ist​, über sonstige
 
 
 
 
 
 
 
 
 
 
 
 
Bedingungen der klinische Prüfung […] 
§ 67 (1) AMG (​Anzeigepflicht​) 
●
Ist […] eine klinische Prüfung bei Menschen anzuzeigen, so ​sind der zuständigen
 
 
 
 
 
 
 
 
 
 
 
 
Behörde auch deren Sponsor, […] sowie ​der Prüfer und sein Stellvertreter​,
 
 
 
 
 
 
 
 
 
 
 
soweit erforderlich auch mit Angabe der Stellung Leiter der klinischen Prüfung,
 
 
 
 
 
 
 
 
 
 
 
namentlich zu benennen​. 
 
 
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ANNEX V: Declaration of Helsinki, World Medical 
Association General Assembly 
 
Adopted by the 18th World Medical Association General Assembly held in Helsinki, 
Finland, June 1964 and revised by the 29th World Medical Association General Assembly 
held in October 1975 in Tokyo,  
the 35th World Medical Association General Assembly held in Venice in October 1983,  
the 41st World Medical Association General Assembly celebrated in Hong Kong in 1989,  
the 48th World Medical Association General Assembly held in Somerset West, South 
Africa in October 1996,  
the 52nd World Medical Association General Assembly celebrated in Edinburgh, Scotland 
in October 2000 ,  
Paragraph 29 Clarification note, added by the World Medical Association General 
Assembly, Washington 2002, 
and the 59th World Medical Association General Assembly held in Seoul, Korea, October 
2008  
 
INTRODUCTION 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a
 
 
 
 
 
 
 
 
 
 
 
  
statement of ethical principles for medical research involving human subjects, including
 
 
 
 
 
 
 
 
 
 
 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs
 
  
 
 
 
 
  
 
 
 
 
 
 
 
should not be applied without consideration of all other relevant paragraphs. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other
 
 
  
 
 
 
 
 
 
 
 
participants in medical research involving human subjects to adopt these principles. 
It is the duty of the physician to promote and safeguard the health of patients, including
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
those who are involved in medical research. The physician's knowledge and conscience
 
 
 
 
 
 
 
 
 
 
 
 
are dedicated to the fulfilment of this duty. 
The Declaration of Geneva of the WMA binds the physician with the words, "The health of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
my patient will be my first consideration," and the International Code of Medical Ethics
 
 
 
 
 
 
 
 
 
 
 
 
 
 
declares that, "A physician shall act in the patient's best interest when providing medical
 
 
 
 
 
 
 
 
 
 
 
 
 
 
care." 
Medical progress is based on research that ultimately must include studies involving
 
 
 
 
 
 
 
 
 
 
 
 
human subjects. Populations that are under-represented in medical research should be
 
 
 
 
 
 
 
 
 
 
 
provided appropriate access to participation in research. 
In medical research involving human subjects, the well-being of the individual research
 
 
 
 
 
 
 
 
 
 
 
 
subject must take precedence over all other interests.  
The primary purpose of medical research involving human subjects is to understand the
 
 
 
 
 
 
 
 
 
 
 
 
 
causes, development and effects of diseases and improve preventive, diagnostic and
 
 
 
 
 
 
 
 
 
 
 
therapeutic interventions (methods, procedures and treatments). Even the best current
 
 
 
 
 
 
 
 
 
 
interventions
must
be
evaluated
continually
through
research
for
their
safety,
 
 
 
 
 
 
 
 
 
 
effectiveness, efficiency, accessibility and quality. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects and protect their health and rights. Some research populations are particularly
 
 
 
 
 
 
 
 
 
 
 
 
vulnerable and need special protection. These include those who cannot give or refuse
 
 
 
 
 
 
 
 
 
 
 
 
 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
GEIS–30_H_V03F_2015-02-11 
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Physicians should consider the ethical, legal and regulatory norms and standards for
 
 
 
 
 
 
 
 
 
 
 
 
research
involving
human subjects in their own countries as well as applicable
 
 
 
 
 
 
 
 
 
 
 
 
international norms and standards. No national or international ethical, legal or regulatory
 
 
 
 
 
 
 
 
 
 
 
 
requirement should reduce or eliminate any of the protections for research subjects set
 
 
 
 
 
 
 
 
 
 
 
 
 
forth in this Declaration. 
 
PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
It is the duty of physicians who participate in medical research to protect the life, health,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal
 
 
 
 
 
 
 
 
 
 
information of research subjects. 
Medical research involving human subjects must conform to generally accepted scientific
 
 
 
 
 
 
 
 
 
 
 
principles, be based on a thorough knowledge of the scientific literature, other relevant
 
 
 
  
 
 
 
 
 
 
 
 
sources
of
information,
and
adequate
laboratory
and,
as
appropriate,
animal
 
 
 
 
 
 
 
 
 
 
experimentation. The welfare of animals used for research must be respected.  
Appropriate caution must be exercised in the conduct of medical research that may harm
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the environment. 
The design and performance of each research study involving human subjects must be
 
 
 
 
 
 
 
 
 
 
 
 
 
clearly described in a research protocol. The protocol should contain a statement of the
 
 
  
 
 
 
 
 
  
 
 
 
ethical considerations involved and should indicate how the principles in this Declaration
 
 
 
 
 
 
 
 
 
 
 
 
have been addressed. The protocol should include information regarding funding,
 
 
 
 
 
 
 
 
 
 
sponsors, institutional affiliations, other potential conflicts of interest, incentives for
 
 
 
 
 
 
 
 
 
 
subjects and provisions for treating and/or compensating subjects who are harmed as a
 
 
 
 
 
 
 
 
 
 
 
  
consequence of participation in the research study. The protocol should describe
 
 
 
 
 
 
 
 
 
 
 
arrangements for post-study access by study subjects to interventions identified as
 
 
 
 
 
 
 
 
 
 
 
beneficial in the study or access to other appropriate care or benefits. 
The research protocol must be submitted for consideration, comment, guidance and
 
 
 
 
 
 
 
 
 
 
 
approval to a research ethics committee before the study begins. This committee must be
 
  
 
 
 
 
 
 
 
 
 
 
 
independent of the researcher, the sponsor and any other undue influence. It must take
 
 
 
 
 
 
 
 
 
 
  
 
 
into consideration the laws and regulations of the country or countries in which the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
research is to be performed as well as applicable international norms and standards but
 
 
 
 
 
 
 
 
 
 
 
 
 
 
these must not be allowed to reduce or eliminate any of the protections for research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects set forth in this Declaration. The committee must have the right to monitor
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ongoing studies. The researcher must provide monitoring information to the committee,
 
 
 
 
 
 
 
 
 
 
 
especially information about any serious adverse events. No change to the protocol may
 
 
 
 
 
 
 
 
 
 
 
 
 
be made without consideration and approval by the committee. 
Medical research involving human subjects must be conducted only by individuals with the
 
 
 
 
 
 
 
 
 
 
 
 
 
appropriate
scientific
training
and
qualifications. Research on patients or healthy
 
 
 
 
 
 
 
 
 
 
volunteers requires the supervision of a competent and appropriately qualified physician or
 
 
 
 
  
 
 
 
 
 
 
other health care professional. The responsibility for the protection of research subjects
 
 
 
 
 
 
 
 
 
 
 
 
must always rest with the physician or other health care professional and never the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
research subjects, even though they have given consent. 
Medical research involving a disadvantaged or vulnerable population or community is only
 
 
  
 
 
 
 
 
  
 
justified if the research is responsive to the health needs and priorities of this population or
  
 
  
 
 
 
 
 
 
 
 
 
 
 
community and if there is a reasonable likelihood that this population or community stands
 
  
   
 
 
 
 
 
 
 
 
to benefit from the results of the research. 
Every medical research study involving human subjects must be preceded by careful
 
 
 
 
 
 
 
 
 
 
 
 
assessment of predictable risks and burdens to the individuals and communities involved
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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in the research in comparison with foreseeable benefits to them and to other individuals or
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
communities affected by the condition under investigation. 
Every clinical trial must be registered in a publicly accessible database before recruitment
 
 
 
 
 
 
  
 
 
 
 
 
of the first subject. 
Physicians may not participate in a research study involving human subjects unless they
 
 
 
 
  
 
 
 
 
 
 
 
are confident that the risks involved have been adequately assessed and can be
 
 
 
 
 
 
 
 
 
 
 
 
 
satisfactorily managed. Physicians must immediately stop a study when the risks are
 
 
 
 
 
 
 
 
 
 
 
 
found to outweigh the potential benefits or when there is conclusive proof of positive and
 
 
 
 
 
 
 
 
  
 
 
 
 
 
beneficial results. 
Medical research involving human subjects may only be conducted if the importance of the
 
 
 
 
 
 
 
 
  
 
 
 
 
objective outweighs the inherent risks and burdens to the research subjects. 
Participation by competent individuals as subjects in medical research must be voluntary.
 
 
 
 
 
 
 
 
 
 
 
 
Although it may be appropriate to consult family members or community leaders, no
 
 
 
 
 
 
 
 
 
 
 
 
 
competent individual may be enrolled in a research study unless he or she freely agrees. 
Every precaution must be taken to protect the privacy of research subjects and the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
confidentiality of their personal information and to minimize the impact of the study on their
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
physical, mental and social integrity. 
In medical research involving competent human subjects, each potential subject must be
 
 
 
 
 
 
 
 
 
 
 
 
adequately informed of the aims, methods, sources of funding, any possible conflicts of
 
 
 
 
 
 
 
 
 
 
 
 
 
interest, institutional affiliations of the researcher, the anticipated benefits and potential
 
 
 
 
 
 
 
 
 
 
 
risks of the study and the discomfort it may entail, and any other relevant aspects of the
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
study. The potential subject must be informed of the right to refuse to participate in the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study or to withdraw consent to participate at any time without reprisal. Special attention
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should be given to the specific information needs of individual potential subjects as well as
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to the methods used to deliver the information. After ensuring that the potential subject has
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
understood the information, the physician or another appropriately qualified individual must
 
 
 
 
 
 
 
 
 
 
 
then seek the potential subject's freely-given informed consent, preferably in writing. If the
 
 
 
 
 
 
 
 
 
 
  
 
consent cannot be expressed in writing, the non-written consent must be formally
 
 
 
 
 
 
 
 
 
 
 
 
documented and witnessed. 
For medical research using identifiable human material or data, physicians must normally
 
 
 
 
 
 
 
 
 
 
 
 
seek consent for the collection, analysis, storage and/or reuse. There may be situations
 
 
 
 
 
 
 
 
 
 
 
 
 
where consent would be impossible or impractical to obtain for such research or would
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pose a threat to the validity of the research. In such situations the research may be done
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
only after consideration and approval of a research ethics committee. 
When seeking informed consent for participation in a research study the physician should
 
 
 
 
 
 
  
 
 
 
 
 
be particularly cautious if the potential subject is in a dependent relationship with the
 
 
  
 
 
 
 
  
 
 
 
 
physician or may consent under duress. In such situations the informed consent should be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sought by an appropriately qualified individual who is completely independent of this
 
 
 
 
 
 
 
 
 
 
 
 
relationship. 
For a potential research subject who is incompetent, the physician must seek informed
  
 
 
 
 
 
 
 
 
 
 
 
consent from the legally authorized representative. These individuals must not be included
 
 
 
 
 
 
 
 
 
 
 
 
in a research study that has no likelihood of benefit for them unless it is intended to
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
promote the health of the population represented by the potential subject, the research
 
 
 
 
 
 
 
 
 
 
 
 
 
cannot instead be performed with competent persons, and the research entails only
 
 
 
 
 
 
 
 
 
 
 
 
minimal risk and minimal burden. 
When a potential research subject who is deemed incompetent is able to give assent to
  
 
 
 
 
 
 
 
 
 
 
 
 
 
decisions about participation in research, the physician must seek that assent in addition
 
 
 
 
 
 
 
 
 
 
 
 
 
to the consent of the legally authorized representative. The potential subject's dissent
 
 
 
 
 
 
 
 
 
 
 
 
GEIS–30_H_V03F_2015-02-11 
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should be respected. 
Research involving subjects who are physically or mentally incapable of giving consent, for
 
 
 
 
 
 
 
 
 
 
 
 
 
example, unconscious patients, may be done only if the physical or mental condition that
 
 
 
 
 
 
  
 
 
 
 
 
 
prevents giving informed consent is a necessary characteristic of the research population.
 
 
 
   
 
 
 
 
 
 
In such circumstances the physician should seek informed consent from the legally
 
 
 
 
 
 
 
 
 
 
 
 
authorized representative. If no such representative is available and if the research cannot
 
  
 
 
  
 
  
 
 
 
be delayed, the study may proceed without informed consent provided that the specific
 
 
 
 
 
 
 
 
 
 
 
 
 
reasons for involving subjects with a condition that renders them unable to give informed
 
 
 
 
  
 
 
 
 
 
 
 
 
consent have been stated in the research protocol and the study has been approved by a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
research ethics committee. Consent to remain in the research should be obtained as soon
 
 
 
 
 
 
 
 
 
 
 
 
 
 
as possible from the subject or a legally authorized representative. 
Authors, editors and publishers all have ethical obligations with regard to the publication of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the results of research. Authors have a duty to make publicly available the results of their
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
research on human subjects and are accountable for the completeness and accuracy of
 
 
 
 
 
 
 
 
 
 
 
 
 
their reports. They should adhere to accepted guidelines for ethical reporting. Negative
 
 
 
 
 
 
 
 
 
 
 
 
and inconclusive as well as positive results should be published or otherwise made
 
 
 
 
 
 
 
 
 
 
 
 
 
publicly available. Sources of funding, institutional affiliations and conflicts of interest
 
 
 
 
 
 
 
 
 
 
 
should be declared in the publication. Reports of research not in accordance with the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
principles of this Declaration should not be accepted for publication. 
 
PRINCIPLES FOR MEDICAL RESEARCH WHEN COMBINED WITH MEDICAL CARE 
The physician may combine medical research with medical care only to the extent that the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
research is justified by its potential preventive, diagnostic or therapeutic value and if the
 
 
 
 
 
 
 
 
 
 
 
  
 
physician has good reason to believe that participation in the research study will not
 
 
 
 
 
 
 
 
 
 
 
 
 
 
adversely affect the health of the patients who serve as research subjects. 
The possible benefits, risks, burdens and effectiveness of a new intervention must be
 
 
 
 
 
 
 
  
 
 
 
 
tested against those of the best current proven intervention, except in the following
 
 
 
 
 
 
 
 
 
 
 
 
 
circumstances: 
The use of placebo, or no treatment, is acceptable in studies where no current proven
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
intervention exists; or.  
Where for compelling and scientifically sound methodological reasons the use of placebo
 
 
 
 
 
 
 
 
 
 
 
 
is necessary to determine the efficacy or safety of an intervention and the patients who
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
receive placebo or no treatment will not be subject to any risk of serious or irreversible
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
harm. Extreme care must be taken to avoid abuse of this option. 
At the conclusion of the study, patients entered into the study are entitled to be informed
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
about the outcome of the study and to share any benefits that result from it, for example,
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
access to interventions identified as beneficial in the study or to other appropriate care or
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
benefits. 
The physician must fully inform the patient which aspects of the care are related to the
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
research. The refusal of a patient to participate in a study or the patient's decision to
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
withdraw from the study must never interfere with the patient-physician relationship. 
In the treatment of a patient, where proven interventions do not exist or have been
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ineffective, the physician, after seeking expert advice, with informed consent from the
 
 
 
 
 
 
 
 
 
 
 
 
patient or a legally authorized representative, may use an unproven intervention if in the
 
  
 
 
 
 
 
 
 
  
 
 
physician's judgment it offers hope of saving life, re-establishing health or alleviating
 
 
 
 
 
 
 
 
 
 
 
 
suffering. Where possible, this intervention should be made the object of research,
 
 
 
 
 
 
 
 
 
 
 
 
designed to evaluate its safety and efficacy. In all cases, new information should be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
recorded and, where appropriate, made publicly available. 
GEIS–30_H_V03F_2015-02-11 
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SAP_001.pdf: 


GEIS-30 STUDY 
Statistical analysis plan 
2 
COORDINATORS OF THE STUDY 
 
COORDINATOR INVESTIGATOR GENERAL OF THE STUDY: 
Dr. Claudia Valverde Morales 
Vall d'Hebron University Hospital 
Passeig Vall d'Hebron 119 - 129, Barcelona. 
 
COORDINATOR INVESTIGATOR OF THE STUDY IN GERMANY: 
Dr. Bernd Kasper 
University Medical Center Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
 
COORDINATOR OF THE TRANSLATIONAL STUDY: 
Dr. José Antonio López Guerrero 
Laboratory of the Molecular Biology 
Institute 
Prof. Beltrán Báguena 8 -11, 46009, Valencia 
 
GEIS TECHNICAL SECRETARY: 
Technical Secretariat GEIS 
C / Secretary Coloma 64-68, esc B mezzanine 5ª 
08024 Barcelona 
Tel: 93 434 44 12 
Fax: 93 253 11 68 
Mail: secretaria@grupogeis.org 


GEIS-30 STUDY 
Statistical analysis plan 
3 
INDEX 
 
1. 
SUMMARY 
5 
1.1.  SPONSOR OF THE STUDY 
5 
1.2. TITLE OF THE STUDY 
5 
1.3. PROTOCOL CODE 
5 
1.4. COORDINATING INVESTIGATORS 
5 
1.4.1. COORDINATOR GENERAL COORDINATOR OF THE STUDY: 
5 
1.4.2. COORDINATOR OF THE STUDY IN GERMANY: 
5 
1.4.3. COORDINATOR OF THE TRANSLATIONAL STUDY 
5 
1.5. ETHICAL COMMITTEE OF CLINICAL RESEARCH THAT HAS APPROVED THE 
STUDY 
5 
1.6. RESPONSIBLE MONITOR 
6 
1.7. STUDY TREATMENT 
6 
1.8. PHASE OF THE STUDY 
6 
1.9. MAIN OBJECTIVE OF THE STUDY 
6 
1.10. DESIGN 
6 
1.11. DISEASE OF STUDY 
6 
1.12. PRINCIPAL VARIABLE 
6 
1.13. STUDY POPULATION. NUMBER. TOTAL PATIENTS 
6 
1.13.1. SAMPLE SIZE 
6 
1.14. DURATION OF THE TREATMENT 
6 
1.15. ESTIMATED CALENDAR OF THE STUDY 
6 
1.16. OBJECTIVES OF THE STUDY 
7 
1.16.1. PRIMARY OBJECTIVE 
7 
1.16.2. SECONDARY OBJECTIVES 
7 
1.16.3. TRANSLATIONAL OBJECTIVES 
7 
1.16.4. POPULATIONS 
7 
1.17. GENERAL INCLUSION CRITERIA 
8 
2. 
RESULTS 
11 
2.1. BASIC CHARACTERISTICS 
11 
2.1.1. SOCIODEMOGRAPHIC CHARACTERISTICS 
11 
2.1.2. VITAL SIGNS 
12 
2.1.3. HAEMATOLOGICAL PROFILE 
12 
2.1.4. COAGULATION PROFILE 
12 
2.1.5. BIOCHEMICAL PROFILE 
12 
2.1.6. THYROID FUNCTION 
13 
2.1.7. URIANALYSIS 
14 
2.1.8. PREGNANCY TEST 
15 
2.1.9. FUNCTIONAL STATUS: ECOG 
15 
2.1.10. TUMOR CHARACTERISTICS AND PRE-TREATMENT LIPOSARCOMA 
16 
2.1.10.1. INITIAL DIAGNOSIS 
16 
2.1.10.2. RADIOTHERAPY 
18 
2.1.10.2.1. RELAPSE AND TYPE OF TREATMENT 
18 
2.1.10.3. PREVIOUS CHEMOTHERAPY 
19 
2.1.11. PREVIOUS PATHOLOGY 
20 
2.1.12. PHYSICAL EXAM 
21 
2.2. COMPLIANCE WITH TREATMENT VISITS 
23 
2.3. POPULATIONS ITT and PP 
24 
2.4. DURATION OF THE TREATMENT WITH PAZOPANIB 
24 
2.5. GLOBAL MONITORING 
25 
2.6. EFFICACY: MAIN ENDPOINT 
26 
2.6.1. EFFICACY BASED ON LOCAL ASSESSMENTS. ITT 
26 
2.6.2. EFFICACY BASED ON LOCAL ASSESSMENTS. PP 
26 
2.6.3. BASED ON CENTRALIZED ASSESSMENTS. ITT 
28 


GEIS-30 STUDY 
Statistical analysis plan 
4 
2.6.4. EFFICACY BASED ON CENTRALIZED ASSESSMENTS. PP 
29 
2.7. EFFICACY: PROGRESSION FREE SURVIVAL SECONDARY ENDPOINT (PFS) 
30 
2.7.1. PFS. LOCAL ASSESSMENT. ITT 
30 
2.7.2. PFS. LOCAL ASSESSMENT. PP 
31 
2.7.3. PFS. CENTRAL ASSESSMENT. ITT 
32 
2.7.4. PFS. CENTRAL ASSESSMENT. PP 
33 
2.8. EFFICACY: OVERALL SURVIVAL SECONDARY ENDPOINT (OG) 
35 
2.8.1. OS. ITT 
35 
2.8.2. OS. PP 
36 
2.9. GMI: GROWTH MODULATION INDEX 
38 
2.10. ECOG EVOLUTION 
39 
2.11. SAFETY: AEs AND TOXICITIES 
39 
3. 
ANNEX I: EFFICACY ACCORDING TO GMI 
44 
3.1. MAIN ENDPOINT ACCORDING TO GMI 
44 
3.1.1. RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO GMI. ITT 
44 
3.1.2. RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO GMI. PP 
44 
3.1.3. RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO GMI. ITT. IN EACH 
COHORT 
44 
3.1.4. RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO GMI. PP. IN EACH 
COHORT 
45 
3.2. ENDPOINT SECUNDARIO PFS ACCORDING TO GMI 
46 
3.2.1. PFS ACCORDING TO GMI. LOCAL ASSESSMENT 
46 
3.2.2. PFS ACCORDING TO GMI. LOCAL ASSESSMENT. IN COHORTE A 
46 
3.2.3. PFS ACCORDING TO GMI. LOCAL ASSESSMENT. IN COHORT B 
47 
3.3. SECONDARY ENDPOINT SG ACCORDING TO GMI 
48 
3.3.1. OS ACCORDING TO GMI. 
48 
3.3.2. OS ACCORDING TO GMI. IN COHORT TO 
49 
3.3.3. OS ACCORDING TO GMI. IN COHORT B 
49 
3.4. ECOG (BASAL) ACCORDING TO GMI 
51 
3.4.1. ECOG BASAL ACCORDING TO GMI. ITT 
51 
3.4.2. ECOG BASAL ACCORDING TO GMI. PP 
51 
3.5. GRADE FNCLCC (BASAL) ACCORDING TO GMI 
51 
3.5.1. GRADE FNCLCC BASAL ACCORDING TO GMI. ITT 
51 
3.5.2. GRADE FNCLCC BASAL ACCORDING TO GMI. PP 
52 
4. 
ANNEX II: LISTING OF ALL RELATED TOXICITIES 
52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
5 
1. SUMMARY 
 
1.1. 
SPONSOR OF THE STUDY OF THE  
GRUPO ESPAÑOL DE INVESTIGACIÓN EN SARCOMAS, GEIS 
C / Velázquez nº 7, 3rd floor 
28001 - MADRID - Spain. 
 
GEIS 
Secretariat Technical Secretariat GEIS 
C / Secretary Coloma 64-68, esc B mezzanine 5ª 
08024 Barcelona 
Tel .: 93 434 44 12 
Fax: 93 253 11 68 
Mail: secretaria@grupogeis.org 
 
1.2. 
TITLE OF THE STUDY  
Pazopanib phase II clinical trial to evaluate activity and tolerability in patients with 
advanced and / or metastatic liposarcoma who have relapsed to standard therapy or in 
those in whom there is no standard therapy. 
 
1.3. 
CODE OF THE PROTOCOL  
GEIS-30 
NºEudraCT: 2012-002745-38 
 
 
1.4. 
COORDINATING INVESTIGATORS  
1.4.1. 
Research General Coordinator of the study: 
Dr. Claudia Morales Valverde 
Hospital Universitari Vall d'Hebron 
Passeig Vall d'Hebron 119-129, Barcelona. 
1.4.2. 
Coordinator of the study in Germany: 
Dr. Bernd Kasper 
University Medical Center Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
1.4.3. 
Coordinator of the Translational Study 
Dr. José Antonio López Guerrero 
Laboratory of Molecular Biology 
Fundación Instituto Valenciano de Oncología 
Prof. Beltrán Báguena 8- 11, 46009, Valencia 
  
1.5. 
ETHICAL COMMITTEE OF CLINICAL INVESTIGATION THAT HAS 
APPROVED THE STUDY  
CEICHospital Universitari Vall d´Hebron 
Passeig de la Vall d.Hebron s / n  
08035-Barcelona 
1.6. 
MONITOR RESPONSIBLE  
MARKETING PHARMACEUTICAL & CLINICAL INVESTIGATION - MFAR SL 
Calle Secretari Coloma 64-68, esc.B. , entlo. 5ª 
08024 - Barcelona 
Tel: +34 93 434 44 12 
Fax: +34 93 253 11 68 
e-mail: investigacion@mfar.net 
 


GEIS-30 STUDY 
Statistical analysis plan 
6 
1.7. 
STUDY TREATMENT  
Single arm of treatment with Pazopanib 800 mg (2x400mg or 4x200 mg) administered 
as single agent once a day. 
 
1.8. 
PHASE OF THE STUDY  
Phase II study of two cohorts, open, non-randomized and multicenter with 11 
participating centers in Spain and 5 in Germany. Patients will receive oral Pazopanib at 
a dose of 800mg once daily until disease progression, development of unacceptable 
toxicity, non-compliance, withdrawal of consent by the patient, or decision of the 
investigator. 
 
1.9. 
MAIN OBJECTIVE OF THE STUDY  
The primary objective of this study is to evaluate the activity of Pazopanib in patients 
with advanced and / or metastatic liposarcoma through progression-free survival (PFS) 
determined at 12 weeks after the start of treatment (according to RECIST criteria 1.1 
and central radiological review). 
 
1.10. 
DESIGN  
Phase II study of two cohorts, open, non-randomized and multicenter with 11 
participating centers in Spain and 5 in Germany. To evaluate the activity and tolerability 
of pazopanib in patients with advanced and / or metastatic liposarcoma who have 
relapsed after standard treatment or for whom there is no established treatment. 
The drug will be investigated separately in the following liposarcoma subtypes (cohorts): 
● Well-differentiated liposarcoma / dedifferentiated liposarcoma (ALT-WD) 
● Myxoid liposarcoma / round cell liposarcoma. 
 
1.11. 
DISEASE IN STUDY  
Advanced and / or metastatic liposarcoma. 
 
1.12. 
MAIN ASSESSMENT VARIABLE  
The primary efficacy endpoint for this study is progression-free survival (PFS) 
determined 12 weeks after the start of treatment (according to RECIST 1.1 criteria and 
central radiological review). 
 
1.13. 
STUDY POPULATION. NUMBER. TOTAL PATIENTS  
Patients with advanced or metastatic liposarcoma who have recurred after standard 
treatments or for whom there is no established treatment will be included. 
 
1.13.1. Sample size 
Estimation of 74 patients (Maximum of 37 patients in 2 different cohorts). 
 
1.14. 
DURATION OF TREATMENT 
Treatment will continue until disease progression, development of unacceptable toxicity, 
non-compliance, withdrawal of consent by the patient or decision of the investigator. 
 
 
1.15. 
ESTIMATED CALENDAR OF THE STUDY  
Start date: Third quarter of 2012. 
First visit of the first patient (PVPP): Fourth quarter of 2012. 
Total duration of the recruitment period: 30 months. 
First visit of the last patient (PVUP): Second quarter of 2015. 
Follow-up period: 12 months. 
End of study date: March 2, 2018. 
 


GEIS-30 STUDY 
Statistical analysis plan 
7 
1.16. 
OBJECTIVES OF THE STUDY 
 
1.16.1. Primary objective 
The objective of this study is to evaluate the activity of Pazopanib in patients with 
advanced and / or metastatic liposarcoma by means of progression-free survival (PFS) 
determined after 12 weeks of treatment (according to the RECIST criteria v1.1 and 
central radiological revision). 
 
1.16.2. Secondary objectives: 
● Median progression-free survival (median PFS). 
● Objective tumor response [Complete confirmed response (CR) and partial 
response (PR) defined by RECIST 1.1]. 
● Time to start of response. 
● Duration of response. 
● Overall survival (OS). 
● Clinical benefit rate (CBR). 
● Growth modulation index (GMI). 
● Security profile (according to CTCAE, version 4.0). 
 
1.16.3. Translational objectives 
 
PRIMARY OBJECTIVES: 
● To assess the influence of the tumor's angiogenic state on the response to 
Pazopanib. 
● To assess the profile of serum cytokines as an indicator of response to 
Pazopanib. 
SECONDARY OBJECTIVES: 
● To assess the density of microvessels (DMV) and the pathways of p53, MDM2, 
PTEN, and VEGF / PDGF by immunohistochemistry, their correlation with 
prognosis, and their role as predictors of treatment with Pazopanib (response, 
PFS, and OS). 
● Assess serum levels of various angiogenic factors / cytokines using Luminex 
XMAP Technology at baseline, after the first 3 weeks of treatment, at the time of 
maximum response and in tumor progression and its predictive value for survival 
and response to treatment: VEGF-A , PlGF-1, SDF-1 alpha (CXCL12), TNF 
alpha, IL-8, IL-6, PDGF-beta, HGF, E-Selectin, ICAM1, MMP-9 and FGFb. 
● Analyze the presence of mutations in PIK3CA to demonstrate whether those 
liposarcomas with mutations in PIK3CA define a subgroup of patients with a 
different response to Pazopanib. 
 
1.16.4. Populations 
Population for efficacy.  
● Analysis by Intention to Treat (ITT): Efficacy analyzes will be calculated on the 
population by intention to treat. All patients participating in the study will be 
included in the efficacy analysis. 
● Analysis by Protocol (PP): Efficacy analyzes will be calculated on the per 
protocol population. All patients participating in the study and who have received 
at least 3 weeks of treatment with Pazopanib (without major protocol deviations) 
will be included in the efficacy analysis. 
 
Population for security.  
● Any patient included in the study who has received at least a single dose of study 
medication will be evaluable for toxicity analyzes. 
 


GEIS-30 STUDY 
Statistical analysis plan 
8 
1.17. 
GENERAL INCLUSION CRITERIA 
A subject will be considered eligible for inclusion in this study if they meet each and 
every one of the following criteria: 
 
1. Subjects must give their informed consent before performing any of the study 
evaluations or procedures and must be willing to comply with the treatment and 
established monitoring. 
 
2. Age ≥ 18 years. 
 
3. Histological diagnosis of liposarcoma of intermediate or high grade of malignancy 
with metastatic or locally advanced disease. A paraffin-fixed tumor block and / or 
lamellae with representative sections stained with H / E (hematoxylin / eosin) 
must be available for its central pathological review and classification of tumors 
into 2 eligible subtypes: 
● Well-differentiated liposarcoma / Undifferentiated liposarcoma (ALT- WD) 
● Myxoid liposarcoma / Round cell liposarcoma. 
 
4. Patients must present documented disease progression within 6 months prior to 
the patient's entry into the study. 
 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
 
6. Measurable disease by RECIST criteria v1.1. There must be at least one 
measurable lesion located outside of a previously irradiated area. If the only 
measurable lesion is in a previously irradiated area, there should be documented 
progression after radiation therapy within 6 months prior to the patient's entry into 
the study. 
 
7. The patient should not be considered a candidate for surgery or to receive radical 
radiotherapy. Eg Patients in whom surgery / radiotherapy cannot have a curative 
intention due to the extension of the disease. In the case of radiotherapy, it may 
be limited by previous irradiation on the same area. 
 
8. The patient must have been considered a non-candidate for systemic 
chemotherapy or must have received at least one line of chemotherapy for 
metastatic or refractory disease. Up to a maximum of 3 previous lines are 
allowed for advanced / metastatic disease.  
Eg patients not candidates for chemotherapy treatment: 
● By age, concomitant pathology or negative of the patient. 
● Patients who received anthracyclines in the adjuvant setting are generally 
not eligible to receive this drug as the first line for advanced disease. 
● Monorenal patients or> 60 years are usually not good candidates for 
treatment with standard doses of ifosfamide.  
 
9. Tumor tissue from all subjects is required for biomarker study before / during 
treatment with the study drug. 
 
10. The patient must be able to swallow and retain the study medication. 
 
11. Adequate organ and system function, as defined in Table 1. 
 
 
Table 1. Definitions of adequate organic function. 


GEIS-30 STUDY 
Statistical analysis plan 
9 
 
● Subjects should not have received transfusions within 7 days prior to 
screening evaluation. 
● Subjects receiving anticoagulant therapy are eligible if their INR is stable 
and within the recommended range for the desired level of 
anticoagulation. 
● Concomitant elevations of bilirubin and AST / ALT above 1.0 x ULN are 
not allowed. 
● If UPC ≥ 1, a 24-hour urine protein determination should be performed. 
Subjects must have a value <1 g to be eligible. The use of urinary dipstick 
is not allowed to assess basal kidney function. 
 
12. A woman is eligible to participate in this study if: She has no reproductive 
potential, which includes, in addition to pathological situations of infertility: 
● Hysterectomized patients. 
● Patients with bilateral oophorectomy. 
● Patients with bilateral tubal ligation. 
● Post-menopausal patients. 
 
Women who do not use hormone replacement therapy must have had a complete 
cessation of menstruation for a period ≥ 1 year and be over 45 years old, OR, in some 
cases, have FHS levels> 40 mIU / mL and estradiol levels < 40pg / mL (<140 pmol / L). 
Women using hormone replacement therapy must have experienced a complete 
cessation of menstruation for a period of ≥ 1 year and be older than 45 years OR have 
documented evidence of menopause due to hormonal values of FSH and estradiol prior 
to initiation of hormonal treatment. 
In the case of fertile women, those patients who have a negative result of a serum 
pregnancy test during the 2 weeks prior to the first dose of the study drug (preferably as 
close to the first dose of the drug as possible) are eligible if they agree to use 
appropriate contraceptive measures. The appropriate methods (when used continuously 
and according to the instructions of the doctor and the product) are the following: 
● Complete sexual abstinence that will begin during the 14 days prior to the first 
exposure to the study drug, will be continued throughout treatment within the 
clinical trial and will continue until at least 21 days after the last dose of the drug. 
● Oral contraceptives, both progestins as monotherapy and in combination with 
other agents. 
● Injectable progesterone. 


GEIS-30 STUDY 
Statistical analysis plan 
10 
● Levonorgestrel implants. 
● Vaginal ring with estrogens. 
● Percutaneous contraceptive patches. 
● Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure 
rate of less than 1% per year. 
● Sterilized male partner (vasectomy with documented azoospermia) prior to the 
entry of their partner into the study (provided they are a monogamous partner). 
● Double barrier method: Male condom and cervical diaphragm / cap with vaginal 
spermicidal agent (foam / gel / film / cream / suppository). 
● Breastfeeding women should discontinue the natural feeding of the baby before 
receiving the first dose of the study drug until 14 days after the last dose of 
treatment. 
 
13. Left ventricular ejection fraction (LVEF) above the lower limit of normal for the 
institution, either by echocardiogram or MUGA. 


GEIS-30 STUDY 
Statistical analysis plan 
11 
2. EXPECTED RESULT ANALYSIS 
These table summarize the expected results analysis of the clinical trial using ITT (Intent 
to Treat), PP (Per Protocol) populations for efficacy analysis, and those patients 
evaluable for toxicity for safety analyzes. This report will include complete patient follow 
up through the end of the estudy. 
 
 
Table 2. Patients evaluable for the study according to cohort 
 
Cohort A 
Cohort B 
Total 
Hospital 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
2.1. 
BASAL CHARACTERISTICS Baseline 
Characteristics will be presented for all evaluable patients, globally and according 
to each cohort 
 
2.1.1. 
SOCIODEMOGRAPHIC CHARACTERISTICS  
The proportion of men / women. 
 
Table 3. Sex 
 
Cohort A 
Cohort B 
Total 
p-value 
Sex 
N (%) 
N (%) 
N (%) 
 
Male 
 
 
 
Female 
 
 
 
Total 
 
 
 
 
 
1: Chi-square test 
 
Mean age. 
Table 4. Age 
Cohort A 
Cohort B 
Total 
p-
value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) 
Age 
 
 
 
 
 
 
 
 
 
 
1: Test Mann-Whitney U 
 
 
 
 
 
2.1.2. 
VITAL SIGNS  
 
 


GEIS-30 STUDY 
Statistical analysis plan 
12 
Table 5. Vital Signs 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
( Min-Max) 
Height 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
BP Systolic  
 
 
 
 
 
 
 
 
 
BP 
Diastolic  
 
 
 
 
 
 
 
 
 
 
Body 
temperature  
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
2.1.3. 
HAEMATOLOGICAL PROFILE  
 
 
Table 6. Haematological profile 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) 
N Mean ( 
SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max) 
Hemoglobin   
 
 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
 
Lymphocytes  
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
2.1.4. 
COAGULATION PROFILE  
 
 
Table 7. Coagulation profile 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
Prothrombin  
 
 
 
 
 
 
 
 
 
INR  
 
 
 
 
 
 
 
 
 
 
PTT  
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U Test 
 
2.1.5. 
BIOCHEMICAL PROFILE 
 
 
Table 8. Biochemical profile 
Cohort A 
Cohort B 
Total 
p-
value1 
N
Mean 
(SD) 
Medi ana 
(Min-Max) 
N Mean 
(SD) 
Median 
(Min-Max) 
N Mean 
(SD) 
Median 
(Min-Max) 
Protein 
 
 
 
 
 
 
 
 
 
 
Albumin 
 
 
 
 
 
 
 
 
 
 
BUN  
 
 
 
 
 
 
 
 
 
 
Creatinine  
 
 
 
 
 
 
 
 
 
 
Clearance  
 
 
 
 
 
 
 
 
 
 
SGOT / AST  
 
 
 
 
 
 
 
 
 
 
SGTP / ALT  
 
 
 
 
 
 
 
 
 
 
Alkaline 
Phosphatase  
 
 
 
 
 
 
 
 
 
 
Bilirubin 
 
 
 
 
 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
13 
Phosphorus  
 
 
 
 
 
 
 
 
 
 
Sodium  
 
 
 
 
 
 
 
 
 
 
Potassium  
 
 
 
 
 
 
 
 
 
 
Calcium  
 
 
 
 
 
 
 
 
 
 
Chloride 
 
 
 
 
 
 
 
 
 
 
Magnesium  
 
 
 
 
 
 
 
 
 
 
Amylase 
 
 
 
 
 
 
 
 
 
 
Lipase  
 
 
 
 
 
 
 
 
 
 
Lactate 
dehydrogenase  
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
2.1.6. 
THYROID FUNCTION 
 
 
Table 9. Thyroid function 
Cohort A 
Cohort B 
Total 
p-
value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) 
TSH  
 
 
 
 
 
 
 
 
 
 
T4  
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
14 
2.1.7. 
URIANALYSIS 
 
Table 10. Urinalysis 
 
 
Cohort A 
Cohort B 
Total 
p-value 
 
 
N (%) 
N (%) 
N (%) 
 
Dipstick Protein  
Normal 
 
 
 
 
Abnormal 
 
 
 
Not applicable 
 
 
 
Total 
 
 
 
Microscopic 
analysis  
Normal 
 
 
 
 
Abnormal 
 
 
 
Not applicable 
 
 
 
Total 
 
 
 
24-Hour 
proteinuria 
Normal 
 
 
 
 
Abnormal 
 
 
 
Not applicable 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Table 11. Urinalysis results 
 
 
Cohort A 
Cohort B 
Total 
p-value 
 
 
N (%) 
N (%) 
N (%) 
 
Result 
Dipstick 
Protein  
Normal / No result 
 
 
 
 
(+) 
 
 
 
0.25 
 
 
 
1+ 
 
 
 
13 
 
 
 
14 
 
 
 
25 mg / dl 
 
 
 
negative 
 
 
 
traces 
 
 
 
Total 
 
 
 
Abnormal 
microscopic 
analysis 
Normal / No result 
 
 
 
 
Erythrocyts 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
Table 12. 24-hour proteinuria 
Cohort A 
Cohort B 
Total 
p-
value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
24-Hour 
Result 
proteinuria 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U Test 
 
 
 
 
2.1.8. 
PREGNANCY TEST 
  
 
Table 13. Pregnancy test 


GEIS-30 STUDY 
Statistical analysis plan 
15 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
Pregnancy 
test) 
Negative 
 
 
 
 
Total 
 
 
 
Type of Test Serum 
 
 
 
 
Total 
 
 
 
 
 
1: Chi-square test 
 
Table 14. Test details of pregnancy 
Patient 
Cohort 
Sex 
Age 
Pregnancy 
test 
Type of 
pregnancy 
test 
Reason test not performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.9. 
FUNCTIONAL STATUS: ECOG 
 
Table 15. ECOG at baseline 
ECOG at 
baseline 
Cohort A 
Cohort B 
Total 
 
N (%) 
N (%) 
N (%) 
p- 
value1 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-Max) 
p-
value3 
Baseline 
ECOG 
 
 
 
 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test; 3: Test Mann-Whitney 


GEIS-30 STUDY 
Statistical analysis plan 
16 
2.1.10. TUMOR 
CHARACTERISTICS 
AND 
PRETREATMENT 
LIPOSARCOMA 
2.1.10.1. 
Initial diagnosis 
 
 
Table 16. Location of the tumor 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Location of 
the tumor  
pelvic girdle 
 
 
 
 
Upper Limbs 
 
 
 
Lower extremities 
 
 
 
Retro-peritoneum 
 
 
 
Others 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisherexact test 
 
Other locations: 
 
Table 17. Other tumor locations 
Patient 
Cohort 
Other locations 
 
 
 
 
 
 
 
 
 
 
 
 
Table 18. Histological type (local review) 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Histological 
type 
Well-differentiated 
Liposarcoma 
 
 
 
 
Undifferentiated 
 
 
 
Pleomorphic 
 
 
 
Myxoid 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Histological diagnosis was also analyzed centrally. 
 
Table 19. Histological type (centralized review) 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Histological 
type 
(centralized) 
Liposarcoma distinct 
 
 
 
 
well differentiated liposarcoma / 
dedifferentiated 
 
 
 
liposarcoma undifferentiated 
 
 
 
liposarcoma myxoid 
 
 
 
Total 
 
 
 
 
 
1: Chi -square; 2: Test Fisherexact 
 
comparison: 


GEIS-30 STUDY 
Statistical analysis plan 
17 
 
Table 20. GradeFNCLCC 
GradeFNCLCC 
Cohort A 
Cohort B 
Total 
 
N (%) 
N (%) 
N (%) 
p-
value3 
1 
 
 
 
 
2 
 
 
 
3 
 
 
 
Total 
 
 
 
N 
Mean 
(SD) 
Median  
(Min-Max ) N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-Max) 
p-
value3 
Degree 
FNCLCC 
 
 
 
 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test; 3: Mann-Whitney U test 
 
Previous treatments: 
 
Table 21. Initial treatment 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Radiotherap
y for primary 
tumor 
Yes 
 
 
 
 
No 
 
 
 
Total 
 
 
 
Initial 
treatment 
Yes 
 
 
 
 
No 
 
 
 
Total 
 
 
 
Type of 
initial 
treatment 
Radical surgery 
 
 
 
 
Wide 
 
 
 
 Marginal positive resection 
 
 
 
Only biopsy 
 
 
 
Others 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Other initial treatments: 
 
Table 22. Other initial treatments 
Patient 
Cohort 
Other types 
 
 
 
 
 
 
 
 
 
 
 
Elapsed time between initial treatment and Pazopanib treatment: 
 
Table 23. Time from initial treatment to start of Pazopanib (years) 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) 
Time from 
initial tt to 
Pazopanib 
 
 
 
 
 
 
 
 
1: Mann U-test Whitney 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
18 
 
2.1.10.2. 
RADIOTHERAPY 
 
 
Table 24. Radiotherapy 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Radiotherapy 
Yes 
 
 
 
 
No 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Elapsed time between initial treatment and Pazopanib treatment: 
 
Table 25. Duration of radiotherapy (months) 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
medium  
(Min-Max) 
N 
Mean 
(SD) 
median  
(min-max) 
Duration of 
radiotherapy
(months) 
 
 
 
 
 
 
 
 
1: Test Mann-Whitney 
 
 
2.1.10.2.1. 
RELAPSE and type of treatment 
 
 
 
Table 26. Relapses and type of treatment 
 
Cohort a 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
relapse 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Metastasis 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Local relapse 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Other relapse 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
radical surgery 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
wide Resection 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Positive 
marginal 
resection 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Only biopsy 
No 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
19 
Yes 
 
 
 
Total 
 
 
 
Other 
treatments 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
 
2.1.10.3. 
PREVIOUS CHEMOTHERAPY 
 
 
Table 27. Previous chemotherapy 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
Previous 
chemotherapy 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
The following table will include all the chemotherapy lines prior to Pazopanib. 
Patients could have received more than one line of chemotherapy.  
 
Table 28. Prior Chemotherapy:List of treatments 
Prior Chemotherapy 
Cohort A 
Cohort B 
Total 
N (%) 
N (%) 
N (%) 
Adriamicine-Ifosfamide / 21 days 
 
 
 
Adriamicine 
 
 
 
Adriamicine / Ifosfamide / D 
actinomycin 
 
 
 
CCGM Phase I 
 
 
 
Cisplatin / Doxorubicin 
 
 
 
Dacarbazine 
 
 
 
Dacarbazine /Gemcitabin 
 
 
 
Docetaxel 
 
 
 
Docetaxel/ Gemcitabin 
 
 
 
Doxorubicin 
 
 
 
Epirubicin 
 
 
 
Eribulin 
 
 
 
Gemcitabin 
 
 
 
Gemcitabin / Taxotere 
 
 
 
Ifosfamide 
 
 
 
Mesna Ifosfamide + 
 
 
 
Ifosfamide / ADRIBLASTIN + G-CSF 
 
 
 
Ixoten 
 
 
 
Nilotinib 
 
 
 
p53-HDM2inhibitor interaction 
 
 
 
Tegafur 
 
 
 
TH-302 
 
 
 
Trabectedin 
 
 
 
 
 
Best initial response to chemotherapy: 
 


GEIS-30 STUDY 
Statistical analysis plan 
20 
prior chemotherapy Table 29. 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
Best previous 
response 
CR 
 
 
 
 
PR 
 
 
 
SD 
 
 
 
PD 
 
 
 
WITHOUT 
ASSESSMENT 
 
 
 
Total 
 
 
 
Relapse in 
last previous 
chemotherapy 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Global number of cycles and duration of initial chemotherapy: 
 
Table 30. Number of cycles and duration of previous chemotherapy 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-
Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max) 
Total number of 
chemotherapy 
cycles 
 
 
 
 
 
 
 
 
Duration of 
previous 
chemotherapy, 
until relapse 
(prior to 
Pazopanib) 
(days) 
 
 
 
 
 
 
 
 
Time from 
previous relapse 
to start with 
Pazopanib 
(days)PREVIOUS
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
2.1.11. PATHOLOGY 
 
 
Table 31. Previous pathologies 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Previous 
pathologies  
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
The following table will include all pathologies prior to the start of treatment with 
Pazopanib. The patients could have presented more than one pathology. 


GEIS-30 STUDY 
Statistical analysis plan 
21 
 
Table 32. List of previous pathologies Previous 
pathologies 
Cohort A 
Cohort B 
Total 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.12. PHYSICAL EXAMINATION 
 
 
Table 33. Physical exam 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Cardiovascular  
Normal 
 
 
 
 
Total 
 
 
 
Respiratory  
Normal 
 
 
 
 
Abnormal 
 
 
 
Total 
 
 
 
CNS  
Normal 
 
 
 
 
Not performed 
 
 
 
Not applicable 
 
 
 
Total 
 
 
 
Gastrointestinal  
Normal 
 
 
 
 
Abnormal 
 
 
 
Total 
 
 
 
Musculoskeletal  
Normal 
 
 
 
 
Abnormal 
 
 
 
Not performed 
 
 
 
Total 
 
 
 
Dermatological  
Normal 
 
 
 
 
Abnormal 
 
 
 
Not performed 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
The list of patients with abnormal results on the physical examination will be 
presented in the following table: 
 
Table 34. Patients with abnormal results  


GEIS-30 STUDY 
Statistical analysis plan 
22 
Patient 
Cohort 
Examination 
Result 
Specify 
 
 
 
 
 
 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
23 
2.2. 
COMPLIANCE WITH TREATMENT VISITS 
 
The status of completion of visits at the time of database lock: 
 
Table 35. Completion of treatment visits 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
Baseline visit 
completed 
Yes 
 
 
 
 
Total 
 
 
 
Visit day 1 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Visit week 1 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Visit week 3 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Visit week 5 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Visit week 7 
completed 
Yes 
 
 
 
 
Total 
 
 
 
Visit week 9 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Visit week 12 
completed 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Complete completion 
(from baseline to 
week 12) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
24 
2.3. 
 ITT and PP POPULATIONS 
To determine ITT and PP populations, the definitions specified in the protocol will 
be followed: 
● Analysis by Intention to Treat (ITT): Efficacy analyses will be calculated on 
the population by intention to treat. All patients participating in the study 
will be included in the efficacy analysis. 
● Analysis by Protocol (PP): Efficacy analyzes will be calculated on the 
protocol population. All patients participating in the study and who have 
received at least 3 weeks of treatment with Pazopanib (without major 
protocol deviations) will be included in the efficacy analysis. 
 
 
Table 36. ITT and PP Populations 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
 
ITT 
population 
Yes 
 
 
 
 
Total 
 
 
 
Duration tt 
Pazopanib 
(weeks) 
<3 weeks 
 
 
 
 
≥3 weeks 
 
 
 
Ongoing  
(no end date of tt) 
 
 
 
Total 
 
 
 
Population 
PP 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Test Fisherexact 
 
Pacientes with less than 3 week of pazopanib treatment: 
 
Table 37. Patients with duration of pazopanib <3 weeks 
Study Subject 
ID 
Cohort 
PP 
population 
Reason excluded from PP 
population 
Tx Pazopanib 
duration (days) 
 
 
 
 
 
 
 
 
 
 
 
2.4. 
Duration of pazopanib 
 
 
Table 38. Duration of Pazopanib treatment (days) 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean (SD) Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min -Max) 
Duration of 
treatment 
with 
Pazopanib2 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test; 2: For a patient that the end date of treatment with Pazopanib was not available, 
the date of PD / Exitus was taken as the end date of treatment. 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
25 
2.5. 
GLOBAL FOLLOW-UP 
 
 
 
Table 39. Global follow-up (weeks) ITT and PP 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) 
N Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max)- 
Global 
follow-up 
ITT 
 
 
 
 
 
 
 
 
 
 
Global 
follow-up 
PP 
 
 
 
 
 
 
 
 
 
 
1: Test Mann-Whitney 
 


GEIS-30 STUDY 
Statistical analysis plan 
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2.6. 
EFFICACY: MAIN ENDPOINT 
 
Following the instructions of the protocol primary efficacy endpoints in 
populations ITT and PP will be calculated following the criteria:  
Patients who are alive and without evidence of progression at this time will be 
considered successes, and those who have progressed or died at this time will 
be considered treatment failures. Patients in whom progression is unknown or 
not available will also be considered failures. Diagnosis of progression should be 
based on measurements of tumor lesions, according to the RECIST 1.1 criteria. 
 
2.6.1. 
EFFICACY BASED ON LOCAL ASSESSMENTS. ITT  
 
The tables below will analyze the response at 6 and 12 weeks, based on local 
assessments TAC. 
 
 
Table 40. Response to treatment: Local assessments at 6 and 12 weeks ITT 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
SD 
 
 
 
 
PD 
 
 
 
Total 
 
 
 
Response 
to 
12 weeks 
SD 
 
 
 
 
PD 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Test exacto de Fisher 
 
Responses will be recoded according to clinical benefit (CR, RP or EE) and in 
the ITT population, both at 6 and 12 weeks. 
 
Table 41. Clinical benefit, response to treatment: Local assessments at 6 and 12 weeks ITT 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
2.6.2. 
EFFICACY BASED ON LOCAL ASSESSMENTS. PP   
 
In the PP population, both at 6 and 12 weeks. 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
27
 
Table 42. Response to treatment: Local assessments at 6 and 12 weeks PP 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
SD 
 
 
 
 
PD 
 
 
 
Total 
 
 
 
Response 
to 
12 weeks 
SD 
 
 
 
 
PD 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
The responses will be recoded according to the clinical benefit (CR, RP or EE) 
and in the PP population, both at 6 and 12 weeks. 
 
Table 43. Clinical benefit, response to treatment: Local evaluations at 6 and 12 weeks PP 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 


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Statistical analysis plan 
28
2.6.3. BASED ON CENTRALIZED ASSESSMENTS. ITT 
 
The tables below will record the response at 6 and 12 weeks, based on 
centralized assessments TAC. As for the local evaluations. The centralized 
evaluations will be reviewed following the criteria specified in the protocol for the 
evaluation of the main endpoint: 
"Patients who are alive and without evidence of progression at this time will be 
considered as successes, and those who have progressed or died at this time 
will be considered as treatment failures. Patients in whom it is unknown whether 
or not there is progression will also be considered as failures. " 
 
In the ITT population, both 6 and 12 weeks. 
 
Table 44. Response to treatment: Value. Centralized at 6 and 12 weeks ITT 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
PD 
 
 
 
 
SD 
 
 
 
PR 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
PD 
 
 
 
 
SD 
 
 
 
PR 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Responses will be recoded according to clinical benefit (CR, RP or EE) and in 
the ITT population. 
 
Table 45. Clinical benefit, response to treatment: Value. centralized at 6 and 12 weeks ITT 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD ) 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
 
 
 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
29
2.6.4. 
EFFICACY BASED ON CENTRALIZED ASSESSMENTS. PP   
 
 
 
Table 46. Response to treatment: Centralized evaluations at 6 and 12 weeks PP 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
PD 
 
 
 
 
SD 
 
 
 
PR 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
PD 
 
 
 
 
SD 
 
 
 
PR 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Responses will be recoded according to clinical benefit (CR, RP or EE) and in 
the PP population. 
 
Table 47. Clinical benefit, response to treatment: Centralized evaluations at 6 and 12 
weeks PP 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% CI) 
Response 
at 
6 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
Response 
at 
12 weeks 
CLINICAL 
BENEFIT 
Yes 
 
 
 
 
No (PD) 
 
 
 
Total 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 


GEIS-30 STUDY 
Statistical analysis plan 
30
2.7. EFFICACY: SECONDARY ENDPOINT PROGRESSION FREE 
SURVIVAL (PFS) 
 
2.7.1. 
 PFS. LOCAL ASSESSMENT. ITT  
 
Table 48. Progression-free survival at 12 and 24 weeks according to cohorts (local 
assessment. ITT) 
Progression-free survival 
N 
events 
N 
patients 
at risk 
% Estimated 
cumulative survival 
ratio  
95% CI 
 
at 12 weeks 
Cohort 
A 
 
 
 
 
 
Cohort 
B 
 
 
 
 
at 24 weeks 
Cohort 
A 
 
 
 
 
Cohort 
B 
 
 
 
 
 
Strategy N (%) 
events 
Median 
(weeks) Min-Max Standard 
error 
95% CI 
p-
value1 
Progression-
free survival 
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 1. Progression-free survival according to cohorts ( Local assessment ITT). Kaplan-
Meier curve.
 
 
Table 49. Progression during follow-up (local assessment. ITT) 
 
Cohort A 
Cohort B 
Total 
p-
value 
 
N (%, 95% CI) N (%, 95% CI) 
N (%, 
95% CI) 
Progression-
free survival 
PD 
 
 
 
 
Alive: Free of 
progression 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
Table 50. Types of progressions / censorship during follow-up (local assessment. ITT) 
 
Cohort 
A 
Cohort 
B 
Total 
p-value 
 
N (%, 
95% CI) 
N (%, 
95% CI) 
N (% , 
95% CI) 
Progression-
free survival 
Progression-Disease 
 
 
 
 
progression Clinical 
progression 
 
 
 
Alive without PD at the end 
of follow-up 
 
 
 
Alive without PD: censored 
by surgery 
 
 
 
Alive without PD: 
abandonment due to 
patient decision 
 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 


GEIS-30 STUDY 
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Table 51. Time to PD (weeks) (Local assessment. ITT) 
 
Cohort A 
Cohort B 
Total 
p-value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min- Max) N 
Mean 
(SD) 
Median  
(Min-
Max) 
Time to PD 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
2.7.2. 
PFS. LOCAL ASSESSMENT. PP 
 
Table 52. Progression-free survival at 12 and 24 weeks according to cohorts (local 
assessment. PP) 
Progression-free survival N events N patients 
at risk 
% Estimated cumulative 
survival ratio  
95% CI 
 
at 12 
weeks 
Cohort A 
 
 
 
 
 
Cohort B 
 
 
 
 
at 24 
weeks 
Cohort A 
 
 
 
 
Cohort B 
 
 
 
 
 
Strategy 
N (%) 
events 
Median 
(weeks) 
Min-Max 
Standard error 
95% CI 
p-value1 
Progressi
on-free 
survival 
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 2. Progression-free survival according to cohorts ( Local assessment PP). Kaplan-
Meier curve. 
 
Table 53. Progression during follow-up (local. PP) 
 
 Cohort A 
Cohort B 
Total 
p-
value 
 
N (%, 95% CI) 
N (%, 95% CI) 
N (%, 95% 
CI) 
Progressio
n-free 
survival 
PD 
 
 
 
 
Alive: Free of 
progression 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
Table 54. Types of progressions / censorship during follow-up (local. PP) 
 
Cohort A 
Cohort B 
Total 
p-value 
 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (% , 95% 
CI) 
Progressio
n-free 
survival 
Progression-Disease 
 
 
 
 
progression Clinical progression 
 
 
 
Alive without PD at the end of follow-
up 
 
 
 
Alive without PD: censored by 
surgery 
 
 
 
Alive without PD: abandonment due 
to patient decision 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
32
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
 
Table 55. Time to PD (weeks) (Local. PP) 
 
Cohort A 
Cohort B 
Total 
p-value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min- Max) N 
Mean 
(SD) 
Median  
(Min-
Max) 
Time to PD 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
2.7.3 PFS. CENTRAL ASSESSMENT. ITT  
 
To describe the event in PFS, the protocol will be followed:  
“Overall progression-free survival will be calculated from the date of initiation of 
treatment to the first date of documented progression or date of death, whatever 
the cause. Live patients with no evidence of progression at the time of analysis 
will be censored on the date of the last follow-up. " 
 
 
Table 56. Progression-free survival at 12 and 24 weeks according to cohorts (Central 
assessment. ITT) 
Progression-free survival 
N 
events 
N 
patients 
at risk 
% Estimated 
cumulative survival 
ratio  
95% CI 
 
at 12 weeks 
Cohort 
A 
 
 
 
 
 
Cohort 
B 
 
 
 
 
at 24 weeks 
Cohort 
A 
 
 
 
 
Cohort 
B 
 
 
 
 
 
Strategy N (%) 
events 
Median 
(weeks) Min-Max Standard 
error 
95% CI 
p-
value1 
Progression-
free survival 
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 3. Progression-free survival according to cohorts ( Central assessment ITT). 
Kaplan-Meier curve. 


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Table 57. Progression during follow-up (Central assessment. ITT) 
 
Cohort A 
Cohort B 
Total 
p-
value 
 
N (%, 95% CI) N (%, 95% CI) 
N (%, 
95% CI) 
Progression-
free survival 
PD 
 
 
 
 
Alive: Free of 
progression 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
 
Table 58. Time to PD (weeks) (Central assessment. ITT) 
Cohort A 
Cohort B 
Total 
p-value1 
N Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min- Max) N Mean 
(SD) 
Median 
(Min-
Max) 
Time to 
PD 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
Table 59. Follow-up time (weeks) (Central assessment. ITT) 
Cohort A 
Cohort B 
Total 
p-value1 
N Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median 
(Min-
Max) 
Follow-
up time 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: 
Mann-WhitneyU 
test
 
 
 
2.7.4. PFS. CENTRAL ASSESSMENT. PP 
 
 
Table 60. Progression-free survival at 12 and 24 weeks according to cohorts (Central 
assessment. PP) 
Progression-free survival 
N 
events 
N 
patients 
at risk 
% Estimated 
cumulative survival 
ratio  
95% CI 
 
at 12 weeks 
Cohort 
A 
 
 
 
 
 
Cohort 
B 
 
 
 
 
at 24 weeks 
Cohort 
A 
 
 
 
 
Cohort 
B 
 
 
 
 
 
Strategy N (%) 
events 
Median 
(weeks) Min-Max Standard 
error 
95% CI 
p-
value1 
Progression-
free survival 
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 


GEIS-30 STUDY 
Statistical analysis plan 
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Figure 4. Progression-free survival according to cohorts ( Central assessment. PP). 
Kaplan-Meier curve. 
 
 
Table 61. Progression during follow-up (Central assessment. PP) 
 
Cohort A 
Cohort B 
Total 
p-
value 
 
N (%, 95% CI) N (%, 95% CI) 
N (%, 
95% CI) 
Progression-
free survival 
PD 
 
 
 
 
Alive: Free of 
progression 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
Table 62. Time to PD (weeks) (Central assessment. PP) 
Cohort A 
Cohort B 
Total 
p-value1 
N Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min- Max) N Mean 
(SD) 
Median 
(Min-
Max) 
Time to 
PD 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
 


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Statistical analysis plan 
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2.8. 
EFFICACY:ENDPOINT SECONDARY GLOBAL SURVIVAL (OS) 
 
2.8.1. 
OS. ITT  
 
 
Table 63. Overall survival at 12 and 24 weeks according to cohorts (ITT) 
Overall survival 
N 
events 
N 
patients 
at risk 
% Estimated 
cumulative survival 
ratio  
95% CI 
 
at 12 
weeks 
Cohort 
A 
 
 
 
 
 
Cohort 
B 
 
 
 
 
at 24 
weeks 
Cohort 
A 
 
 
 
 
Cohort 
B 
 
 
 
 
 
Strategy N ( %) 
events 
Median 
(weeks) Min-Max 
Standard 
error 
95% CI 
p-value1 
Overall 
survival
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 5. Overall survival according to cohorts (ITT). Kaplan-Meier curve.
 
 
Table 64. Exitus during follow-up and at 12 weeks (ITT) 
 
Cohort A 
Cohort B 
Total 
p-value 
 
N (%, 95% CI) N (%, 95% 
CI) 
N (%, 95% 
CI) 
Overall 
survival 
Exitus 
 
 
 
Live 
 
 
Loss Follow-up 
 
 
Total 
 
 
Reason 
Exitus 
No 
 
 
 
Disease 
progression 
 
 
Kidney failure 
 
 
Clinical 
deterioration 
 
 
Post-surgical 
complications 
 
 
Unknown 
 
 
Total Overall 
 
 
survival 
at 12 
weeks 
Exitus 
 
 
 
 
Live 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
Table 65. Time to exit (weeks) (ITT) 
 
Cohort A 
Cohort B 
Total 
p-value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-
Max) 


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Exit time 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
 
 
2.8.2. 
OS. PP  
 
 
Table 66. Overall survival at 12 and 24 weeks according to cohorts (PP) 
Overall survival 
N events N patients 
at risk 
% Estimated cumulative 
survival ratio  
95% CI 
 
at 12 
weeks 
Cohort A 
 
 
 
 
 
Cohort B 
 
 
 
 
at 24 
weeks 
Cohort A 
 
 
 
 
Cohort B 
 
 
 
 
 
Strategy 
N ( %) 
events 
Median 
(weeks) 
Min-Max 
Standard error 
95% CI 
p-value1 
Overall 
survival 
A 
 
 
 
 
 
 
B 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 6. Overall survival according to cohorts (PP). Kaplan-Meier curve.
 
 
Table 67. Exitus during follow-up and at 12 weeks (PP) 
 
Cohort A 
Cohort B 
Total 
p-value 
 
N (%, 95% CI) N (%, 95% 
CI) 
N (%, 95% 
CI) 
Overall 
survival 
Exitus 
 
 
 
Live 
 
 
Loss Follow-up 
 
 
Total 
 
 
Reason 
Exitus 
No 
 
 
 
Disease 
progression 
 
 
Kidney failure 
 
 
Clinical 
deterioration 
 
 
Post-surgical 
complications 
 
 
Unknown 
 
 
Total Overall 
 
 
survival 
at 12 
weeks 
Exitus 
 
 
 
 
Live 
 
 
 
Total 
 
 
 
1: Pearson Chi-square; 2: Fisher's exact test 
 
 
 
 
 


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Table 68. Time to exit (weeks) (PP) 
 
Cohort A 
Cohort B 
Total 
p-value1 
N 
Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) N 
Mean 
(SD) 
Median  
(Min-
Max) 
Exit time 
(weeks) 
 
 
 
 
 
 
 
 
 
 
1: 
Mann-Whitney 
U-test
 


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2.9. 
GMI: GROWTH MODULATION INDEX 
 
Following the definition in the protocol, the GMI will be calculated as "the ratio 
between time to progression with pazopanib (TTPp) divided by time to 
progression with the previous line of treatment (TTPp-1)".  
 
The time to PD with pazopanib is presented in the section EFFICIENCY: MAIN 
ENDPOINT and the duration of the previous chemotherapy until relapse is 
presented in Table 30. Number of cycles and duration of the previous 
chemotherapy.  
 
Table 69. Growth modulation index (GMI) (ITT) 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max) 
N 
Mean 
(SD) 
Median  
(Min-Max) 
Growth 
modulation 
index (GMI) 
 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
Table 70. Categorized GMI (ITT) 
 
Cohort A 
Cohort B 
Total 
p-value 
 
N (%) 
N (%) 
N (%) 
 
GMI  
categorized 
<1 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
Table 71. Growth modulation index (GMI) (PP) 
Cohort A 
Cohort B 
Total 
p-
value1 
N Mean 
(SD) 
Median  
(Min-Max) N Mean 
(SD) 
Median  
(Min-Max ) N Mean 
(SD) 
Median  
(Min-Max) 
 
Growth 
modulation index 
(GMI) 
 
 
 
 
 
 
 
 
 
1: Mann-Whitney U test 
 
 
Table 72. Categorized GMI (PP) 
 
Cohort A 
Cohort B 
Total 
p-value 
 
N (%) 
N ( %) 
N (%) 
 
GMI  
categorized 
<1 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 


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2.10. 
ECOG EVOLUTION 
 
 
Table 73. ECOG evolution during treatment (ITT) 
 
 
Cohort A 
Cohort B 
Total 
 
N (%) 
N (%) 
N (%) 
p-value1 
Performance 
Status ECOG 
(baseline) 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
Performance 
ECOG Status 
Day 1 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 1 
0 
 
 
 
 
1 
 
 
 
2 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 3 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 5 
0 
 
 
 
 
1 
 
 
 
2 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 7 
0 
 
 
 
 
1 
 
 
 
2 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 9 
0 
 
 
 
 
1 
 
 
 
2 
 
 
 
Total 
 
 
 
Performance 
Status ECOG 
Week 12 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
p-value3 
Basal vs. day 1 
 
 
 
 
Basal vs. week 1 
 
 
 
Basal vs. week 3 
 
 
 
Basal vs. week 5 
 
 
 
Basal vs. week 7 
 
 
 
Basal vs. week 9 
 
 
 
Basal vs. week 12 
 
 
 
1: Pearson's Chi-square; 2: Fisher's exact test; 3: Marginal homogeneity test 
 
 
 
2.11. SAFETY: SAEs AND TOXICITIES 
 
 
Following the criteria established in the protocol, "Any patient included in the 
study and who has received at least a single dose of study medication will be 
evaluable for toxicity analyzes." 
 
 
 


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AES and Toxicities Table 74. All monitoring 
 
CohortA 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
AE 
Yes 
 
 
 
 
Total 
 
 
 
toxicity 
(related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
≥3 AE grade 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
toxicity grade 
≥3 (related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
SAE (at least 
one per 
patient)3 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test; 3: patients could present more than one SAE 
 
 
Table 75. AEs and Toxicities with start date prior to treatment 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
AE 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
AE grade ≥ 3 
No 
 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Table 76. AEs and Toxicities during treatment 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
AE 
Yes 
 
 
 
 
Total 
 
 
 
Toxicity 
(related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
AE grade ≥3 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Toxicity grade 
≥3 
(related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Table 77. ESA and Toxicities after treatment 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
AE 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 


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41
Toxicity 
(related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
AE grade ≥3 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Toxicity grade 
≥3 
(related) 
No 
 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
Table 78. AE and Toxicities with no known date 
 
Cohort A 
Cohort B 
Total 
p-value 
N (%) 
N (%) 
N (%) 
AE 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Toxicity 
(related) 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
AE grade ≥3 
No 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Toxicity grade 
≥3 (related) 
No 
 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
The frequencies of all toxicities with grade ≥3 are presented below.  
 
Table 79. Frequencies of AEs grade ≥ 3 
 
Cohort A 
Cohort B 
Total 
N (%) 
N (%) 
N (%) 
Abscess of tumor mass - Grade 3 
 
 
 
ALT increased - Grade 3 
 
 
 
Anemia - Grade 3 
 
 
 
Ascites - Grade 3 
 
 
 
AST increased - Grade 3 
 
 
 
Asthenia - Grade 3 
 
 
 
Back pain - Grade 3 
 
 
 
Bilirubin increased - Grade 3 
 
 
 
Cardiac dysrhythmia / chest pain - Grade 3 
 
 
 
Diarrhea - Grade 3 
 
 
 
Fatigue - Grade 3 
 
 
 
Femur fracture - Grade 3 
 
 
 
Gastrointestinal bleeding - Grade 5 
 
 
 
General Status deterioration - Grade 5 
 
 
 
Ggt increased worsening - Grade 3 
 
 
 
Hypertension - Grade 3 
 
 
 
Hyporexia - Grade 3 
 
 
 
Muscle weakness - Grade 3 
 
 
 
Myocardial infarction - Grade 3 
 
 
 
Nausea - Grade 3 
 
 
 
Neutropenia - Grade 3 
 
 
 


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Pain - Grade 3 
 
 
 
Toothache - Grade 3 
 
 
 
Vomiting - Grade 3 
 
 
 
 
The frequencies of all (related) treatment toxicities with grade ≥3.  
 
Table 80. Frequencies of (related) toxicities grade ≥ 3 
 
Cohort A 
Cohort B 
Total 
N (%) 
N (%) 
N (%) 
ALT increased - Grade 3 
 
 
 
AST increased - Grade 3 
 
 
 
Asthenia - Grade 3 
 
 
 
Bilirubin increased - Grade 3 
 
 
 
Diarrhea - Grade 3 
 
 
 
Hypertension - Grade 3 
 
 
 
Muscle weakness - Grade 3 
 
 
 
Myocardial infarction - Grade 3 
 
 
 
Nausea - Grade 3 
 
 
 
Neutropenia - Grade 3 
 
 
 
Vomiting - Grade 3 
 
 
 
 
 
 
 
 


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All reported SAEs are listed below, by cohort. 
 
Table 81. List of all SAEs reported 
Coho
rt 
ID 
Hospital 
Sex 
Toxicity 
. 
Paz
o. 
When the AE is 
presented 
StartT
X 
dateSt
artAE 
dateE
nd 
date 
AE 
Result 
Continue
d 
SA
E 
SAE 
solution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In APPENDIX II: LISTED ALL TOXICITIES RELATED  


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3. APPENDIX I: EFFICACY ACCORDING TO GMI 
 
 
3.1. ENDPOINT MAIN ACCORDING TO GMI 
 
 
In the sections presented below , the possible relationship between the main 
efficacy variables and the categorized GIM variables is analyzed: <1, 1-1.33 
and> 3 (see Table 69. Growth modulation index (GMI) (ITT) and Table 71. 
Modulation index Growth (GMI) (PP). 
  
3.1.1. 
RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO 
GMI. ITT  
The tables below show the response to treatment at 6 and 12 weeks, based on 
local assessments of the TACs based on the categorized GMI variable: <1, 1-
1.33 and> 3. 
 
 
Table 82. Response to treatment according to GMI: Local assessment at 6 and 12 weeks 
ITT 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% CI) 
Clinical benefit at 
week 6 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
 
Yes 
 
 
 
 
Total 
 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
 
Yes 
 
 
 
 
Total 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
3.1.2. 
RESPONSE LOCAL ASSESSMENTS AND ACCORDING TO 
GMI. PP  
 
Table 83. Response to treatment according to GMI: Local evaluations at 6 and 12 weeks PP 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (% , 
95% CI) 
N (%, 95% CI) 
Clinical benefit at 
week 6 (CR, PR or 
SD) local 
No 
(PE) 
 
 
 
 
 
Yes 
 
 
 
 
Total 
 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PE) 
 
 
 
 
 
Yes 
 
 
 
 
Total 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
 


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3.1.3. RESPONSE LOCAL ASSESSMENTS AND ACCORDING 
TO GMI. ITT. IN EACH COHORT 
The tables shown below show the response to treatment at 6 and 12 weeks, in 
the ITT population, based on local assessments of TACs based on the 
categorized GMI variable: <1, 1-1.33 and> 3, separated according to each 
cohort. 
 
Table 84. Response to treatment according to GMI: local assessments at 6 and 12 weeks 
ITT. Cohort A 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% CI) 
Clinical benefit at 
week 6 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
Table 85. Response to treatment according to GMI: Local assessments at 6 and 12 weeks 
ITT. Cohort B 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% CI) 
Clinical benefit at 
week 6 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
3.1.4. RESPONSE LOCAL ASSESSMENTS AND ACCORDING 
TO GMI. PP. IN EACH COHORT 
The tables shown below show the response to treatment at 6 and 12 weeks, in 
the PP population, based on local assessments of TACs based on the 
categorized GMI variable: <1, 1-1.33 and> 3, separated according to each 
cohort. 
 
Table 86. Response to treatment according to GMI: Local evaluations at 6 and 12 weeks 
PP. Cohort A 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% CI) 
Clinical benefit a 
week 6 (CR, PR or 
No 
(PD) 
 
 
 
 


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46
SD) local 
Yes 
 
 
 
Total 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
Table 87. Response to treatment according to GMI: Local assessments at 6 and 12 weeks 
PP. Cohort B 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% CI) 
Clinical benefit a 
week 6 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
Clinical benefit at 
week 12 (CR, PR or 
SD) local 
No 
(PD) 
 
 
 
 
Yes 
 
 
 
Total 
 
 
 
 
 
1: 
Chi-square; 
2: 
Fisher 
exact


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3.2. SECONDARY ENDPOINT PFS ACCORDING TO GMI 
 
3.2.1. PFS ACCORDING TO GMI. LOCAL ASSESSMENT 
 
Figure 7. PFS according to GMI (Local Assessment. ITT). Kaplan-Meier curve. 
 
Table 88. PFS according to GMI (Local assessment. ITT) 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 8. PFS according to GMI (Local Assessment. PP). Kaplan-Meier curve. 
 
 
Table 89. PFS according to GMI (Local assessment. PP) 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
3.2.2. 
PFS ACCORDING TO GMI . LOCAL ASSESSMENT. IN 
COHORT A 
 
Figure 9. PFS according to GMI (local assessment. ITT). Kaplan-Meier curve. Cohort A 
 
 
Table 90. PFS according to GMI (local assessment. ITT) Cohort A 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Test of Log- rank 
 
 
Figure 10. PFS according to GMI (Local assessment. PP). Kaplan-Meier curve. Cohort A 
 
 
Table 91. PFS according to GMI (local assessment. PP) Cohort A 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 


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Statistical analysis plan 
48
 
 
1: Log Test- rank 
 
 
3.2.3. PFS ACCORDING TO GMI. LOCAL ASSESSMENT. IN 
COHORT B 
 
Figure 11. PFS according to GMI (local assessment. ITT). Kaplan-Meier curve. Cohort B 
 
 
Table 92. PFS according to GMI (local assessment. ITT) Cohort B 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 12. PFS according to GMI (Local assessment. PP). Kaplan-Meier curve. Cohort B 
 
 
 
Table 93. PFS according to GMI (local assessment. PP) Cohort B 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
PFS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
3.3. SECONDARY ENDPOINT OS ACCORDING TO GMI 
 
3.3.1. 
OS ACCORDING TO GM. 
 
 
Figure 13. OS according to GMI (ITT). Kaplan-Meier curve. 
 
 
Table 94. OS according to GMI (ITT) 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
 


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Statistical analysis plan 
49
 
Figure 14. OS according to GMI (PP). Kaplan-Meier curve. 
 
 
Table 95. OS according to GMI (PP) 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
3.3.2. 
OS ACCORDING TO GMI. IN COHORT A 
 
Figure 15. OS according to GMI (ITT). Kaplan-Meier curve. Cohort A 
 
 
Table 96. OS according to GMI (ITT) Cohort A 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
Figure 16 OS according to GMI (PP). Kaplan-Meier curve. Cohort A 
 
 
Table 97. OS according to GMI (PP) Cohort A 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
1-1.33 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 
 
 
3.3.3. 
OS ACCORDING GMI. IN COHORT B 
 
Figure 17. OS according to GMI (ITT). Kaplan-Meier curve. Cohort B 
 
 
Table 98. OS according to GMI (ITT) Cohort B 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank test 


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Statistical analysis plan 
50
 
 
Figure 18. OS according GMI (PP). Kaplan-Meier curve. Cohort B 
 
 
Table 99. OS according to GMI (PP) Cohort B 
 
GMI 
N (%) 
events 
Median 
(weeks) 
Standard 
error 
95% CI 
p-value1 
OS 
<1 
 
 
 
 
 
> 1.33 
 
 
 
 
Overall 
 
 
 
 
 
 
1: Log-rank 
 
 
 
 
 
 
 
 


GEIS-30 STUDY 
Statistical analysis plan 
51
3.4. ECOG test (BASAL) ACCORDING GMI 
 
3.4.1. 
ECOG BASAL ACCORDING TO GMI. ITT  
 
The following tables analyze the possible relationship between the variables 
ECOG baseline and categorized GMI: <1, 1-1.33 and> 3. 
 
Table 100. Baseline ECOG according to GMI (ITT) 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (%, 95% 
CI) 
N (% , 95% CI) 
Performance 
status 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher exact test 
 
3.4.2. 
ECOG BASAL ACCORDING TO GMI. PP  
 
 
Table 101. Baseline ECOG according to GMI (PP) 
 
Categorized GMI 
 
<1 
1-1.33 
> 1.33 
Total 
p-value 
N (%, 
95% CI) 
N (%, 95% 
CI) 
N (%, 
95% CI) 
N ( %, 95% CI) 
Performance 
status 
0 
 
 
 
 
1 
 
 
 
Total 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
3.5. GRADE FNCLCC (BASAL) ACCORDING TO GMI 
 
3.5.1. 
 GRADE FNCLCC BASAL ACCORDING TO GMI. 
ITT   
 
The following tables analyze the possible relationship between the variables 
grade FNCLCC baseline and categorized GMI: <1, 1-1.33 and> 3. 
 
 
Table 102. GRADE FNCLCC baseline according to GMI (ITT) 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-
value 
N (%, 95% CI) N (%, 95% CI) N (%, 95% CI) N ( %, 95% CI) 
GRADE 
FNCLCC 
1 
 
 
 
 
0.0172 
2 
 
 
 
 
3 
 
 
 
 
Total 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 


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Statistical analysis plan 
52
 
 
 3.5.2. 
GRADE FNCLCC BASAL ACCORDING TO GMI. PP  
 
Table 103. GRADE FNCLCC baseline according to GMI (PP) 
 
GMI categorized 
 
<1 
1-1.33 
> 1.33 
Total 
p-
value 
N (%, 95% CI) N (%, 95% CI) N (%, 95% CI) N ( %, 95% CI) 
GRADE 
FNCLCC 
1 
 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
Total 
 
 
 
 
 
 
1: Chi-square; 2: Fisher's exact test 
 
 
4. ANNEX II: LISTING OF ALL RELATED 
TOXICITIES All the related toxicities collected in the database are listed below, 
by cohort. 
 
Table 104. List of all related toxicities 
Cohort ID Hospital 
Sex 
Toxicity 
Relati
ve. 
Pazo. 
When the AE is 
presented 
StartT
X 
dateSt
art 
date 
AE 
End 
date 
AE 
Result 
Continuo
us 
SA
E 
SAE 
solution