Conditions: Angiosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
Open-label phase II trial investigating the efficacy and safety of the investigational combination of pazopanib and paclitaxel.

Detailed description:
Open-label phase II trial investigating the efficacy and safety of the investigational combination of pazopanib and paclitaxel.This multi-center, open-label, prospective, single arm phase II study was designed to evaluate the clinical efficacy and safety of the experimental combination of pazopanib with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma.The safety evaluations (physical examination, laboratory checks as defined in protocol, toxicity/adverse event assessment according Eastern Cooperative Oncology Group version 4.0) are scheduled every cycle at day 1, 8, 15 and 29 (= day 1 of the next cycle).

Arms:
arm 1: Paclitaxel administered every 28 days at day 1, day 8 and day 15 as a 2h intravenous infusion in a dose of 70mg/m2 in combination with pazopanib in a daily oral dose of 800mg (2x400mg)

Interventions: intervention 1: Pazopanib + Paclitaxel
Intervention descriptions: intervention 1: pazopanib in combination with paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Protocol 
 
 
 
 
 
 
EVA (evaluation of votrient in angiosarcoma) is a single-arm, multicenter, open 
label phase II trial to evaluate the efficacy of pazopanib in combination with 
paclitaxel in advanced and relapsed angiosarcoma 
 
 
 
 
 
 
 
 
 
 
 
 
EudraCT Nr.: 2012-005846-39  
Novartis Common Code (NCC): CPZP034BDE01T 
Phase: Phase II 
Version: 3.0 dated 28.Januar 2016 
Study Code: GISG-06 
 
 
 
 
 
 
 
CONFIDENTIAL:  
 
This protocol contains confidential information and is intended solely to guide the trial. Parties not involved in the 
clinical trial must not be allowed to view the protocol. The protocol may not be used for any other purpose without 
the prior written consent of the sponsor. 
 
 


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Sponsor: 
University Heidelberg,  
Medical Faculty Mannheim,  
represented by the chancellor of Heidelberg University 
Zentrale Universitätsverwaltung 
Seminarstr 2 
69117 Heidelberg 
Tel. +49 6221 54-2100 & -2001 
Fax: +49 6221 54-2618 
kanzler@zuv.uni-heidelberg.de 
 
 
Principal Investigator  
Prof. Dr. Peter Hohenberger MD 
University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, 
Division of Surgical Oncology & Thoracic Surgery 
Theodor-Kutzer-Ufer 1-3, 
68167 Mannheim,  
Tel.: 0621/3832609, Fax 0621/3831479,  
Peter.Hohenberger@umm.de 
 
 
Medical Study Coordinator/Author of protocol: 
Dr. Daniel Pink, MD 
Klinik für Hämatologie, Onkologie und Palliativmedizin 
Sarkomzentrum Berlin-Brandenburg 
HELIOS Klinikum Bad Saarow 
Pieskower Str. 33 
15526 Bad Saarow 
Tel.: +49 33631 7 3527, Fax: +49 33631 7 3528 
daniel.pink@helios-gesundheit.de 
 
 
 
 
 
 


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Biometry 
Dr. rer. nat. Geraldine Rauch  
Institut für Medizinische Biometrie und Informatik (IMBI)  
Im Neuenheimer Feld 305 
69120 Heidelberg  
Tel.: +49 (0)6 221 56 1932  
Fax: +49 (0)6 221 56 41 95  
rauch@imbi.uni-heidelberg.de 
 
 
Data management 
Institut für Medizinische Biometrie und Informatik (IMBI)  
Im Neuenheimer Feld 130  
69120 Heidelberg  
Tel.: +49 (0)6 221 56 5500  
Fax : +49 (0)6 221 56 41 95  
 
Regulatory Affairs Management as delegated by Sponsor 
Studienzentrale (GISG) der Sektion  
Spezielle Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Klinik  
Mannheim University Medicine, Medical Faculty Mannheim  
Theodor-Kutzer-Ufer 1-3  
68167 Mannheim  
Tel.: +49 (0) 621-383-3433 
Fax: +49 (0) 621-383-1479 
studien@gisg.de 
 
 
SARCOMA PLATFORM AUSTRIA (SPA) 
Lindgrabengasse 8 
A-1230 Vienna 
Austria 
marika.rosner@gmail.com 
 
Monitoring 
Studienzentrale (GISG) der Sektion  
Spezielle Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Klinik  
Mannheim University Medicine, Medical Faculty Mannheim  
Theodor-Kutzer-Ufer 1-3  
68167 Mannheim  
Tel.: +49 (0) 621-383-3433 
Fax: +49 (0) 621-383-1479 
studien@gisg.de 
 
 
Koordinationszentrum für Klinische Studien (KKS) at Heidelberg University Hospital  
Voßstr. 2/ Gebäude 4410  
69115 Heidelberg  
Tel.: 06221/56-39039  
Fax: 06221/56-33508  
 
 
 
 


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SARCOMA PLATFORM AUSTRIA (SPA) 
Lindgrabengasse 8 
A-1230 Vienna 
Austria 
marika.rosner@gmail.com 
 
 
Pharmakovigilance/SAE reporting  
Dr. med. Jacek Hajda  
Koordinationszentrum für Klinische Studien (KKS) at Heidelberg University Hospital  
Voßstr. 2/ Gebäude 4410  
69115 Heidelberg  
Tel.: +49 (0) 6221/5634507  
Fax: +49 (0) 6221/5633725  
 


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Study Sites  
 
Germany: 
 
Mannheim: 
Prof. Dr. med. Peter Hohenberger  
01 
 
Spezielle Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Klinik  
 
 
Universitätsmedizin Mannheim, Universität Heidelberg,  
 
 
Medizinische Fakultät Mannheim  
 
 
Theodor-Kutzer-Ufer 1-3  
 
 
68167 Mannheim  
 
 
Tel.: +49 (0) 621 383 3433 
Fax: +49 (0) 621 3831479  
 
 
Berlin: 
PD Dr. med. Peter Reichardt  
02 
 
HELIOS Klinikum Berlin-Buch 
 
 
Klinik für Interdisziplinäre Onkologie 
 
 
Sarkomzentrum Berlin-Brandenburg  
 
 
Schwanebecker Chaussee 50 
 
 
13125 Berlin 
 
 
Tel.: +49 (0) 30 9401 54850 
 
 
Fax: +49 (0) 30 9401 54859 
 
Hannover 
PD Dr. V. Grünwald 
03 
 
Universität Hannover 
 
 
Hämatologie, Hämostaseologie und Onkologie  
Medizinische Hochschule Hannover 
 
 
Carl-Neuberg-Str. 1 
 
 
30625Hannover 
Tel.: +49 (0) 511 532-0 
Fax: +49 (0) 511 532-5550 
 
Dresden 
Dr. med. Stephan Richter  
04 
 
Universitätsklinikum Carl Gustav Carus, Medizinische Klinik I, 
 
 
Fetscherstraße 74 
 
 
01307 Dresden 
 
 
Tel.: +49 (0) 351 4587109 
 
 
Fax: +49 (0) 351 458 5362 
 
Essen  
PD Dr. med. S. Bauer 
05 
 
Universitätsklinikum Essen 
 
 
Innere Klinik (Tumorforschung) 
 
 
Hufelandstr. 55 
 
 
45122 Essen 
Tel.: +49 (0) 201 723 85558 
Fax: +49 (0) 201 723 5618 
 
München 
Dr. Lars Lindner 
06 
 
Klinikum der Universität München Campus Großhadern  
 
 
Medizinische Klinik und Poliklinik III  
 
 
Marchioninistraße 15  
 
 
81377 München 
 
 
Tel.: +49 (0) 89 7095 7777  
 
 
 
Fax: +49 (0) 89 7095 4776 


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Hamburg 
Dr. med. Maxim Kebenko 
07 
 
Universitätsklinikum Hamburg Eppendorf 
 
 
Medizinische Klinik II 
 
 
Hämatologie und Sektion Pneumologie 
 
 
Haus Ost 24, Postfach 2. Stock 
 
 
Martinistraße 52 
 
 
20246 Hamburg 
 
 
Tel.: +49 (0) 40 7410 0 
 
 
Fax: +49 (0) 40 7410 58581 
 
Bad Saarow Dr. med. Daniel Pink 
11 
 
Klinik für Hämatologie, Onkologie und Palliativmedizin 
 
 
Sarkomzentrum Berlin-Brandenburg 
 
 
Pieskower Straße 33 
 
 
15526 Bad Saarow 
 
 
Tel.: +49 (0) 33631 735 27 
 
 
Fax: +49 (0) 033631 7 35 28 
 
 
 
Austria: 
 
Wien:  
Prof. Dr. Thomas Brodowicz (Medizinischer Koordinator Österreich) 
08 
 
AKH-Wien / Medical University of Vienna 
Dep. of Internal Medicine I,  
Klinische Abteilung für Onkologie 
Währinger Gürtel 18-20 
1090 Wien; Austria 
 
 
Tel.: +43-1-40400-4429-0 
 
Fax: +43-1-40400-4452-0 
 
Graz  
Univ. Prof. Dr. med. Herbert Stöger 
09 
 
Medizinische Universität Graz 
Klinische Abteilung für Onkologie 
Auenbruggerplatz 15 
8036 Graz; Austria 
 
 
Tel.: +43-316-385 1 3711 
 
Fax: +43-316-385 1 3355 
 
 
Cooperating partners for translational research project  
 
Prof. Dr. med. C. A. Schmidt, kommissarischer Direktor der Klinik und Poliklinik für Innere 
Medizin C; Hämatologie und Onkologie – Transplantationszentrum, Universitätsmedizin 
Greifswald, Sauerbruchstraße, Diagnostikzentrum, 17475 Greifswald, Germany oder other 
cooperating institutions  


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Table of contents  
 
Table of contents  
Table of contents ................................................................................................................... 7 
Schedule of study assessments ............................................................................................ 9 
1 
Introduction and Study’s rationale ..........................................................................12 
1.1 
Angiosarcomas: INtroduction and systemic therapy ................................... 12 
1.2 
Pazopanib ................................................................................................... 14 
1.3 
Combination of antiangiogenic substances and chemotherapy of sarcomas
 15 
1.4 
Experience with combination of Paclitaxel and Pazopanib.......................... 15 
1.5 
Study rationale ............................................................................................ 16 
2 
Objectives ad Endpoints ........................................................................................17 
2.1 
Objectives ................................................................................................... 17 
2.2 
Primary endpoint ......................................................................................... 17 
2.3 
Secondary endpoints .................................................................................. 17 
2.4 
Subgoupanalyses ........................................................................................ 17 
3 
Study concept und Design .....................................................................................17 
4 
Study Subjects .......................................................................................................18 
4.1 
Subject Number .......................................................................................... 18 
4.2 
Inclusion criteria .......................................................................................... 18 
4.3 
Exclusion criteria ......................................................................................... 20 
5 
Combination therapy ..............................................................................................22 
5.1 
Medication ................................................................................................... 22 
5.1.1 
Study drug Pazopanib (GW786034, Votrient ®) ............................................... 22 
5.1.2 
Paclitaxel ............................................................................................................ 26 
5.2 
Therapy ....................................................................................................... 26 
5.2.1 
Paclitaxel ............................................................................................................ 27 
5.2.2 
Pazopanib ........................................................................................................... 27 
5.2.3 
Storage, issue and return of study drug Pazopanib ............................................ 28 
5.2.4 
Duration of treatment ......................................................................................... 28 
5.2.5 
Concomitant medication .................................................................................... 28 
5.2.6 
Non-permitted medication .................................................................................. 29 
5.2.7 
Special recommendations regarding anticoagulation ......................................... 34 
5.2.8 
Special recommendations regarding potentially hypoglycemia-inducing 
therapies including insulin ............................................................................................... 35 
5.3 
Dose- and application modifications ............................................................ 35 
5.3.1 
Dose- and application modification of Pazopanib ............................................. 36 
5.3.2 
Dosis- und Applikationsmodifikation von Paclitaxel ........................................ 45 
6 
Assessments and follow-up ...................................................................................46 
6.1 
Assessments before study enrollment ........................................................ 46 
6.2 
Assessments during treatment .................................................................... 48 
6.2.1 
During treamtenmt with Paclitaxel on day 1, day 8 und day 15 in every cycle . 48 
6.2.2 
Additonal aassessments at beginnung of every cycle in the first 12 weeks ....... 48 
6.2.3 
Every 8 weeks or when clinically indicated every 4 weeks, especially during 
monotherapy with pazopanib. .......................................................................................... 49 
6.3 
Behandlungsende/ Sicherheitsnachbeobachtung („Safety Follow-Up“) ...... 49 
6.4 
Follow-Up .................................................................................................... 50 
6.5 
Exclusion of patients from the study or termination of study participation ... 51 
6.6 
Premature termination of clinical study........................................................ 51 
7 
Adverse events ......................................................................................................51 


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7.1 
Definitions ................................................................................................... 51 
7.1.1 
Adverse events ................................................................................................... 51 
7.1.2 
Serious adverse events ....................................................................................... 52 
7.1.3 
Schwangerschaft ................................................................................................. 52 
7.1.4 
Expected and unexpected events ........................................................................ 52 
7.1.5 
suspected unexpected serious adverse reaction (SUSAR) ................................. 53 
7.1.6 
Study specific SAEs ........................................................................................... 53 
7.1.7 
Exceptions for SAE reporting ............................................................................ 53 
7.2 
Observation period and documentation....................................................... 54 
7.3 
Meldung schwerwiegender unerwünschter Ereignisse durch den Prüfer .... 56 
7.4 
Expedited reporting by the sponsor: reporting of adverse events to the ethics 
committee, competent authority and all investigators .................................. 57 
7.5 
Ermergency treatment ................................................................................. 57 
8 
Statistical methods .................................................................................................58 
8.1 
Statistical analysis and justification for subject number ............................... 58 
8.2 
Analysis populations ................................................................................... 60 
9 
Data management .................................................................................................60 
9.1 
Data collection ............................................................................................. 60 
9.2 
Data handling .............................................................................................. 60 
9.3 
Storage and archiving of data ..................................................................... 61 
10 
Ethical and legal aspects .......................................................................................61 
10.1 Good clinical practise .................................................................................. 61 
10.2 Practice of Informing and Consenting Study Subjects ................................ 61 
10.3 Data protection ............................................................................................ 62 
10.4 Responsibilities of the investigator .............................................................. 62 
10.5 Approval of protocol and protocol amendments .......................................... 62 
10.6 Ongoing information from the Ethics Committee and the Competent Autority
 63 
10.7 Notification of German local authorities ....................................................... 63 
10.8 Registration of Clinical trial .......................................................................... 64 
10.9 Insurance .................................................................................................... 64 
11 
Translationale Research ........................................................................................64 
11.1 Rationale ..................................................................................................... 64 
11.2 Patient informatioj and informed consent to translational research ............. 66 
11.3 Collection, storage and pseudonymization of samples ............................... 66 
11.4 Processing of the obtained samples ........................................................... 67 
11.5 Data protection and traceability of results ................................................... 67 
12 
Quality assurance ..................................................................................................68 
12.1 Monitoring ................................................................................................... 68 
12.2 Audits and Inspections ................................................................................ 68 
13 
Agreements ...........................................................................................................69 
13.1 Financing of the clinical trial ........................................................................ 69 
13.2 Financial disclosure ..................................................................................... 69 
13.3 Reports ........................................................................................................ 69 
13.4 Publication ................................................................................................... 69 
14 
SIGNATURES .......................................................................................................70 
15 
INVESTIGATOR’s DECLARATION ........................................................................71 
16 
Appendix A – Bibliographie ....................................................................................72 
17 
Appendix B: CYP3A3/4 influencers of Plasma-Pazopanib-concentrations .............75 
 
 
 


 
 
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Schedule of study assessments  
 
(1) All la assessments can be performed 1-2 days before visit  
(2) Hb, Hkt, Erys Leukos, Thrombos, Differential blood count, plastine time (PTT) 
(4) ECG in the first 12 weeks only at beginning of each cycle, then evey 8 weeks.  
(5) Tumor control until progresion of disease  
(6) if clinically indicated  
(7) if Paclitaxel treatments end based on Polyneuropathy, follow up is done by phone after 4 weeks  
(8) CT oder MRI of thorax and abdomen and of all known tumor locations  
(9) Skin lesion will be summarized as target and non-target lesions and photografically documented combined with a  mm ruler as panoramic shot and as zoomed shot. A lesion defined as target lesion needs to have a minimal size of 
≥ 1,0 cm at start. Raised lesions will be measured by a caliber.  
(10) Lab parameters and vital signs have to be determined in week 3, 5, 7 and 9 and months 3 and 4 during Panzopanib application. If clinically indicated, these determinations should be stricter (at least every 4 weeks).  
Event 
Baseline 
Treatment period 
End of treatment / Safety 
Follow-Up 
Follow-Up 
Planned visits 
Screening 
- 28 days 
6 cycles (á 4 weeks) always 
day 1, 8 and 15 before 
application of Paclitaxel 
Every 8 weeks 
(+/- 7 days) 
30 days after end of 
tretament with Pazopanib 
every 12 weeks 
(+/- 14 days) 
Informed consent 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Anamnesis 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
 
Vital signs 
X 
X10 
X10 
X 
 
ECOG-Performance Status 
X 
X 
X 
X 
 
Blood count, Serum-Chemistry1,2 
X 
X10 
X10 
X 
 
Coaggzlation1,3 
X 
X 
X 
X 
 
Beta-HCG 
X 
 
X 
X 
 
Urine status /UPC 
X 
X 
X 
X 
 
TSH, 
X 
 
X 
X 
 
ECG 
X 
X4 
X 
X 
 
Echo 
X 
 
 
X6 
 
Documentation of measurable skin lesions 
(measuring and photo)9 
X 
 
X 
X 
X5 
Tumor assessment8 
X 
 
X 
X 
X5 
Paclitaxel 
 
day 1, 8 and 15 
 
 
 
Pazopanib 
 
daily 
 
 
Tumor therapy after end of teatment 
 
 
 
X 
Concomitant medication 
X 
X 
 
Adverse events7 
 
X 
 


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ABBREVIATIONS 
 
AMG   
Deutsches Arzneimittelgesetz (=German Pharmaceuticals Act) 
AS 
 
Angiosarcoma(s) 
AE 
 
Adverse Event 
BET 
 
Brust erhaltende Therapie (=Breast-conserving therapy) 
BfArM   
Bundesinstitut für Arzneimittel und Medizinprodukte  
CA  
 
Competent Authority 
CRF   
Case Report Form  
CTCAE  
Common Toxicity Criteria for Adverse Events  
CVA 
 
Cerebrovascular Accident 
DGHO  
Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie (=German 
Society of hematology and medical oncology) 
DLT   
Dose limiting Toxcity  
DMC   
Data Monitoring Committee  
DVT 
 
Deep venous thrombosis 
ECOG  
Eastern Cooperative Oncology Group 
EC  
 
Ethic Committee  
GCP   
Good Clinical Practice  
GCP-V  
GCP-Verordnung  
IB  
 
Investigator´s Brochure (Prüferinformation)  
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
IMBI 
 Institut für Medizinische Biometrie und Informatik (=Institute of Biometry and 
informatics) 
INN  
 
International Nonproprietary Name (generic name)  
INR  
 
International normalized ratio (coagulation test)  
ISF  
 
Investigator site file  
ISRCTN  
International Standard Randomised Controlled Trial Number  
KKS HD  
Koordinationszentrum für Klinische Studien Heidelberg  
LKP   
Leiter der Klinischen Prüfung (gem. AMG §40) (=National Coordinator) 
OS 
 
Overall survival 
PDGF  
Platelet Derived Growth Factor 
PDGFR 
Platelet Derived Growth Factor Receptor 
PE 
 
Pulmonary embolism 
PFS-R  
Rate of progression-free survival  


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PID 
 
Patient identificator 
PPE 
 
Palmar-plantar Erythrodysesthesia Syndrom 
PSN 
 
Pseudonym 
R 
 
Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
 
Ribonucleic acid 
SAE 
  
Serious Adverse Event  
SAR   
Serios Drug Reaction  
STS 
 
Soft Ttissue Sarcoma 
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TIA 
Transitory Ischemic Attack 
TMF   
Trial Master File  
AE  
 
Adverse Event 
ULN   
Upper Level of Normality  
VEGF  
Vascular Endothelial Growth Factor 
 
 


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1 
Introduction and Study’s rationale  
1.1 
Angiosarcomas: Introduction and systemic therapy 
 
Angiosarcomas (AS) are very rare tumor diseases, accounting for approximately 2-3% of all 
soft tissue sarcomas; thus, approximately 60 to 90 new cases per year can be assumed in 
Germany [18]. In principle, angiosarcomas can occur anywhere in the body, with approximately 
60% arising cutaneously (especially head/neck) and the remainder in the soft tissues or 
internal organs. The three most common localizations are the skin of the head and neck, the 
chest, and the extremities. The median age at initial diagnosis was 52-65 years in different 
case series. AS of the head/neck and chest are more common in women; both sexes are 
equally affected in the other localizations [19, 20, 21, 22]. 
Some AS occur secondary to radiation or in chronic lymphedema (the latter: 
lymphangiosarcoma; Stewart-Treves syndrome) - e.g., in a case series [1], 59% of 
angiosarcomas of the breast were secondary angiosarcomas after BET and radiation therapy 
of a breast carcinoma. 
The treatment of choice for localized AS, as for other AS, is complete resection possibly 
followed by postradiation. After 5 years, 31-41% of patients with non-metastatic 
angiosarcomas are still alive [18, 19, 20, 21, 22].  
Approximately 15% of patients with AS are already metastasized at initial diagnosis; a relevant 
proportion of other patients develop metastases in the course of their disease. Metastatic AS 
are not curable in the vast majority of cases; thus, patients are usually in a basic palliative 
situation in which systemic drug therapy is the primary treatment. The median overall survival 
of patients with metastatic AS is 8-12 months [18, 19, 20, 21, 22]. 
Case reports and smaller retrospective analyses exist suggesting efficacy of various 
chemotherapeutic agents such as anthracyclines, ifosfamide, liposomal doxorubicin, 
vinorelbine, trosfosfamide, or of "molecular targeted agents" such as thalidomide, sunitinib, 
sorafenib, pazopanib, and bevacizumab. Some larger studies that have evaluated the efficacy 
of doxorubicin-based chemotherapy regimens (e.g., doxorubicin+ifosfamide) in patients with 
various soft tissue sarcomas have also included patients with AS; however, in most cases, 
they have not been specifically evaluated [18].  
Overall, as with systemic treatment of patients with other soft tissue sarcomas, doxorubicin or 
the doxorubicin+ifosfamide combination is believed to be standard therapy in patients with 
advanced or metastatic AS [18]. 
 
 
 


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In advanced or metastatic AS, unlike other soft tissue sarcomas, therapy with paclitaxel is also 
effective both in the first line and in pretreated patients. It is administered both tri-weekly at a 
dose of 175mg/m2 and weekly at 60-80mg/m2. The efficacy of paclitaxel in patients with AS 
was initially reported in the form of case reports and retrospective analyses; but was later 
confirmed by a prospective phase II study ("AngioTax" study) [2]. In this study, 30 patients 
were treated weekly with paclitaxel 80mg/m2. The objective response rate in this study was 
19%. After 3 months, 75% of patients were progression-free; after 6 months, 24% of patients 
were still progression-free. The efficacy of paclitaxel in this study appeared to be comparable 
in pretreated and chemonaive patients; although the case number was certainly too small for 
more extensive analyses. 
Overall, chemotherapy with paclitaxel is a standard guideline-based treatment option for 
patients with advanced and metastatic angiosarcoma [37]. 
 
In two other prospective phase II trials of new agents in patients with different soft tissue 
sarcoma subtypes, patients with AS were evaluated in a subgroup-specific manner. One of the 
two studies evaluated the efficacy of imatinib, which was summarily found to be unconvincingly 
effective in AS [3].  
In the other study, in which a total of 145 patients with advanced and metastatic soft tissue 
sarcomas were treated with the RAF kinase and VEGF-R inhibitor sorafenib 800mg daily, 37 
patients with AS were also included and evaluated as planned stratum. Of these 37 patients, 
5 had a true response to therapy (response rate 14%); 65% of patients were progression-free 
at 3 months and 31% at 6 months [4] 
 
Case reports or initial results of prospective studies have also been published or presented at 
congresses for other substances that, like sorafenib, inhibit the VEGF receptor (e.g., sunitinib, 
pazopanib [6, 7]) or bind to VEGF and thus suppress its effect (bevacizumab [8]), suggesting 
that these drugs may also be effective in the treatment of patients with AS. 
This clinical observation is in good agreement with various in vitro or preclinical studies that 
have shown that VEGF receptors are mutated and/or overexpressed in a high proportion of 
AS, that the downstream signaling cascade of these receptors is also often strongly activated 
in AS, and that these alterations are often detectable even in early AS; thus, in the 
pathogenesis of AS they probably play a major role (review e.g. [5]). 
 
 
 
 


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In summary, although several effective systemic therapy options exist for the treatment of 
patients with advanced and metastatic AS, such that patients with AS now live longer with 
optimal therapy than they did a decade ago; nevertheless, most patients continue to die from 
their disease, e.g., due to secondary resistance. Thus, there is an urgent need to improve 
systemic therapy. 
One approach is the search for additional effective substances that are also effective in AS 
resistant to other drugs; another approach is the combination of already existing substances 
with as few side effects as possible, such as paclitaxel applied weekly with a VEGF inhibitor. 
 
1.2 
Pazopanib 
 
Pazopanib is a multi-tyrosine kinase inhibitor approved in Europe for the treatment of advanced 
and/or metastatic renal cell carcinoma and for the treatment of certain subtypes of soft tissue 
sarcoma. Pazopanib is taken orally at a dose of 800 mg 1x daily as continuous therapy. 
 
Pazopanib inhibits the tyrosine kinase-mediated action of the receptors of VEGFR 1, 2, and 3, 
as well as PDGFR-α, PDGFR-β, and c-kit. This results in simultaneous antiproliferative and 
antiangiogenic effects. The most common adverse effects include decreased appetite, 
disturbances in taste perception, hypertension, diarrhea, nausea, vomiting, abdominal pain, 
change in hair color, fatigue, and elevated liver enzymes; although pazopanib appears to have 
a particularly favorable side effect profile compared with other multi-tyrosine kinase inhibitors 
that inhibit VEGF-R, among others. 
Clinical efficacy and tolerability were evaluated in a phase II and a phase III trial for patients 
with advanced soft tissue sarcoma (STS).  
In the randomized, placebo-controlled phase III trial in STS, pazopanib significantly prolonged 
progression-free survival compared with placebo [9]. This study did not specifically evaluate 
the efficacy of pazopanib in patients with AS, so no further experience is available to date in 
this regard. Few published single case reports or unpublished anecdotal experience from large 
sarcoma centers exist that pazopanib can result in a longer lasting treatment response in 
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1.3 
Combination of antiangiogenic substances and chemotherapy of sarcomas 
 
The combination of antiangiogenic agents with chemotherapy is a common therapeutic 
approach in many solid tumors. In recent years, several of these combination therapies have 
been approved in Europe for the treatment of patients with solid tumors in specific settings 
(e.g., bevazicumab and chemotherapy for metastatic colorectal carcinoma, lung carcinoma, 
breast carcinoma).  
It is suggested that weekly low-dose paclitaxel may also have antiangiogenic effects [10]; thus, 
in particular, the combination of this compound with antiangiogenic drugs is also of interest 
and has been investigated, leading, for example, to the approval of the combination of 
bevazicumab with paclitaxel in the first-line treatment of patients with metastatic breast 
carcinomas (in the pivotal trial, patients had received weekly paclitaxel). 
 
To review the combination of antiangiogenic agents with chemotherapy in patients with soft 
tissue sarcomas, there are only sporadic published prospective studies [12, 16] and few other 
published experiences in the form of single case reports or case collections [11, 13, 14]; 
especially for the use of such combinations in patients with advanced or metastatic AS, there 
are only single case reports without major significance [15]. 
 
1.4 
Experience with combination of Paclitaxel and Pazopanib 
 
A phase I study was conducted to evaluate the combination of pazopanib with weekly paclitaxel 
in patients with various advanced solid tumors to evaluate the maximum tolerated regimen 
(MTR) and dose-limiting side effects and pharmacokinetics of pazopanib in this combination 
[17]. In this study, paclitaxel was given weekly on days 1, 8, and 15 every 28 days in 
combination with daily oral pazopanib. 
There were 26 patients enrolled in the study and 17 of these patients were treated with the 
MTR of pazopanib 800mg/day combined with paclitaxel 80mg/m2 on day 1, 8 and 15 every 28 
days. The pazopanib at this dose resulted in 14% lower paclitaxel clearance and 31% higher 
maximum paclitaxel concentration than when paclitaxel was given alone. When the 
combination was given in the MTR, the paclitaxel AUC was 26% higher than when paclitaxel 
mono was given at the same dose. These changes were explained by the fact that pazopanib 
is a weak inhibitor of CYP3A4 and CYP2C8. 
 
 


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The most common side effects of the combination were fatigue (69%), nausea (58%), diarrhea 
(54%), alopecia (35%), vomiting (35%), and rash (31%). Most adverse events (92%) were 
classified as grade 1/2 adverse events. 
Transaminase elevations were observed, leading to dose reductions of pazopanib in 4 of 10 
patients (at all dose levels). 
Arterial hypertension was the most common cardiovascular adverse event, with arterial 
hypertension already present in some patients before study inclusion. Dose modifications of 
antihypertensives were necessary in a proportion of patients. 
 
Dose limiting side effects (DLT) were grade-3 abscess and grade-2 hyperbilirubinemia at the 
MTR dose level; no DLT occurred at the other dose levels. 
In summary, the authors concluded that pazopanib at a dose of 800mg/day can be safely 
combined with paclitaxel at therapeutic doses of 80mg/m² when applied every 28 days on days 
1, 8, and 15. 
There is no published experience on combination therapy of paclitaxel with pazopanib in 
angiosarcoma. 
 
1.5 
Study rationale 
 
Due to the very limited prognosis of patients with advanced and metastatic AS, there is a great 
need for more effective therapeutic options, as described in 1.1, which lead to a longer 
response to therapy, especially if they are well tolerated. 
Since both paclitaxel and VEGF inhibitors appear to be effective and tolerable systemic 
therapy options in patients with AS as outlined above, and since pazopanib is the only VEGF-
R inhibitor with a proven efficacy that has a marketing authorization for the treatment of patients 
with advanced soft tissue sarcomas, the combination of paclitaxel and pazopanib appears to 
be a particularly interesting combination therapy to investigate for patients with advanced or 
metastatic AS. 
The combination of paclitaxel with pazopanib is a safe therapy with few side effects in the MTR 
established in the cited phase I study. 
In the Angiotax study [2], patients were treated with paclitaxel 80mg/m² weekly, and due to 
dose reductions and treatment delays, the mean applied paclitaxel dose was 53.4 mg/m²/week 
in all patients who received at least two cycles of chemotherapy.  
Due to the above described increases in maximum paclitaxel concentration and paclitaxel AUC 
in combination with pazopanib, and because the risk of e.g. peripheral nerve damage during 
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use the paclitaxel in the EVA study at a slightly reduced dose of 70mg/m² (not 80mg/m² as in 
the MTR of the phase I study), despite the low side effect rate of the MTR in the phase I study. 
 
2 
Objectives ad Endpoints  
2.1 
Objectives 
The objective of this phase II study is to evaluate the efficacy of pazopanib in combination with 
paclitaxel in the treatment of patients with advanced or metastatic angiosarcoma. Secondary 
objective is to evaluate the tolerability of the combination. 
2.2 
Primary endpoint 
The primary endpoint is progression-free survival at 6 months (PFS). 
2.3 
Secondary endpoints 
The secondary endpoints are overall survival (OS), response (R), (according to RECIST 
version 1.1), and severity of incident adverse events or toxicities (according to CTCAE, version 
4.0). 
2.4 
Subgoupanalyses 
The following subgroup analyses are planned:  
1. cutaneous AS vs. visceral AS (PFS, OS, R). 
2. primary AS vs. secondary AS (PFS, OS, R) 
 
3 
Study concept und Design 
 
This is a multicenter, open-label, prospective, single-arm phase II study designed to evaluate 
the clinical efficacy and safety of the experimental combination of pazopanib with paclitaxel in 
the treatment of patients with advanced or metastatic angiosarcomas. 
Angiosarcomas are rare serious diseases for which new therapeutic approaches are needed 
on the one hand, but on the other hand only a very limited number of patients are likely to be 
available for study participation even in large centers. For this reason, a multi-arm study design 
and randomization were deliberately avoided in order to allow the study to be conducted in a 
manageable period of time and thus to generate usable results. 
 
 


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Paclitaxel is given weekly on days 1, 8 and 15 every 28 days as a 2 hour intravenous infusion 
at a dose of 70mg/m² for 6 cycles in combination with pazopanib at a daily oral dose of 800mg. 
If progression is not observed after 6 cycles of combination therapy, pazopanib is taken alone 
until progression. 
 
Safety assessments (physical examination, laboratory controls, toxicity determination/side 
effect profile according to CTCAE version 4.0) will be performed in each therapy cycle on day 
1, 8, 15 and 29 (= day 1 of the next therapy cycle).  
Response will be documented clinically by photography for measurable skin lesions and 
determined radiologically by CT/MRI according to RECIST version 1.1 for the other target 
lesions every 8 weeks. 
4 
Study Subjects  
4.1 
Subject Number 
 
A maximum of 44 participants are to be enrolled in the clinical trial. Enrollment and treatment 
of participants will be conducted in 10 study centers in Germany and Austria. Patients who 
have taken pazopanib at least once will not be replaced even if they withdraw from the study 
early. Otherwise, patient replacement is planned. 
 
4.2 
Inclusion criteria 
 
Inclusion criteria 
 
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 .Procedures conducted as part of the subject’s routine clinical management (e.g., 
blood count, imaging studies) and obtained prior to signing informed consent may be 
utilized for screening or baseline purposes provided these procedures are conducted 
as specified in the protocol 
2. 
Patient is able to give informed consent and able to understand the nature and scope 
of the clinical trial  
3. 
Age ≥ 18 years  
4. 
Life expectancy > 3 months  
5. 
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6. 
Histologically confirmed angiosarcoma, primary and secondary angiosarcoma (e.g. 
radiation-induced or angiosarcoma in chronical lymphedema) are eligible Patienten mit 
histologisch gesichertem Angiosarkom. Es können Patienten mit primären oder 
sekundären Angiosarkomen (z.B. strahleninduziert bzw. AS in chronischem 
Lymphödem) eingeschlossen werden. 
7. 
Tumor must be locally advanced (unresectable) or metastatic. A progression must be 
documented within a 6-month period prior to screening. 
 
8. 
ECOG performance status  ≤ 1  
 
9. 
At least one measurable skin lesion or one measurable radiological (CT or MRI) target 
lesion (RECIST 1.1)  
10. 
Adequate organ system function as described in table 1 
 
 
Table 1: Definitions for adequate organ functions  
Blood count 
Absolute Neutrophile number (ANC) 
Hemoglobine 
Thrombocytes 
Coaggulation 
Prothrombin time (PT) or INR 
partial Thromboplastinzeit (PTT) 
Liver 
Total bilirubine 
ASAT and ALAT 
Kindney 
Serum creatinine 
if Serum creatinine >1.5 mg/dL, then 
calculated glomerular filtration rate (GFR) 
Protein/creatinine ratio (UPC) 
if UPC ≥1, then 24h-Urine protein 
 
≥1.5 X 109/L 
≥9 g/dL (5.6 mmol/L) 
≥100 X 109/L 
 
≤1.2 X upper normal limit (ULN) 
≤1.2 X ULN 
 
≤1.5 X ULN 
≤2.5 X ULN 
 
≤1.5 mg/dL (133 μmol/L) 
 
≥50 mL/min 
<1 
<1g 
 
11.  
Women can participate in the study if they are unable to give birth (i.e. there is a 
physiological inability to become pregnant). This includes all women  
- after a hysterectomy, 
- after a bilateral ovariectomy,  
- after bilateral tubal ligation, 
 


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- postmenopausal women whose last menstrual bleeding was more than 1 year ago. 
 
Women of childbearing potential must agree to adequate contraception and have a 
negative serum pregnancy test within two weeks prior to the first dose of study drug.  
 
The pregnancy test should be as close as possible to the first dose application of study 
drug. Contraceptive measures must be continued for 6 months after the end of therapy. 
Appropriate contraceptive methods are as follows if used continuously and according 
to the package insert and as directed by the physician: 
 
- An intrauterine device with a documented failure rate (Pearl index) less than 1% per 
year. 
- A partner who was vasectomized prior to the patient's study entry, who is also the 
only sexual partner of this woman. 
- Absolute sexual abstinence from 14 days prior to study drug intake, during intake until 
at least 6 months after last study drug intake. 
- Double barrier contraception (condom with spermicidal creams or contraceptive foam; 
diaphragm with spermicides; or condom and diaphragm with spermicides). 
- Breastfeeding women should discontinue this before starting study medication and 
should refrain from breastfeeding for the duration of treatment and until 14 days after 
the last dose of study medication. 
 
 
Note: Oral contraceptives do not provide adequate protection due to potential drug 
interactions.  
 
4.3 
Exclusion criteria 
 
1. patients requiring active therapy for a malignancy other than angiosarcoma. 
2. treatment with a taxane within the last 12 months before study inclusion. 
3.Presence of CNS or leptomeningeal sarcomatosis. Screening with head imaging (cranial CT 
or MRI) is necessary only if clinical abnormalities are present.  
4. clinically significant gastrointestinal disorders/ abnormalities that could increase the risk for 
gastrointestinal bleeding.  
a. 
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b. 
Known intraluminal metastasis/metastases at risk for bleeding 
c. 
Chronic inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other 
gastrointestinal findings with increased risk of perforation 
d. 
Patient history of abdominal fistulae, gastrointestinal perforations, or intra-abdominal 
abscesses within 28 days prior to initiation of study treatment 
5. clinically significant gastrointestinal disorders/ abnormalities that could affect absorption of 
the study drug  
a. 
Malabsorption syndrome 
b. 
Gastrectomy or major surgical resection of the small intestine 
6. presence of uncontrolled infections 
7. QT prolongation on ECG, QTc > 480 ms. 
8. clinically significant cardiovascular disease within the last 6 months prior to study inclusion, 
e.g., apoplexy (CVA) including transient ischemic attacks (TIA), myocardial infarction, unstable 
angina, NYHA III or IV heart failure, pulmonary artery embolism, untreated deep vein 
thrombosis (DVT) (patients with deep vein thrombosis who have been fully anticoagulated for 
at least 6 weeks may be included) 
9. "Major" surgical procedure within the last 28 days, non-healing wound or fracture 
10. poorly controlled hypertension (defined as systolic blood pressure of ≥150 mmHg or 
diastolic blood pressure of ≥100 mmHg). Note: Initiation or adjustment of antihypertensive 
medication is permitted prior to study entry. 
11. hemoptysis (≥½ teaspoon of fresh blood within 8 weeks before first administration of study 
medication). 
12.Presence of massive bleeding or bleeding tendency. 
13. presence of endobronchial lesions and/or lesions in the pulmonary vasculature 
14. uncontrolled cerebral seizures, CNS or psychiatric disease that jeopardizes patient safety 
or impairs compliance for medication use 
15. pregnant women and nursing mothers 
16. patient is unable or unwilling to discontinue taking medications not allowed by the protocol 
for at least 14 days prior to administration of the first study medication and for the duration of 
the study.  
17. chemotherapy or radiotherapy 14 days prior to the first dose of study medication. 
 
 
 
 
 


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18. any persistent toxicity from previous anti-cancer therapies that is >Grade 1 and/or 
progressive in severity, except alopecia. 
19. concurrent participation in another interventional clinical trial or 
 
Participation in a clinical trial, 4 weeks prior to study initiation. 
 
Note: Any treatment with pazopanib prior to study inclusion is NOT allowed. 
 
5 
Combination therapy 
5.1 
Medication 
5.1.1 Study drug Pazopanib (GW786034, Votrient ®) 
The "small molecule" VEGF receptor inhibitor, pazopanib (GW786034) is in clinical 
development for the treatment of a variety of human cancers. 
Pazopanib has been approved by the EMA for the first-line treatment of adult patients with 
advanced renal cell carcinoma and for the treatment of patients who had received prior 
cytokine therapy for their advanced disease, as well as for the treatment of adult patients with 
selected subtypes of advanced soft tissue sarcoma who had received prior chemotherapy for 
their metastatic disease or who had progressed within 12 months of (neo-)adjuvant therapy.  
Pazopanib is a potent and highly selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 
tyrosine kinases. In preclinical angiogenesis studies, pazopanib inhibited VEGF-dependent 
angiogenesis in a dose-dependent manner. Twice-daily application of pazopanib in xenograft 
tumor models significantly inhibited tumor growth in mice implanted with various human tumor 
cells. 
 
5.1.1.1 Non-clinical studies 
A number of non-clinical pharmacological, pharmacokinetic and toxicological studies have 
been performed with pazopanib. These are described in the current investigator brochure 
 
5.1.1.2 Effects on human beings 
More than 1400 tumor patients have been enrolled in completed or ongoing clinical trials with 
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administration, has an adequate safety profile and is promisingly effective in the treatment of 
various oncological situations. 
5.1.1.3 Summary of pharmacokinetic and pharmacodynamic  data 
The results of pharmacokinetic and pharmacodynamic analyses show that pazopanib is 
absorbed after oral administration. A plateau level is achieved with continuous administration 
of 800 mg daily. Pazopanib has been tested at doses up to 2,000 mg in clinical trials without 
dose-limiting toxicity. 
 
5.1.1.4 Drug interactions  
In vitro data indicate that pazopanib is a potential inhibitor of CYP2C9, CYP1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Under high concentrations, 
pazopanib may lead to induction of human CYP3A4. Simultaneous administration of 
pazopanib and drugs that are substrates for CYP450 enzymes and that have the potential to 
cause serious and life-threatening side effects is prohibited. 
 
5.1.1.5 Summary of adverse events (AE) and serious adverse reactions 
 
The most common documented adverse reactions are diarrhea, fatigue, nausea, hypertension, 
hair color changes (depigmentation), anorexia, vomiting, dysgeusia, headache, abdominal 
pain, rash, increase in ASAT and ALAT, constipation, cough, and arthralgias.  
Most of these adverse events were classified as Grade 1 or 2 according to CTCAE version 
4.0.  
The most common Grade 3 or 4 events are hypertension, fatigue, diarrhea, and increase in 
transaminases ALAT and ASAT.  
Less common adverse events include hand-foot syndrome, mucositis/stomatitis, proteinuria, 
venous thrombosis, and bleeding.  
Uncommon was the occurrence of intestinal perforation and arterial thrombosis.  
Serious adverse events that occurred in patients enrolled in pazopanib trials (regardless of 
treatment assignment) were vomiting, diarrhea, abdominal pain, hypertension, hypertensive 
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Within one study, nephrotic syndrome due to thrombotic microangiopathy occurred with 
pazopanib. An association with pazopanib cannot be ruled out. The event was resolved. 
A single fatal liver failure occurred with the combination of gemcitabine and pazopanib. 
Although liver failures including fatal outcomes have been reported for both agents, this SAR 
was considered unexpected. 
There is no clinical evidence that pazopanib affects QTc time. Nevertheless, within clinical 
trials with pazopanib, severe adverse events due to QT-time prolongation or the occurrence of 
torsade de pointes arrhythmia occurred twice. One patient received amiodarone as part of the 
event and another patient discontinued pazopanib due to spinal hemorrhage caused by 
hemangioblastoma. Seven days after the event, the patient developed polymorphic ventricular 
tachycardia. Both SARs could be resolved  
 
5.1.1.6 EORTC Phase II Study ( EORTC62043/ EVG20002) 
Pazopanib was evaluated in patients with relapsed and refractory soft tissue sarcomas in a 
single-arm phase II EORTC study. This study was stratified according to histology 
(liposarcomas vs. leiomyosarcomas vs. synovial sarcomas vs. other soft tissue sarcomas).  
The drug was well tolerated: of 142 study participants, 6 patients were documented with grade 
3-4 neutropenia, 2 patients with grade 3-4 thrombocytopenia, 9 patients with grade 3-4 
bilirubinemia, 5 patients with ASAT elevation, 7 patients with ALAT elevation, and 4 patients 
with creatinine elevation.  
Other main toxicities encountered were (all grades; grades 3-4) fatigue (36.6%; 7.7%), 
hypertension (40.1%; 7.7%), nausea (35.9%; 0.7%), diarrhea (30.3%; 3.5%), and 
hypopigmentation (36.6%; 0%). 
 
5.1.1.7 Summary of laboratory abnormalities under pazopanib treatment 
Pazopanib studies conducted to date indicate that the following therapy-induced laboratory 
abnormalities (all grades) commonly occur in patients treated with pazopanib: ASAT and ALAT 
elevation; hyperbilirubinemia; elevation of alkaline phosphatase, amylase, lipase, and 
creatinine; hyponatremia; hyperkalemia; lymphopenia; leukopenia; thrombocytopenia; 
neutropenia and anemia; hyperglycemia; and TSH elevation.  
There was rarely a simultaneous increase in transaminases and bilirubin. For example, only 2 
(<1%) patients were noted in the VEG102616 study.  
Elevations of lipase and amylase were primarily grade 1 and 2, and most were asymptomatic, 
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hyperkalemia did not occur simultaneously in the same patient, so there was no evidence of 
adrenocortical insufficiency. 
 
5.1.1.8 Summary of data on efficacy in STS  
 
The efficacy and safety of pazopanib in soft tissue sarcoma was evaluated in a randomized 
double-blind placebo-controlled multicenter phase III study (VEG110727). A total of 369 
patients with advanced soft tissue sarcoma were randomized to receive 800 mg of pazopanib 
once daily or placebo. Essentially, only patients with selected histologic soft tissue sarcoma 
subtypes were allowed to participate in the study; therefore, the efficacy and safety of 
pazopanib can be considered proven only for these soft tissue sarcoma subtypes. 
Patients with the following tumor types were included: 
Fibroplastic sarcomas (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid 
fibrosarcoma, malignant solitary fibrous tumors); so-called fibrohistocytic sarcomas 
(pleomorphic malignant fibrous histiocytoma[MFH], giant cell MFH, inflammatory MFH); 
Leiomyosarcoma; malignant glomus tumors; skeletal muscle sarcomas (pleomorphic and 
alveolar rhabdomyosarcomas); vascular sarcomas (epithelial hemangioendothelioma, 
angiosarcoma); Sarcomas of uncertain differentiation (synovial sarcoma, epithelioid 
sarcoma, alveolar soft tissue sarcoma, clear cell sarcoma, desmoplastic small and round cell 
tumors, extrarenal rhabdoid tumor, malignant mesenchymoma, perivascular epithelioid cell 
tumors, intimal sarcoma) excluding chondrosarcoma, Ewing tumor/primitive neuroectodermal 
tumors (PNET); malignant peripheral nerve sheath tumors; undifferentiated soft tissue 
sarcomas not otherwise specified (NOS); and other sarcoma types (unless listed as excluded). 
Patients with the following tumor types were excluded: 
Adipocytic sarcoma (all subtypes); all rhabdomyosarcomas that are not alveolar or 
pleomorphic; 
chondrosarcoma; 
osteosarcoma; 
Ewing 
tumor/PNET, 
GIST; 
dermatofibrosarcoma protuberans; inflammatory myofibroblastic sarcoma; malignant 
mesothelioma; and mixed mesodermal tumors of the uterus. Note that patients with adipocytic 
sarcoma were excluded from the pivotal phase III study because in the previous phase II study 
(VEG20002), the observed effect of pazopanib (PFS at week 12) in adipocytic sarcoma did not 
reach the required response rate to allow further clinical review. Other main inclusion criteria 
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sarcoma with disease progression within 6 months of metastatic disease therapy or recurrence 
within 12 months of (neo-)adjuvant therapy. 
Ninety-eight percent (98%) of study participants had received doxorubicin, 70% ifosfamide, 
and 65% at least three or more chemotherapeutic agents before enrollment. 
Patients were stratified by baseline WHO general status (WHO Performance Status [PS] 0 or 
1) and number of prior lines of systemic therapy for advanced disease (0 or 1 versus 2+). In 
each treatment group, there was a slightly higher percentage of patients with more than 2 prior 
lines of systemic therapy for advanced disease (58% and 55% in the placebo and pazopanib 
treatment arms, respectively) compared with no or 1 prior line of systemic therapy (42% and 
45% in the placebo and pazopanib treatment arms, respectively). 
The median duration of follow-up of study participants (defined as day of randomization to day 
of last contact or death) was comparable in both study arms; 9.36 months [range, 0.69 to 23.0 
months] in the placebo arm and 10.04 months [range, 0.2 to 24.3 months] in the pazopanib 
arm. 
The primary objective of this study was progression-free survival (PFS by independent 
radiologic assessment); secondary end points included overall survival (OS), overall response 
rate, and duration of response. 
Investigator assessment showed a similar prolongation of PFS in the pazopanib arm compared 
to the placebo arm (HR in the overall ITT population: 0.39; 95% CI, 0.30 to 0.52, p<0.001).  
No significant difference in OS was observed between the two treatment arms at the time of 
final analysis after 76% (280/369) of events occurred (HR: 0.87; 95% CI, 0.67; 1.12; p<0.256). 
 
5.1.2 Paclitaxel 
Paclitaxel is a widely used cytotoxic drug. It is indicated as monotherapy or combination 
therapy for advanced or metastatic non-small cell lung cancer, ovarian cancer, and breast 
cancer, among others. Chemotherapy with paclitaxel is a guideline-based treatment option for 
patients with advanced and metastatic angiosarcoma. 
 
5.2 
Therapy 
In this study, an interval of 4 weeks (28 days) of drug use is referred to as a "treatment period" 
or "treatment cycle."  
 
 
 


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The investigational drug pazopanib is used as an add-on to guideline-compliant chemotherapy 
with paclitaxel. 
5.2.1 Paclitaxel 
Paclitaxel will be purchased through the participating center. Paclitaxel will be given every 28 
days on days 1, 8, and 15 as a 2-h intravenous infusion at a dose of 70 mg/m² in 
combination with pazopanib at a daily oral dose of 800 mg.  
 
Paclitaxel will be provided as a guideline-compliant routine chemotherapy by the responsible 
pharmacy at the study sites as a commercial product. There is no separate labeling or 
additional study-related documentation. 
 
5.2.2 Pazopanib 
 
Pazopanib is available as 200 mg and 400 mg white tablets, each containing pazopanib 
monohydrochloride salt corresponding to the free base of 200 and 400 mg. 
  
We recommend the application of two 400 mg tablets to reach the initial dose of 800 mg. The 
200 mg tablets should be used only in case of dose de-escalation.  
 
All patients will receive pazopanib 800 mg orally once daily during study treatment.  
- Pazopanib should be taken at least one hour before and two hours after meals. Care must 
be taken not to crush or divide the tablets, as this will alter bioavailability. The tablets must be 
taken undivided.  
- The time of day when the study medication is taken should be relatively constant. 
- If a dose is forgotten, the dose must be taken as soon as possible but at least 12 hours before 
taking the next dose. 
- If the next dose is less than 12 hours away, the patient should skip the missed dose and take 
the next dose as scheduled. 
- If the patient vomits after taking pazopanib, the next dose should be taken as scheduled. The 
tablet that may have been vomited will not be replaced. 
 
 
 


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. 
5.2.3 Storage, issue and return of study drug Pazopanib 
The study drug Pazopanib is provided by the company Novartis Pharma GmbH. The study 
drug is delivered in doses of 68 tablets 400mg each and 34 tablets 200mg each. Pazopanib 
should not be stored above 25°C for an extended period of time. The investigator will dispense 
the study medication to the study participants. Study participants will be instructed to bring the 
study medication and empty doses to each study visit. Continuous intake of study medication 
will be verified and documented at regularly scheduled study visits. Empty or opened tablet 
doses will be stored at the center until monitoring. The destruction of the empty or opened 
tablet doses will be carried out by the responsible monitor directly at the study center after 
monitoring has been completed. 
 
5.2.4 Duration of treatment 
Treatment with paclitaxel is administered over 6 cycles. Premature discontinuation of paclitaxel 
therapy is necessary in the event of disease progression or intolerable side effects (see section 
5.3.2). In particular, in the presence of peripheral polyneuropathy CTC AE grade 2 (or higher), 
therapy with paclitaxel should be discontinued. Pazopanib therapy is continued if paclitaxel is 
discontinued after the 6th treatment cycle without progression. Pazopanib therapy is continued 
until progression or the occurrence of limiting side effects. If intolerable pazopanib-related 
adverse events occur during combination therapy, paclitaxel therapy will be continued as 
monotherapy up to and including cycle 6 if no disease progression or intolerable adverse 
events occur. 
.  
5.2.5 Concomitant medication 
All concomitant medications taken during the study must be documented in the patient record. 
Patients should receive any necessary supportive treatment while on therapy in the study. This 
includes transfusion of blood and blood products, treatment with antibiotics, erythropoietin, 
bisphosphonates and adequate pain therapy if indicated. 
5.2.5.1 Prophylaxis of hypersensitivity reactions 
 
Paclitaxel contains macrogolglycerol ricinoleate 35 (Ph.Eur.), which may cause allergic 
reactions. Paclitaxel should be used only under the supervision of a physician experienced in 
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equipment must be available for emergency treatment. Patients must have been pretreated 
with corticosteroids, antihistamines, and H2 antagonists: 
-Dexamethasone 4 mg orally approximately 12 hours prior to paclitaxel 
-Dexamethasone 12 mg i.v. 30 to 60 minutes before paclitaxel, 
-Diphenhydramine 50 mg i.v. or comparable antihistamine 30 to 60 minutes before paclitaxel. 
-Cimetidine 300 mg i.v. or ranitidine 50 mg i.v. 30 to 60 minutes before paclitaxel 
 
 
5.2.5.2 Antiemesis 
Antiemetic prophylaxis with granisetron 1 mg i.v. or ondansetron 8 mg i.v. is recommended 
before any administration of paclitaxel. In case of emesis, proceed according to local 
institutional guidelines. 
. 
5.2.5.3 Antibiotics 
In patients with diarrhea and neutropenia, even in the afebrile situation, empiric use of 
antibiotics as prophylaxis for sepsis should be strongly considered. The approach should be 
based on local institutional guidelines or on DGHO guidelines. Of importance, quinolone 
antibiotics are not recommended because of potential QT time prolongation. 
 
5.2.5.4 Growth factors 
Hematopoietic growth factors (e.g., G- or GM-CSF) should be used according to local 
institutional guidelines for therapy of febrile neutropenia or as primary or secondary prophylaxis 
for delayed hematologic reconstitution in the previous treatment cycle. Growth factor therapy 
must be completed at least 48 hours prior to initiation of re-chemotherapy. 
5.2.6 Non-permitted medication 
Patients must not receive any other antitumor drug therapy during the study treatment. This 
excludes the administration of biphosphonates mentioned under the conditions of chapter 
5.2.5. 
Concurrent treatment with potent CYP3A4 (see Appendix B), P-glycoprotein (P-gp), and breast 
cancer resistance protein (BCRP) inhibitors should be avoided due to the risk of increased 
exposure to pazopanib. Consideration should be given to switching to other drugs that do not  
 
 


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inhibit CYP3A4, P-gp, or BCRP, or inhibit them only slightly. 
Concurrent treatment with CYP3A4 inducers should be avoided because of the risk of 
decreased pazopanib exposure. 
Cases of hyperglycemia have been observed with concomitant treatment with ketoconazole. 
Grapefruit juice should be avoided during treatment with pazopanib. 
5.2.6.1 CYP3A4-, P-gp-, BCRP-Inhibitors 
 
In vitro studies suggest that oxidative metabolism of pazopanib in human liver microsomes 
occurs primarily via CYP3A4, and to a lesser extent via CYP1A2 and CYP2C8. Therefore, 
CYP3A4 inhibitors and inducers may alter the metabolism of pazopanib.  
 
Pazopanib is a substrate for CYP3A4, P-gp, and BCRP. Co-administration of pazopanib (400 
mg once daily) with the potent CYP3A4 and P-gp inhibitor ketoconazole (400 mg once daily) 
for 5 consecutive days resulted in mean increases in AUC(0 - 24) and Cmax of pazopanib of 
66% and 45%, respectively, relative to pazopanib alone (400 mg once daily for 7 days). A 
comparison of the pharmacokinetic parameters Cmax (range of mean values 27.5 to 58.1 
μg/ml) and AUC(0 - 24) (range of mean values 48.7 to 1040 μg*h/ml) after administration of 
800 mg pazopanib alone and after administration of 400 mg pazopanib with 400 mg 
ketoconazole (mean Cmax 59.2 μg/ml, mean AUC(0 - 24) 1300 μg*h/ml) indicates that in the 
presence of a strong CYP3A4 and P-gp inhibitor, dose reduction of pazopanib to 400 mg once 
daily results in systemic exposure similar to that after administration of 800 mg pazopanib once 
daily alone in the majority of patients. However, systemic exposure to pazopanib may be higher 
in some patients than after 800 mg of pazopanib alone. Co-administration of pazopanib with 
other potent CYP3A4 family inhibitors (e.g., itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase 
pazopanib concentrations. Grapefruit juice contains a CYP-3A4 inhibitor and may likewise 
increase plasma pazopanib concentrations. 
Administration of 1,500 mg lapatinib (a substrate and weak inhibitor of CYP3A4and P-gp and 
a strong inhibitor of BCRP) with 800 mg pazopanib resulted in an increase in mean AUC(0-24) 
and Cmax values of approximately 50% to 60% compared with 800 mg pazopanib alone. 
Inhibition of P-gp and/or BCRP by lapatinib likely contributed to the increased pazopanib 
exposure. Concomitant administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor 
such as lapatinib may increase plasma pazopanib concentrations. Similarly, concomitant 
administration of pazopanib with potent P-gp or BCRP inhibitors may alter pazopanib exposure 
and distribution, including distribution to the central nervous system (CNS). Combinations with  


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potent P-gp or BCRP inhibitors should be avoided; alternatively, the choice of a concomitant 
medication with little or no P-gp or BCRP inhibitory potential is recommended. 
 
Drugs that inhibit CYP3A4 may result in increased pazopanib plasma concentrations. 
Concomitant use of potent CYP3A4 inhibitors is prohibited from 14 days prior to 
initiation of study medication until the end of study treatment, so selection of alternative 
concomitant medications with only low or no inhibition of CYP3A4 is recommended. If no 
medically acceptable alternative to a potent CYP3A4 inhibitor is available, the pazopanib dose 
should be reduced to 400 mg daily when administered concomitantly. In such cases, special 
attention should be paid to side effects. If potentially drug-related adverse events occur, further 
dose reduction should be considered. 
 
Strong CYP3A4 inhibitors are besides others: 
- Antibiotics: Clarithromycin, telithromycin, troleandomycin. 
- HIV protease inhibitors: ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir 
- Antifungals: Itraconazole, ketoconazole, vorikonazole, fluconazole 
- antidepressants: nefazodone 
- Third-generation antihistamines: Terfenadine 
- Food: grapefruit juice 
 
5.2.6.2  CYP3A4-, P-gp-, BCRP-Inducers 
CYP3A4 inducers may decrease plasma pazopanib concentrations. It is recommended to 
choose alternative concomitant drugs with only little or no induction of CYP3A4, explicitly 
excluding from this recommendation the prophylactic administration of steroids prior to the 
application of paclitaxel mentioned in the protocol under "Prophylaxis of Hypersensitivity 
Reactions". 
 
CYP3A4-Inducers are bisides others: 
 
- Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40mg), prednisone (>10mg), 
methylprednisolone (>8mg), dexamethasone (>1.5mg). 
- Anticonvulsants: phenytoin, carbamazepine, phenobarbital, oxcarbazepine. 
- HIV virustatics: Efavirenz, Nevirapine 
- Others: modafinil, pioglitazone, troglitazone 
 


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- Medicinal plants/natural products: Amber 
CYP3A4 inducers such as rifampicin may lead to a decrease in plasma pazopanib 
concentrations. Concomitant administration of pazopanib with potent P-gp or BCRP inducers 
may alter pazopanib exposure and distribution, including distribution to the CNS. The choice 
of an alternative concomitant medication with little or no enzyme- or transporter-inducing 
potential is recommended 
 
5.2.6.3 Effect of Pazoplanib on other medication  
In vitro human liver microsome studies demonstrated that pazopanib inhibits CYP enzymes 
1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 enzymes 
was demonstrated in a PXR assay in human cells in vitro. Clinical pharmacology studies with 
once-daily administration of 800 mg pazopanib demonstrate that pazopanib has no clinically 
relevant effect on the pharmacokinetics of caffeine (CYP1A2 model substrate), warfarin 
(CYP2C9 model substrate), or omeprazole (CYP2C19 model substrate) in cancer patients.  
Pazopanib administration resulted in an increase in mean AUC and Cmax values of midazolam 
(CYP3A4 
model 
substrate) 
of 
approximately 
30% 
and 
an 
increase 
in 
the 
dextromethorphan/dextrophan ratio of 33% to 64% in urine after oral administration of 
dextromethorphan (CYP2D6 model substrate). Concomitant administration of 800 mg 
pazopanib once daily and 80mg/m² paclitaxel (CYP3A4 and CYP2C8 substrate) once weekly 
resulted in a mean increase in AUC and Cmax values of paclitaxel of 25% and 31%, 
respectively. 
Based on IC50 values in vitro and Cmax values in plasma in vivo, the pazopanib metabolites 
GSK1268992 and GSK1268997 could contribute to the net inhibitory effect of pazopanib on 
BCRP. Furthermore, inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract 
cannot be excluded. Caution is required when pazopanib is co-administered with other oral 
BCRP and P-gp substrates. In vitro, pazopanib inhibited the human organic anion transport 
polypeptide (OATP1B1). An influence of pazopanib on the pharmacokinetics of OATP1B1 
substrates (e.g., statins) cannot be excluded. 
Pazopanib is an inhibitor of uridine diphospho-glucuronosyl transferase enzyme 1A1 
(UGT1A1) in vitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and 
UGT1A1. Co-administration of 400 mg pazopanib once daily with 250 mg/m² cetuximab and 
150 mg/m² irinotecan resulted in an approximately 20% increase in the systemic exposure of 
SN-38. Pazopanib may have a greater effect on the disposition of SN-38 relative to subjects  
 
 


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with the wild-type allele in subjects with the UGT1A1*28 polymorphism. However, the UGT1A1 
genotype is not always predictive of the effect of pazopanib on SN-38 disposition. Caution 
should be exercised when pazopanib is coadministered with UGT1A1 substrates. 
 
Simultaneous use of pazopanib and certain drugs (substrates of CYP3A4, CYP2C8, and 
CYP2D6) with a narrow therapeutic window should be undertaken with CAUTION because of 
the potential for alteration of the pharmacologic effects of these drugs or the increased risk for 
serious or life-threatening adverse reactions associated with these drugs (see below) due to 
secondary inhibition of CYP enzymes by pazopanib.  
It should be added that although the potential for drug-drug interaction with such drugs 
decreases after pazopanib is discontinued, a fundamental potential for such interactions 
initially remains because of the long half-life of pazopanib (mean 30.9 hours). Therefore, 
CAUTION should be exercised for at least 7 days up to 15 days after the last dose of pazopanib 
when such drugs are used. 
 
These drugs include besides others: 
- Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine (potentially 
increased risk of developing ergot toxicity, which includes severe vasospasm and can lead to 
peripheral but also cerebral ischemia). 
- Neuroleptics: Pimozide (increased risk of QT time prolongation, ventricular arrhythmia, and 
sudden cardiac death) 
- Antiarrhythmics and other drugs that cause QT time prolongation: Bepridil, flecainide, 
lidocaine, mexiletine, amiodarone, quinidines, propafenone 
- Immunomodulators: cyclosporine, tacrolimus, sirolimus (potentially increased risk of nephro- 
and neurotoxicity) 
- Others: quetiapine, risperidone, clozapine, atomoxetine 
 
5.2.6.4 Effect of concomitant use of Pazopanib and Simvastatin 
 
Concomitant use of pazopanib and simvastatin increases the incidence of ALAT (GPT) 
elevations. Results of a meta-analysis of pooled data from clinical trials with pazopanib showed 
that ALAT (GPT) levels >3 × ULN were reported in 126/895 (14%) of patients not taking statins 
compared to 11/41 (27%) of patients taking concomitant simvastatin (p=0.038). If a patient 
receiving concomitant simvastatin develops ALAT (GPT) elevations, pazopanib dosing 
guidelines should be followed and simvastatin should be discontinued. In addition, concomitant  


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use of pazopanib and other statins should be used with caution, as insufficient data are 
currently available to estimate their impact on ALAT (GPT) levels. It cannot be excluded that 
pazopanib affects the pharmacokinetics of other statins (e.g., atorvastatin, fluvastatin, 
pravastatin, rosuvastatin). 
 
5.2.6.5 Influence of food on the pharmacokinetics of Pazopanib 
Administration of pazopanib with high or low fat meals resulted in an approximately 2-fold 
increase in AUC and Cmax values. Therefore, pazopanib should be taken either at least 1 
hour before or 2 hours after a meal 
 
5.2.6.6 Drugs that raise the pH of the stomach 
 
Co-administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib 
by approximately 40% (AUC and Cmax). Co-administration of pazopanib with drugs that raise 
gastric pH should be avoided. If concomitant use of a proton pump inhibitor (PPI) is medically 
necessary, it is recommended that the pazopanib dose be taken on an empty stomach once 
daily in the evening along with the PPI.  
If, in addition to the prophylactic administration of antihistamines prior to paclitaxel mentioned 
in the protocol under "Prophylaxis of Hypersensitivity Reactions," concomitant use of an H2 
receptor antagonist is medically necessary, it is recommended that the pazopanib dose be 
taken on an empty stomach once daily at least 2 hours before or 10 hours after the H2 receptor 
antagonist. Pazopanib should be taken at least 1 hour before or 2 hours after the administration 
of short-acting antacids 
5.2.7 Special recommendations regarding anticoagulation  
Drug interaction studies in cancer patients showed that pazopanib has no effect on the 
metabolism of s-warfarin. Nevertheless, hemorrhagic events have been documented in clinical 
trials with pazopanib. Therefore, caution should be exercised when prescribing pazopanib in 
patients at increased risk of bleeding or patients receiving concurrent anticoagulation (e.g., 
warfarin or its derivatives, low-molecular-weight heparin, unfractionated heparin). Patients 
receiving simultaneous anticoagulation should be monitored regularly for relevant coagulation 
parameters and for clinical indications of bleeding. 
 
 


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5.2.8 Special recommendations regarding potentially hypoglycemia-inducing 
therapies including insulin  
Drug interaction studies in cancer patients found that there are no clinically relevant 
pharmacokinetic interactions between pazopanib and blood glucose-lowering therapies. A 
transient decrease in serum glucose levels (mainly grade 1 and 2, rarely grade 3) was 
observed within clinical trials with pazopanib. In addition, a decrease in blood glucose was 
recently reported in patients treated with the tyrosine kinase inhibitor sunitinib ([38] British 
Journal of Cancer 2008: 99,1380). Such developments may require dose adjustment of 
antihyperglycemic and/or insulin therapy. Patients should be instructed to document their 
symptoms of hypoglycemia (e.g., dizziness, visual disturbances, palpitations, sweating). 
Serum glucose monitoring will be performed during treatment with pazopanib according to 
protocol and clinical indication. 
 
5.3 
Dose- and application modifications  
 
Missed drug doses will not be made up. To allow for practical ease of administration, upward 
or downward rounding of the paclitaxel dose is acceptable (±10%). 
Application of premedication before paclitaxel occurs at least 2 h after or 10 h before pazopanib 
due to drug interactions. 
Adverse reactions are graded according to CTCAE, version 4.0. 
If side effects occur that, in the judgment of the treating investigator, are unlikely to result in 
serious or life-threatening events or delay or interrupt therapy (e.g., alopecia, taste changes, 
etc.), treatment will be continued at the same dose without reduction or interruption 
 
Dose adjustments of the drugs or discontinuation of treatment will occur depending on the 
observed side effects as indicated below.  
Therapy interruptions or dose reductions of investigational drugs may be necessary due to the 
following potential drug-associated adverse events: Bone marrow suppression, arterial 
hypertension, 
proteinuria, 
hepatotoxicity, 
bleeding, 
vascular 
thrombosis, 
thrombocytopenia/neutropenia, prolongation of QTc time, and other adverse reactions 
reported in response to treatment with pazopanib and/or paclitaxel. 
 
 
 


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At each visit to the study site during treatment, patients should first be questioned, examined, 
and evaluated for the occurrence of adverse events and laboratory value changes. 
Specific recommendations for the management of these potential adverse events, as well as 
guidelines for therapy interruptions, dose adjustments, or discontinuation of study treatment, 
are provided below. 
If therapy with pazopanib must be interrupted due to adverse events according to guidelines 
below, therapy with paclitaxel must also be interrupted during this time. 
If a patient's treatment is interrupted for more than 14 days due to side effects or for other 
reasons (unplanned travel or vacation, lack of transportation, etc.), the investigator must 
contact the medical coordinator to discuss and have the specific patient circumstances 
reviewed prior to resuming treatment. Interruption of therapy for > 28 days will result in 
discontinuation of therapy and the pat. will enter the follow-up phase. 
If the dose of pazopanib or paclitaxel has been reduced due to side effects, re-escalation is 
possible if the patient's condition is stable and he/she has fully recovered from the side effects 
at the reduced dose. 
 
5.3.1 Dose- and application modification of Pazopanib  
Permitted dose reduction of Pazopanib: 
 
-If certain side effects occur (see below), two dose reductions are permitted in stages: Initial 
reduction to 600 mg and then to 400 mg as needed. If the side effects persist with the 
application of 400 mg, further titration to 200 mg may be considered. However, the investigator 
should discuss titration to 200 mg with the medical coordinator prior to dose adjustment. 
- After toxicity subsides, stepwise re-escalation can be made under monitoring every 10-14 
days by 200 mg each up to 800 mg provided toxicity does not recur or increase. 
 
Pazopanib dose reduction should be discussed with the medical coordinator if the 
patient is benefiting from therapy and recurrent adverse events occur with 
paclitaxel despite dose reduction to 40mg/m² per week at last and secondary 
prophylaxis with G-CSF (see below). 
If you need further advice or clarification, please contact the medical coordinator via e-
mail: studien@gisg.de 
 
 


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Table 2: Adverse reactions and resulting dose modifications of Pazopannib  
Adverse reaction and description  
Dose modification 
Hypertonus 
(A) Asymptomatic and persistant blood pressure: 
- 
Systolic  > 140 und <170 mmHg, 
- 
Diastolic > 90 und < 110 mmHg, 
- 
Or if there is a clinically significant increase in 
diastolic blood pressure of 20 mmHg (but still 
below 110 mmHg overall). 
1. continuation of the study treatment 
at the current dose 
2. adjustment of existing or application 
of new antihypertensive medication. 
3. discontinuation of antihypertensive 
medication for two weeks to regulate 
blood pressure. If blood pressure is 
not adjustable within two weeks, this 
will result in the procedure as in (B). 
(B) Asymptomatic systolic blood pressure > 170 
mmHg 
- 
or diastolic blood pressure > 110 mmHg 
- 
or failure of blood pressure control within two 
weeks as in (A). 
1. consideration of dose reduction or 
interruption of study treatment 
2. adjustment of existing or application 
of new antihypertensive medication 
3. discontinuation of antihypertensive 
medication for two weeks for blood 
pressure regulation 
4. resumption of study treatment 
with lower dose after blood 
pressure adjustment 
(C) Symptomatic 
hypertension 
or 
recurrent 
systolic blood pressure > 170 mmHg, or 
diastolic blood pressure > 110 mmHg, 
despite modification of antihypertensive 
medication. 
1. interruption of pazopanib intake 
2. adjustment of existing 
antihypertensive medication or 
application of new antihypertensive 
medication 
3. discontinuation of antihypertensive 
medication for two weeks for blood 
pressure control. Recommend 
referral to specialist for evaluation 
and further treatment. 
4. once blood pressure is well 
controlled, resume pazopanib 
intake reduced by 200 mg dose. 


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(D) Refractory arterial hypertension without 
response to above interventions. 
Discontinuation of pazopanib intake 
and follow-up as per protocol. 
Proteinurie 
UPC< 3  
Fortsetzung der Studienbehandlung 
in der derzeitigen Dosis; 
Überwachung nach klinischer 
Indikation 
UPC ≥ 3 rep. 24h-Urin Protein ≥ 3g 
1. interruption of pazopanib 
administration. 
2. weekly UPC or 24h urine protein 
measurement:  
3. UPC < 3 or 24h urine protein 
measurement < 3g Restart treatment 
with dose reduced by 200 mg. 
Recurrence of UPC ≥ 3 or 24h urine 
protein measurement ≥ 3g. 
➔ repetition of 1. and 2, 
4.Recurrence of UPC ≥ 3 or 24h urine 
protein ≥ 3g despite repeated dose 
reduction. ➔Discontinuation of 
Pazopanib intake and „Follow-Up“) as 
per protocol. 
Hemmorhage/ bleedings/ Coaggulopathy 
Grade 1 
If hemoptysis occurs, discontinue 
pazopanib and consider whether 
continued therapy with pazopanib is 
appropriate. 
If other grade 1 bleeding occurs, 
continue study treatment at current 
dose; monitor patient as clinically 
indicated. 
Grade 2 
1. If pulmonary or gastrointestinal 
bleeding (excluding 
hemorrhoidal bleeding) occurs, 
pazopanib use 
 


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 should be discontinued and 
follow-up ("follow up") should 
follow protocol. Otherwise, 
discontinue pazopanib until 
bleeding reaches < grade 1. 
 
2. resumption of study medication at 
reduced dose if necessary with 
appropriate monitoring as clinically 
indicated. 
Grade 3 or 4, or recurrent Grade 2 after dose 
reduction or pause of study medication 
oder 
 
1. discontinuation of pazopanib 
and follow-up according to 
protocol. 
If the adverse event is not clearly a 
clinical consequence associated 
with the study medication, the 
medical coordinator may be 
contacted for discussion of possible 
continuation of the study 
medication. If agreement is reached, 
the patient should be treated at a 
reduced dose. 
Venous Thrombosis (DVT, PE) 
Grade 2 
Continuation of study treatment at 
current dose; monitoring as clinically 
indicated. 
Grade 3 
1. interruption of the study medication 
2. therapy of the patient with low 
molecular weight heparin 
Note: Warfarin is allowed under INR 
control.  
3. continuation of study medication at 
the current dose during the period of 
full-dose anticoagulation if the 
following criteria are met: 


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- Patient must have been treated with 
low molecular weight heparin for at 
least one week. 
- Neither Grade 3 nor Grade 4 
bleeding has occurred while on 
anticoagulation. 
- The patient is monitored during 
anticoagulation and after continuation 
of study medication according to 
clinical indication. 
Grade 4 
Discontinuation of pazopanib use and 
follow-up as per protocol. 
 
Arterielle Thrombose/ Ischämie 
Every grade 
Discontinuation of pazopanib use and 
follow-up as per protocol. 
Thrombocytopenia/ Neutropenia 
Grade 1 or 2 
Continuation of study treatment at 
current dose; monitoring as clinically 
indicated 
Grade 3 or 4 
1. Discontinuation of therapy until 
reduction to Grade 2 toxicity. 
2. resumption of study medication at 
200 mg reduced dose with 
appropriate monitoring as 
clinically indicated. 
3. if there is no improvement to at 
least one grade 2 toxicity or 
recurrent grade 3 and 4 
neutropenia/thrombocytopenia 
occurs, this will result in 
discontinuation of pazopanib and 
follow-up ("follow up") according 
to protocol 
 
Prolonged QTc Intervall 


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QTc * 480 - <500 msec 
Continuation of study treatment at 
current dose; monitoring as clinically 
indicated 
QTc * ≥500 msec 
Discontinuation of study medication 
and follow-up according to protocol 
* Adjustment by using Bazett's formula 
Hepatotoxicity 
In general, many patients take multiple medications simultaneously. It is critical that a 
careful evaluation of all of the patient's medications be performed. Potentially hepatotoxic 
medications should be paused if necessary and replaced with non-hepatotoxic 
equivalents if appropriate 
ALT/ AST ≤3x ULN 
 
Continuation of study treatment at 
current dose; monitoring as clinically 
indicated by liver function tests (LFTs*). 
ALT >3x ULN to ≤8x ULN without bilirubin 
elevation (defined as total bilirubin <2x ULN or 
direct bilirubin of 35%) and without occurrence of 
allergic symptoms (e.g., fever, rash). 
1. continuation of study medication at 
the current dose. 
2. monitor patient closely for any 
clinical signs and symptoms; perform 
weekly or more frequent liver function 
tests if clinically indicated until ALT/ 
AST have dropped to Grade 1 
 
ALT >8x ULN without a bilirubin elevation 
(defined as total bilirubin <2x ULN or direct 
bilirubin 35%) and without the occurrence of 
allergic symptoms (e.g., fever, rash) 
1. discontinuation of study medication 
and follow-up according to study 
protocol. 
2. report the event as SAE to the KKS 
Heidelberg within 24 hours after the 
values become known Every 
reasonable attempt should be made 
to have the patient present to the 
clinic within 24 to 72 hours to check 
the liver values. 
- Imaging of the liver and possibly 
further clinically necessary 
examinations. 
 


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3. closely monitor the patient for any 
clinical signs and symptoms; perform 
weekly or more frequently if clinically 
indicated. Liver function tests until 
ALT/ AST have dropped to grade 1. 
ALT >3x ULN with concomitant elevation of 
bilirubin (defined as total bilirubin ≥2x ULN or 
direct bilirubin >35%) or with presence of allergic 
symptoms (e.g., fever, rash 
 
 
1. Immediate discontinuation of study 
medication. 
Report the event as an SAE to the 
Heidelberg PPS within 24 hours of 
becoming aware of the values Every 
reasonable attempt should be made 
to have the patient present to the 
clinic within 24 hours to check the liver 
values and to perform any other 
necessary investigations. Consultation 
of a gastroenterologist/hepatologist, 
performance of the following 
investigations to exclude possible 
factors involved: 
- Determination of eosinophils in the 
differential BB. 
- Viral serology for hepatitis A, B, C 
and E, CMV, EBV  
- Antinuclear antibodies (ANA), 
antimitochondrial antibodies (AMA), 
anti-smooth muscle antibodies 
- Serum creatinine phosphokinase to 
rule out possible muscle injury Liver 
imaging 
Possibly toxicological blood tests to 
exclude drug or chemical causes 
2. close monitoring of the patient for 
clinical signs and symptoms. 
Documenting the onset or worsening 
of clinical symptoms of hepatitis or 
allergic reaction, such as fatigue,  


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nausea, vomiting, right upper 
abdominal quadrant pain or 
tenderness, febrile exanthema, or 
eosinophilia. 
Perform weekly or if clinically 
indicated even more frequent LFTs 
until a drop to grade 1. 
 
Isolated 
total 
bilirubin 
elevation 
without 
concomitant increase in ALT (defined as ALT 
<3x ULN). 
 
1. isolated hyperbilirubinemia (without 
increase in ALT or other 
signs/symptoms of liver injury) does 
not require dose modification. Study 
drug inhibits UGT1A1 and OATP1B1, 
so this may result in an increase in 
indirect (unconjugated) bilirubin 
without liver injury. 
 
2. If bilirubin is >1.5x ULN without ALT 
elevation, fractionation of bilirubin is 
recommended. Study medication can 
be continued at the same dosage if 
bilirubin is predominantly 
unconjugated. If the direct bilirubin is 
>35%, further investigation should be 
done regarding the cause of the 
cholestasis. 
 
* LFTs include AST, ALT, AP, GGT, total bilirubin. 
 
 
 
 
 
 
 


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Hand-Fuß Syndrom (PPE) 
Grade 1 
Minimal skin changes or painless dermatitis 
(erythema, edema, hyper-keratosis) 
 
Continuation of study treatment at the 
current dose 
Grade 2 
Painful skin changes that limit daily activity 
(ADL's) (skin detachment, blisters, edema, 
bleeding, hyperkeratosis) 
1. interruption of pazopanib intake 
2. clinically necessary symptomatic 
therapy 
 
3. if regression occurs to ≤Grade 1, ➔  
resume study medication at reduced dose 
of 400mg daily. 
4. if regression occurs, dose reduction to 
200mg daily should be considered 
 
Grade 3,  
severe painful skin lesions with patient's 
limitations in daily self-care (ADL's) 
Discontinuation of pazopanib intake and 
follow-up ("follow up") as per protocol. 
 
 
 
Other clinically relevant adverse reactions 
Grade 1 
Fortsetzung der Studienbehandlung in 
der aktuellen Dosis. Weitere 
Kontrollen nach klinischer 
Notwendigkeit. 
 
Grade 2 or Grade 3, if the adverse reaction is 
considered clinically relevant and there is a 
probable association with pazopanbib use 
 
1. Discontinuation of pazopanib until 
the adverse event has resolved to 
grade 1. 
2. resumption of study medication at 
200mg reduced dose with 
appropriate monitoring as 
clinically indicated 
 
 


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Recurrence of grade 2 or grade 3 if the adverse 
reaction is considered clinically relevant 
Discontinuation of pazopanib use 
and follow-up as per protocol. 
 
Grade 4 
Discontinuation of pazopanib use and 
follow-up as per protocol. 
 
5.3.2 Dosis- und Applikationsmodifikation von Paclitaxel 
 
Occurrence of polyneuropathy: 
If grade 1 polyneuropathy newly occurs or worsens during paclitaxel therapy, the paclitaxel 
dose should be reduced to 60mg/m². Otherwise, therapy is continued unchanged. 
If polyneuropathy ≥ Grade 2 occurs, therapy with paclitaxel will be discontinued and will not be 
resumed even if the polyneuropathy resolves. In this case, therapy with pazopanib may be 
continued at an unchanged dose as part of the study. 
At 4 weeks after discontinuation of therapy with paclitaxel due to polyneuropathy, a telephone 
follow-up will be conducted to follow up the AE.Wenn im Rahmen der Paclitaxeltherapie eine 
Polyneuropathie Grad 1 neu auftritt oder sich verschlechtert, soll die Paclitaxel-Dosis auf 
60mg/m² reduziert werden. Ansonsten wird die Therapie unverändert fortgeführt. 
 
Permitted dose reductions of paclitaxel for other adverse reactions: 
For other adverse reactions (not listed below), three dose reductions are allowed in a stepwise 
manner: Initial reduction to paclitaxel 60mg/m² and then as needed to initially paclitaxel 
50mg/m² or finally 40mg/m².  
No further reduction in medication dose is permitted in the event of persistent toxicity despite 
a dose reduction to paclitaxel 40mg/m². The medical coordinator should be contacted in such 
a case for further discussion of the procedure. If the patient benefits from the therapy, a dose 
reduction of pazopanib can be discussed. Otherwise, termination of study medication and 
follow-up is recommended according to protocol 
 
Table 3: Adverse reactions and resulting dose reductions of Paclitaxel  
Thrombocytopenia/ Neutropenia 
Grade 1 
Continuation of study treatment at 
current dose; monitoring as clinically 
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Grade 2 
Continuation of study treatment at 
current dose; monitor as clinically 
indicated. 
For primary prophylaxis of neutropenia, 
consider the use of G-CSF 
Grade 3 or 4 
1. pause study medication until decline 
to Grade 2 toxicity. (If the period of 
pause exceeds two weeks, contact the 
medical coordinator to arrange further 
action). 
2. resumption of study medication at 
reduced dose. 
3. in case of neutropenia: primary 
prophylaxis using G-CSF. 
Recurrent grade 3/4 events despite dose 
reduction to most recently paclitaxel 40mg/m² per 
week and secondary prophylaxis with G-CSF. 
Discontinuation of study medication 
and follow-up according to protocol. 
 
Note: No dose reduction is indicated in the presence of anemia unless the anemia is due to 
bleeding. 
 
 
6 
Assessments and follow-up  
6.1 
Assessments before study enrollment  
For patients who have been informed about the study and have signed the informed consent 
form, the following examinations should be performed as part of the screening process or 
before the start of study therapy: 
 
- Taking a detailed medical history, which includes the complete oncological history. In 
addition, all relevant medications taken up to 2 weeks prior to study inclusion will be recorded. 
 
 
 
 
 


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- Clinical examination including weight, height, check of vital signs (blood pressure, heart rate, 
body temperature) and ECOG performance status. 
 
- Medical history (complaints or remaining side effects of previous therapies, signs and 
symptoms of cancer). 
 
- Blood count and differential, clinical chemistry, thyroid levels, and coagulation (see Table 4). 
 
Tabelle 4: Laboruntersuchungen zum Screening 
Hematological assessments  
Clinical chemistry 
Hemoglobin, hematocrit, erythrocytes, 
leukocytes, platelets, differential BB incl. 
lymphocytes and neutrophils 
Sodium, 
potassium, 
calcium, 
ALAT, 
ASAT, 
total 
bilirubin, 
alkaline 
phosphatase, creatinine, glucose, LDH 
Coaggulation 
Thyroid values 
Prothrombin time (PT) or INR, partial 
thromboplastin time (PTT) 
TSH 
 
 
Note: When pazopanib and warfarin (or its derivatives) are administered simultaneously, 
INR should be monitored within the first three to five days after initiation of therapy, when 
the dose is escalated or de-escalated, when pazopanib administration is interrupted, and 
then at least weekly until INR is stable. Adjustment of the dose of warfarin (or its 
derivatives) may be needed to ensure adequate anticoagulation. 
 
- Urinalysis, protein/creatinine ratio (UPC) 
- Serum pregnancy test (for women of childbearing potential). 
- Cardiac function tests:  
LVEF (echocardiography), 
12-lead ECG, QTc time measurement 
- Radiological examinations not older than 28 days before the start of study medication: 
All localizations/lesions of tumor disease must be detected by MRI or CT and documented 
as a basis for measurement. A CT or MRI examination of the thorax and abdomen is 
mandatory.  
 


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At least one measurable lesion must be identified as a target lesion and measured. These 
examinations must be performed within 28 days prior to initiation of study therapy.  
- If skin manifestations of angiosarcoma are detectable and measurable, these may be 
used as target lesions. Should multiple skin manifestations be measurable, a maximum of 
five should be classified as target lesions. Skin lesions can be documented 
photographically as target or non-target lesions, making sure that the same camera is 
always used. The photographic documentation is carried out by means of a panoramic 
image and close-up images corresponding to the number of target lesions; in this case, the 
size (largest diameter in each case) is recorded by means of a millimeter ruler that is also 
imaged. The baseline measurement of a target lesion must be ≥ 1cm. For raised skin 
lesions, the size may need to be measured using a caliper. Optional measurement of skin 
lesions is also available in the dermatology department. The photographic documentation 
must be printed out and included in the patient's file with the date of recording and the 
patient's name. 
 
6.2 
Assessments during treatment  
In this study, a treatment period or cycle is defined as 28 days. 
- Controls that occur every 7 days or less have a control window of +/-3 days. 
- Controls that occur every 3 to 8 weeks have a control window of +/-7 days. 
- Controls that are performed every 12 weeks have a control window of +/-14 days. 
6.2.1 During treamtenmt with Paclitaxel on day 1, day 8 und day 15 in every cycle 
The following parameters should be determined or examinations should be performed: 
- ECOG performance status, temperature, blood pressure, heart rate and body weight. 
- Physical examination 
- Symptoms of the cancer, therapy side effects, adverse events 
- Concomitant medication 
- Complete hematology and clinical chemistry (see Table 4). 
- INR/ PTT 
- Urine status 
- Beta-HCG every 8 weeks in childbearing women 
6.2.2 Additonal aassessments at beginnung of every cycle in the first 12 weeks  
- 12-lead ECG, QTc time measurement, then every 8 weeks 
 
 


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6.2.3 Every 8 weeks or when clinically indicated every 4 weeks, especially during 
monotherapy with pazopanib.   
.The following parameters should be determined or examinations should be performed: 
- ECOG performance status, temperature, blood pressure, heart rate and body weight. 
- Physical examination 
- Symptoms of the cancer, therapy side effects, adverse events 
- Concomitant medication 
- Complete hematology and clinical chemistry (see Table 4). 
- INR/ PTT 
- TSH 
- Urine status 
- Beta-HCG in childbearing women 
- 12-lead ECG and QTc time measurement 
- Radiological examinations of thorax, abdomen and all tumor localizations (at least CT or MRI 
of thorax and abdomen). 
- For measurable skin manifestations classified as target lesions: Photographic documentation 
via a panoramic image and close-up images corresponding to the number of target lesions, 
here the size (largest diameter in each case) is recorded using a co-imaged millimeter 
ruler. In the case of raised skin lesions, the size may have to be measured with a caliper. 
Optionally, the measurement of the skin lesions is also possible in the dermatology 
department. The photographic documentation must be printed out and included in the 
patient's file with the date the image was taken and the patient's name. 
 
6.3 
Behandlungsende/ Sicherheitsnachbeobachtung („Safety Follow-Up“) 
he end-of-treatment examination appointment will take place 30 days after the last study 
medication. 
The following parameters should be determined or examinations should be performed: 
- ECOG- performance status, blood pressure, heart rate and body weight. 
- Physical examination 
- Symptoms of cancer, side effects of therapy, adverse events 
- Concomitant medication 
- Complete hematology and clinical chemistry (see table) 
- INR/ PTT 
- TSH 
- Urine status  
- Beta-HCG, if indicated at inclusion 


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- 12-lead ECG and QTc time measurement 
- LVEF, if clinically indicated 
Documentation of disease status if these examinations were not performed within four weeks 
prior to end of treatment: 
- Radiological examinations of thorax, abdomen, and all tumor locations (at least CT or MRI of 
thorax and abdomen). 
- For measurable skin manifestations classified as target lesions: Photographic documentation 
via a panoramic image and close-up images corresponding to the number of target lesions, 
here the size (largest diameter in each case) is recorded using a co-imaged millimeter ruler. 
In the case of raised skin lesions, the size may have to be measured with a caliper. Optionally, 
the measurement of the skin lesions is also possible in the dermatology department. The 
photographic documentation must be printed out and included in the patient's file together with 
the date of recording and the patient's name. 
 
6.4 
Follow-Up 
After the end of treatment, all the patients are followed up every 12 weeks (+/-14 days) 
regardless of the reason for the end of treatment, i.e. also in case of premature of treatment, 
e.g. due to progression or at the patient's request, until the last patient has also reached a 
follow-up period of 24 weeks.  
Documentation of disease status is done every 12 weeks (+/- 14 days) until progression: 
- By radiological examinations of thorax, abdomen and all tumor loci¬sations (at least CT or 
MRI of thorax and abdomen). 
- For measurable skin manifestations classified as target lesions: Photographic 
documentation via a panoramic image and close-up images corresponding to the number of 
target lesions; the size (largest diameter in each case) is recorded using a millimeter ruler 
that is also imaged. In the case of raised skin lesions, the size may have to be measured 
with a caliper. Optionally, the measurement of the skin lesions is also possible in the 
dermatology department. The photographic documentation must be printed out and included 
in the patient's file together with the date of recording and the patient's name. 
In addition, further tumor therapies performed after the end of treatment are documented. 
 
 


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6.5 
Exclusion of patients from the study or termination of study participation 
Patients may be excluded from the study by the investigator or may terminate their study 
participation prematurely due to, for example, the following: 
- Withdrawal of informed consent for study participation by the patient. All data collected up to 
this point will be included in the analysis. 
- Termination of the study at the study site 
- Termination of the overall study by the sponsor or a regulatory authority 
 
Patients who withdraw consent to the study prior to receiving study medication will be 
withdrawn from the study and will not require further safety monitoring. These patients will be 
replaced. 
Patients who withdraw consent to study participation after they have already received study 
medication will be followed up for at least 30 days. The aim of this follow-up is to record the 
adverse events 
6.6 
Premature termination of clinical study 
The clinical trial may be terminated at any time by the sponsor for medical/safety reasons, e.g. 
changes in the benefit-risk assessment due to new findings, or administrative reasons, e.g. 
lack of recruitment. The sponsor may also declare the clinical trial at a participating trial site 
terminated, e.g. in case of insufficient recruitment or insufficient quality of the data. 
Furthermore, the clinical trial at an investigational site may also be terminated prematurely due 
to a decision by the investigator 
 
7 
Adverse events 
7.1 
Definitions 
7.1.1 Adverse events  
According to GCP, an Adverse Event (AE) is defined as follows: Any adverse medical event 
that occurs in a patient or participant in a clinical trial after administration of a drug and that is 
not necessarily causally related to that treatment. An AE may therefore be any adverse and 
unintended reaction (including an abnormal laboratory finding), symptom, or condition 
transiently associated with the administration of an investigational drug, whether or not related 
to the investigational drug. 
 
An AE may involve the following:  
- New symptoms/complaints/sensitivity disorders,  


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- new concomitant diagnosis,  
- change in laboratory parameters,  
- intercurrent illnesses and accidents of any kind,  
- Worsening of symptoms/diseases already existing before the start of the clinical trial,  
- Recurrence of disease,  
- Increase in frequency or intensity of episodic illness.  
A pre-existing disease/symptom does not constitute a UE unless there has been an 
unfavorable change in its intensity, frequency, or quality. Such a change must be documented 
by the responsible investigator. 
In the context of surgical procedures, the circumstance necessitating the surgery must be 
documented as a UE and not the surgical procedure itself. Surgical interventions already 
planned before the start of the study and their cause do not constitute a UE.  
Adverse events are classified as "serious" and "non-serious" 
.  
7.1.2 Serious adverse events 
A serious adverse event (SAE) is an AE that occurs regardless of the dosage of the 
investigational product according to the following criteria:  
- Leads to death,  
- Is acutely life-threatening (i.e., the study participant is in acute danger of death at the time of 
the UE),  
- necessitates or prolongs hospitalization,  
- results in permanent or significant disability,  
- Is associated with a congenital anomaly/birth defect; or  
- is otherwise medically relevant.  
 
7.1.3 Schwangerschaft 
If a patient becomes pregnant or suspected of becoming pregnant during the clinical trial, or if 
the partner of a patient participating in the clinical trial becomes pregnant, the pregnancy must 
be reported to the sponsor immediately, within 24 hours, as if it was an SAE. 
 
7.1.4 Expected and unexpected events  
An unexpected adverse event is an event that is inconsistent in nature or severity with current 
information (protocol or SmPC) about the investigational product.  
 


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Reports that provide significant information regarding the specificity or severity of a known 
adverse reaction (protocol or SmPC) are to be classified as `expected 
 
7.1.5  suspected unexpected serious adverse reaction (SUSAR) 
A serious adverse event for which the investigational product cannot be excluded as the 
causative agent (serious adverse drug reaction) and which, in addition, is inconsistent in nature 
or severity with the current information on the investigational product (i.e., is unexpected) is 
termed an "unexpected serious adverse drug reaction" or SUSAR ("suspected unexpected 
serious adverse reaction").  
If either the investigator who first reported the SAE or the second evaluator identifies the SAE 
as possibly related and the SAE is unexpected, it is considered a SUSAR. 
 
7.1.6 Study specific SAEs  
The following events are also considered serious adverse events (SUE) for the purposes of 
this study:  
- ALT >3.0x ULN with concomitant elevation of bilirubin (defined as total bilirubin ≥2.0x ULN, 
with direct bilirubin >35%) or with symptoms of a hypersensitivity reaction (e.g., fever, rash), 
in this case, fractionation of bilirubin should be performed if a test is available. 
- ALT >8.0x ULN without elevation of bilirubin (defined as total bilirubin <2.0x ULN or direct 
bilirubin ≤35%) and without symptoms of a hypersensitivity reaction (e.g., fever, rash), 
again, fractionation of bilirubin should be performed if a test is available. 
 
7.1.7 Exceptions for SAE reporting  
The following events do not require SUE reporting: 
- Hospitalizations that were planned prior to informed consent for study participation and do 
not last longer than expected. 
- Hospitalizations that are solely due to progression of the tumor disease (progressive 
disease). 
 
 
 
 


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7.2 
Observation period and documentation 
All AEs reported by the study participant or observed by the investigator are recorded during 
the clinical trial and must be documented on the designated pages in the CRF. AEs must also 
be recorded in the patient's medical record. In the present clinical trial, all UEs occurring from 
the time the study participant provides informed consent until 30 days after completion of study 
therapy (visit: end of treatment, safety follow-up) will be documented in the CRF. Regardless 
of whether a relationship with the study medication is suspected or not, all participants with 
UEs will be observed until the UEs resolve or until normalization of altered laboratory 
parameters or until a stable condition is reached. 
The assessment of the intensity of a UE is based on a 5-level scale defined in the CTCAE 
version 4.0:  
Grade 1: mild  
Grade 2: moderate  
Grade 3: severe  
Grade 4: life-threatening or with permanent damage  
Grade 5: fatal 
 
All AEs not listed in the CTCAE Version 4.0 are classified in terms of intensity using the 
definitions presented below.  
Mild: An event that results in mild impairment, i.e., activities of daily living can be performed 
without restriction.  
Moderate/medium: An event that leads to a moderate impairment, i.e. the activities of daily 
living are impaired.  
Severe: An event that leads to a significant impairment, i.e. the performance of the activities 
of daily living is not possible. 
 
The investigator will assess the possible relationship to the investigational drug for 
each AE:  
 
Certain: There is a reasonable assumption that the event is due to the investigational drug. 
There is a plausible temporal relationship and an alternative cause is unlikely.  
 
Probable: There is a reasonable belief that the event is due to the investigational product. 
There is a temporal relationship, and a known response pattern occurs, but a possible 
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Possible: There is only a remote possibility that the adverse event and the investigational drug 
are related. Other conditions including concomitant disease, progression or disease 
expression, or response to concomitant medication are likely to explain the reported adverse 
event.  
 
Unlikely: There is little evidence of a causal relationship. A reasonable temporal relationship is 
lacking. The adverse event can be adequately explained by other factors (e.g., patient's clinical 
condition; underlying disease; concomitant therapy). 
 
No relationship: there is no temporal relationship to the investigational product and the 
participant's clinical condition, other therapeutic modalities, or another etiology is a likely 
explanation for the AE. 
 
Unable to Assess: An assessment of the association is not possible based on the available 
information. 
 
The outcome of an adverse event at the time of the last contact is classified as follows:  
 
'Recovered': all signs and symptoms of the UE have disappeared without consequence at the 
time of the last interview.  
 
'Improved': the intensity of signs and symptoms has decreased since the last interview and/ or 
the clinical pattern has changed as is typical of improvement.  
 
'Not recovered': signs and symptoms of UE are more or less unchanged at the time of 
interview.  
 
'Recovered with consequences': Acute signs and symptoms of the UE have disappeared, but 
consequences remain that have their origin in the UE.  
 
'Fatal': has resulted in death. If there are multiple UEs, only the UE that resulted in death 
(possibly investigational drug related) is classified as 'fatal'.  
 
'Unknown': The outcome is not known or not plausible and the information cannot be 
completed or verified. 
 


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Measures related to the investigational drug are categorized as follows:  
'Dose unchanged': no change in the dosage of the investigational drug.  
 
'Dose reduced': the dosage of the investigational medication was reduced  
 
'Drug discontinued': the investigational drug was discontinued  
 
'Unknown': the information is not known or not plausible and the information cannot be 
completed or verified  
 
'Not applicable': the question is not plausible (e.g., because the participant is dead)  
 
The term 'Countermeasures' refers to specific actions taken to treat or alleviate a UE or to 
prevent consequential harm.  
 
Countermeasures of a UE are classified as follows:  
'None': no countermeasures were taken.  
 
'Drug': a new drug was prescribed or the dosage of a drug was changed  
 
'Other': Other countermeasures were taken, e.g. surgery. 
 
7.3 
Meldung schwerwiegender unerwünschter Ereignisse durch den Prüfer 
 
SAEs must be reported to the responsible Safety Officer at KKS Heidelberg on the SAE sheet 
within 24 hours of becoming known or no later than the following working day.  
 
Fax number 06221/56-33725  
 
The initial report should be as complete as possible and include accurate information on the 
current illness and SUE, as well as an assessment of the causal relationship between the UE 
and the investigational product.  
 
 
 


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After processing and recording the SAEs, the KKS Heidelberg will forward all SAEs on behalf 
of the sponsor to Novartis, for drug safety data collection, within 24 h of becoming aware of 
them. 
 
Second assessment 
For all SAEs, a second evaluation is performed by a previously designated person who is 
independent of the reporting investigator. The second evaluator completes a second 
evaluation form for each SUE and faxes it to the responsible person at KKS Heidelberg within 
48 hours.  
The secondary evaluation form contains the following information:  
I) Assessment of the relationship between SAE and investigational product (causality).  
II) Assessment of whether the SAE is "expected" (i.e. described in the SmPC) or not.  
III) Opinion on whether the benefit-risk assessment of the clinical trial has changed due to the 
SUE.  
If either the investigator who first reported the SAE or the second evaluator identifies the SUE 
as possibly related to the investigational product and the SAE is unexpected, then it is a 
"suspected case of unexpected serious adverse drug reaction" (SUSAR). 
7.4 
Expedited reporting by the sponsor: reporting of adverse events to the ethics 
committee, competent authority and all investigators  
 
Suspected cases of unexpected serious adverse drug reactions (SUSARs) must be reported 
by the sponsor to the lead ethics committee, the competent authority (i.e. BfArM) and all 
investigators within the legally specified deadlines. Novartis Pharma GmbH also receives all 
SUSAR notifications in the form of the CIOMS-II sheet sent out.  
 
The reporting (to BOB, ethics committee(s), and investigators) according to the legal 
requirements and to the company Novartis Pharma GmbH is performed by the responsible 
Safety Officer/Safety Data Manager at KKS Heidelberg. Only events that occurred after 
administration of the investigational product are subject to expedited reporting. 
 
7.5 
Ermergency treatment  
Emergency treatment of AEs is guaranteed by the outpatient and inpatient capacities of the 
study centers, which also include an intensive care unit, if necessary in cooperation with other 
clinics of the study centers. The investigator will inform the study participants by telephone or,  


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if necessary, in writing if an identified intercurrent illness requires medical treatment. Possible 
scenarios would be, for example, inpatient admission for drug therapy and monitoring in the 
case of derailed arterial hypertension or outpatient or, if necessary, inpatient infusion therapy 
in the case of diarrhea refractory to therapy with high fluid losses. 
 
8 
Statistical methods  
8.1 
Statistical analysis and justification for subject number  
The primary endpoint of the study is progression-free survival at 6 months. 
The null hypothesis to be tested, H0, states that the proportion of patients p who are 
progression-free and alive at 6 months (PFS rate) is less than or equal to a predefined level 
p0.  
H0: p≤ p0 vs H1: p> p0. 
The p0 as PFS rate at 6 months is not considered promising for the combination therapy 
(paclitaxel and pazopanib) under review. Based on the recently published AngioTax trial (Penel 
et al. 2008; [2]), p0=0.35 is assumed here. This corresponds to a median time to progression 
of 4 months 
Since monotherapy with paclitaxel results in a median progression-free survival of 4 months in 
patients with angiosarcoma, a clinically relevant improvement with combination therapy, i.e. 
simultaneous administration of paclitaxel and pazopanib (instead of the sequential therapy 
possible outside the study), was assumed for this study if a median progression-free survival 
of 7 months would be achieved with the combination. This corresponds to a minimally clinically 
relevant PFS rate at 6 months, of p1=0.55. 
A Simon's two stage optimal design is used to test the null hypothesis, which minimizes the 
expected number of cases assuming the null hypothesis. The one-sided significance level is 5 
 
The maximum recruited number of cases is 44 patients. After inclusion and 6 months follow-
up of the first 14 patients, an interim evaluation will be performed. Recruitment will not be 
stopped for feasibility reasons. If additional patients are recruited during the follow-up period 
of the first 14 patients, the data of these patients will not be included in the interim analysis. 
If, of the first 14 patients, 5 or fewer are progression-free and alive at 6 months, then the study 
is stopped, the null hypothesis is maintained, and the therapy is declared ineffective. 
 
 
 


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If of the first 14 patients, 6 or more are progression-free and alive at 6 months, then the study 
will continue and an additional 30 patients will be recruited. 
If of the 44 patients, a total of 20 or fewer are progression-free and alive at 6 months, then the 
null hypothesis is maintained and therapy is declared ineffective. 
If of the 44 patients, a total of 21 or more are progression-free and alive at 6 months, then the 
null hypothesis is rejected and the therapy is declared effective. 
Wenn von den 44 Patienten insgesamt 21 oder mehr progressionsfrei und lebend nach 6 
Monaten sind, dann wird die Nullhypothese verworfen und die Therapie wird als wirksam 
erklärt. 
 
This design has a power of 80%. 
 
In addition, the PFS rate is calculated and the corresponding 95% confidence interval. 
Since all patients who are not evaluable for disease response at 6 months or whose follow-up 
is not available (lost to follow-up) are counted as progressive patients for the analysis of the 
primary endpoint, there are no missing values for the primary analysis. Patients who withdraw 
consent to the study before receiving study medication will be replaced.  
The primary analysis will be based on the ITT population. 
 
In addition to the primary analysis, PFS rates will be estimated as described in Jung (2004) to 
obtain unbiased estimators. OS rates can then be derived directly from these rates.  
To test for the influence of protocol violations, the analysis described above is repeated based 
on the PP population. 
 
All analyses described above will also be examined for the above subgroups.  
To examine response rates and toxicity rates (AEs/SAEs) absolute and relative frequencies 
and associated 95% confidence intervals will be calculated. All analyses will be repeated for 
the above subgroups. Comparison of patients with cutaneous AS vs visceral AS, or with 
primary AS vs secondary AS in terms of PFS, OS, RR is performed by log rank test and 
chiquadrat test or by graphical representation, depending on the underlying number of cases. 
All analyses will be performed in SAS version 9.1 or higher. A detailed statistical analysis 
strategy will be defined in the Statistical Analysis Plan, which must be completed before the 
start of the analysis 
 
 
 


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8.2 
Analysis populations 
The intention-to-treat (ITT) population includes all patients in the study who have taken the 
study medication at least once. The per protocol (PP) population is the group of patients who 
received treatment with pazopanib or paclitaxel for at least 6 weeks and who had the required 
assessments performed at relevant and pre-specified time points. Patients with serious 
protocol violations or who have received study therapy not in accordance with the protocol 
must be excluded from the PP population. The safety population is the same as the ITT 
population. 
 
All patients who are not evaluable for disease response after 6 months or whose follow-up is 
not available (lost to follow-up) are counted as progressive patients for the analysis of the 
primary endpoint. 
. 
9 
Data management 
9.1 
Data collection 
All entries in the CRF must be verifiable by source documents. Regardless of this, there must 
be minimal documentation in the patient file that provides information about study participation 
and contains all medical information necessary for adequate medical care outside of the 
clinical trial. The investigator is responsible for accurate, timely, and continuous 
documentation.  
Erroneous entries in the CRF must be crossed out with a single line so that the original entry 
remains legible. The correction will be made next to the data field and will include the signature 
of the investigator or authorized member of the study team, date, and reason for the change, 
if applicable. For self-explanatory corrections (e.g., numerical error in date), the reason may 
be omitted. Each final CRF page of a visit must be signed and dated once by the investigator 
to confirm the accuracy of the data 
 
9.2 
Data handling 
In order to achieve a correct transfer of the documentation on the CRFs into the study 
database, double data entry is performed in IMBI by two independent persons. Data 
management is done in the statistical program SAS. Missing and implausible data are queried 
by the data management in writing to the study center using a prepared data validation plan 
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the monitor. The resulting additions and corrections are entered into the SAS files and logged 
in audit files. The processed queries are kept together with the CRFs. At the end of the study, 
after verification that all CRFs are present and the query process is complete, the database is 
closed for analysis. All data management processes are performed according to the valid 
SOPs (Standard Operating Procedures) of the IMBI. 
 
9.3 
Storage and archiving of data  
The investigator shall retain all study documents including patient identification list and relevant 
correspondence in the Investigator Site File (ISF). The ISF, all source documents, and all other 
documents listed in Section 8 of the ICH Consolidated Guideline on GCP shall be archived by 
the investigator after regular or early termination of the trial in accordance with regulatory 
requirements 
 
10 Ethical and legal aspects  
10.1 Good clinical practise  
 
The described procedures for the conduct, evaluation, and documentation of this clinical trial 
are intended to ensure that all participants adhere to the principles of Good Clinical Practice 
(GCP) and the ethical principles set forth in the Declaration of Helsinki. The conduct of the trial 
will be in accordance with local regulatory and enforcement requirements 
10.2 Practice of Informing and Consenting Study Subjects 
Before a study subject can be included in the clinical trial, he or she must be informed orally 
and in writing about the nature, significance and scope of the clinical trial in an understandable 
form and must subsequently consent in writing to participation.  
No non-consenting subjects will be included in this study.  
The study participant will receive a copy of the Patient Information and Consent Form for the 
clinical trial. The original will be retained by the investigator.  
These documents must be written in a language understandable to the study participant. They 
must state who provided the study participant with the information.  
Study participants shall be informed of any new information that could affect their decision to 
participate in the study. The communication of this information is documented 
 
 


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10.3 Data protection 
 The data collected in the course of the clinical trial will be handled in accordance with the 
provisions of statutory data protection. During the clinical trial, participants are identified solely 
by means of an individual identification number (patient number). When study data are stored 
on a computer, the regulations of the Federal Data Protection Act are observed; the data are 
treated as strictly confidential. Organizational measures are in place to protect this data and 
prevent it from being disclosed to unauthorized third parties. The relevant provisions of 
country-specific data legislation are complied with in full.  
With the written consent to participate in the clinical trial, the participant releases the 
investigator from his duty of confidentiality vis-à-vis representatives of the responsible 
authorities (inspectors) and the sponsor (monitors) to the extent that these persons may 
inspect the personal data in order to verify the correct transmission of data and to check the 
proper conduct of the clinical trial.  
The investigator is responsible for keeping an identification list of the study participants 
(identification number and name of the study participant) to enable any necessary 
identification.  
Patients who do not consent to the sharing of their data in pseudonymized form will not be 
included in this clinical trial 
10.4 Responsibilities of the investigator 
The investigator shall ensure that all personnel involved in the clinical trial at the trial site are 
adequately informed of the protocol, any amendments to the protocol, trial treatments, and 
trial-related duties and tasks. The investigator shall maintain a list of the members of the study 
team to whom the investigator has delegated important study-related duties. 
10.5 Approval of protocol and protocol amendments  
Prior to the start of the clinical trial, the protocol, patient information and consent form, as 
well as all other required documents, are submitted to the responsible ethics committee and 
the responsible competent authority for approval.  
The approving assessment of the ethics committee and the approval by the competent 
authority are prerequisites for the start of the clinical trial. The opinion of the EC should 
include the title of the clinical trial, the short title if applicable, the trial sites and all other 
reviewed documents. The date on which the decision was made must be mentioned and the 
opinion must be signed by a member of the Ethics Committee. Complete the affirmative 
evaluation documentation with a list of the ethics committee members who participated in the  


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deliberation and a confirmation that the EC operates in accordance with GCP principles (if 
applicable, the EC's bylaws may be filed with the vote instead). 
All correspondence (written and verbal) with the relevant Ethics Committee and the relevant 
BOB must be documented and retained by the sponsor.  
All ethical and legal requirements must be met before the first study participant is enrolled in 
the clinical trial.  
Trial protocol amendments are made in writing and require the approval of all protocol 
signatories. Subsequent substantial amendments to the protocol also require the consenting 
evaluation by the responsible ethics committee and the approval of the competent authority. 
 
10.6 Ongoing information from the Ethics Committee and the Competent Autority  
The responsible ethics committee and the responsible competent authority must be informed 
of any suspected case of an unexpected serious adverse reaction (SUSAR; see also item 9.4) 
that has become known, as well as of any circumstance that requires a renewed review of the 
benefit-risk assessment of the investigational product. Both institutions will be informed if the 
benefit-risk assessment changes or other new and significant threats to patient safety and well-
being arise.  
During the duration of the trial, a list of all suspected serious adverse events occurring during 
the trial and a report on the safety of the persons concerned (so-called Development Safety 
Update Report (DSUR)) is submitted once a year - or upon request - to the responsible ethics 
committee and the competent authority. 
The termination of the clinical trial must be reported to the responsible ethics committee, the 
competent authority and the responsible state authorities. Within one year after the end of the 
clinical phase (last subject out, LSO) of the trial, a summary of the study results is submitted 
to the responsible ethics committee and the competent authority. 
 
10.7 Notification of German local authorities   
In accordance with AMG §67, the clinical trial must not only be approved by the competent 
authority (CA), but it must also be notified there prior to enrollment of the first study participant. 
Likewise, prior to the start of the trial, notification must be made to the state authorities 
responsible for the investigators. Notification to the CA is the responsibility of the sponsor, 
 
 
 


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 whereas notification to the state authorities is the responsibility of the individual investigators. 
Subsequent changes, termination or, if applicable, discontinuation of the clinical trial must also 
be reported.  
All correspondence (written and verbal) with the authorities must be documented by the 
sponsor or investigator and retained by the sponsor or investigator after completion of the 
clinical trial 
10.8 Registration of Clinical trial  
The sponsor will ensure that the present study is registered at http://www.clinicaltrials.gov 
prior to the start of the clinical phase (first subject in, FSI). The study will be assigned a 
specific number (International Standard Randomised Controlled Trial Number, ISRCTN), a 
prerequisite for publication in a reputable scientific journal 
10.9 Insurance 
For the study participants, a proband insurance policy (maximum € 500,000 per study 
participant) has been taken out with HDI-Gerling Versicherung AG, Am Schönenkamp 45, 
40599 Düsseldorf, Germany, in accordance with the legal requirements. In order not to 
jeopardize the insurance coverage, any damage to health that may have occurred as a result 
of participation in the clinical trial must be reported immediately to the above address. The 
obligation to report lies with the trial participant. The insured person must agree to all measures 
that are suitable to determine the cause and extent of the damage that has occurred and to 
mitigate the damage.  
During the duration of the clinical trial, the study participant may undergo other clinical 
treatment - except in an emergency - only in agreement with his investigator. Furthermore, 
there is an obligation to immediately inform the investigator of all adverse events and also of 
any additional medication taken. The insurance conditions will be handed over to the study 
participant upon request.  
The insurance company must be informed of any subsequent changes that could affect the 
safety of the participants. 
11 Translationale Research 
11.1 Rationale 
Due to the rarity of AS, relatively few studies on genetic alterations in these tumors exist to 
date. After gene amplification analyses, mutation analyses and chromosome analyses were 
initially performed in individual cases [29, 30, 31, 32, 34], several larger series have now also  
 


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been published, in which material from up to 61 patients with primary and secondary AS [35] 
was in part examined with regard to genetic alterations. 
In addition to the aforementioned VEGF-R mutations and alterations in amplification of VEGF-
R genes in AS, alterations in tumor protein 53 (p53) expression [28, 33, 36], the 
PIK3CA/AKT/mTOR signaling cascade [36], and expression of protooncogenes such as MYC 
[35] have now been detected in these tumors. Interestingly, although MYC expression was 
found to be increased in over 50% of secondary AS samples examined in one study; it was 
not detectable in any primary AS and thus appears to be a specific feature of secondary AS 
[35].  
Despite these already known alterations, the pathogenesis of AS remains largely unknown, 
especially to what extent different genetic alterations or other mechanisms contribute to 
disease development in primary and secondary AS. An above-average proportion of 
secondary AS develops after breast-preserving therapy including radiation of breast 
carcinomas. It is unclear whether (genetic) risk factors exist that increase the risk of developing 
secondary AS for a patient with breast carcinoma who is scheduled to receive 
BET/radiotherapy. 
Should further mutations be discovered in the course of genetic analyses of AS that lead to 
altered expression or activity of functionally active proteins and thus to pathogenetically 
relevant changes (e.g., altered signal transduction), additional targets would potentially be 
available for therapeutic interventions, which are urgently needed to improve treatment options 
for patients with AS. 
The optional translational research project aims to answer the following scientific questions in 
the context of this clinical trial in angiosarcomas by collecting fresh tissue, kerosene fixed 
tissue and blood samples after genome-wide sequencing and RNA expression analysis. 
1, Are potentially oncogenetically relevant mutations found in AS that are reproducible in a 
relevant proportion of the cases studied? 
2. do these mutations lead to detectable changes at the RNA and protein level? 
3. are there differences in points 1 and 2 between primary and secondary AS? 
4) Is it possible to detect genetic alterations (see points 1. and 2.) in nucleated blood cells of 
patients with secondary AS that are not present in patients with primary AS? 
 
 
 
 
 


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5. If genetic alterations can be detected in a relevant subgroup of patients, these subgroups 
should be evaluated in comparison to the patients with wild-type AS regarding the outcome in 
the study (primary and secondary study objectives: PFS, R, OS). 
11.2 Patient informatioj and informed consent to translational research  
In the screening phase of the clinical trial, tissue samples (FFPE blocks and, if available, freshly 
frozen tumor material) and one 10 ml blood sample each, which serves as a control and as so-
called healthy tissue, respectively, can be collected after a detailed educational discussion 
including the patient information and after receipt of the signed consent form for translational 
research. 
Patients can only participate in the translational research project if they have consented to 
participate in the clinical trial. Participation in translational research remains optional for 
patients. Consent may be withdrawn at any time. This does not affect participation in the clinical 
trial 
 
11.3 Collection, storage and pseudonymization of samples  
In the context of this study protocol, existing tumor material should be used whenever possible. 
If no suitable material is available, a new sample may be taken in individual cases within the 
framework of this research project after careful consideration of the risks involved in a biopsy 
for purely scientific purposes and detailed information of the patient as well as obtaining the 
patient's consent. 
From the obtained blood sample, nucleated blood cells will be isolated, cryopreserved and 
stored according to the locally established Ficoll standard procedure.  
Storage of the samples may occur at the study site responsible for the study patient until the 
assigned collection by the sponsor. The requirement for this is that the study center meets the 
requirements for storage of blood and tissue samples, according to the state of the art in 
science and technology. If an investigational center does not meet the requirement for sample 
storage, participation in the translational research project is not possible. A review of the 
requirement will be performed during study initiation via a separate checklist or by an 
inspection of the study site. The storage of the samples at the study center is done via a study-
specific patient identifier (PID). 
After collection of the samples from the test center, the samples receive a pseudonym (PSN). 
This pseudonym is a randomly generated letter-number combination. The pseudonymized 
samples are stored in the central tumor bank of the study group (Prof. Dr. med. Hohenberger,  


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Section of Special Surgical Oncology and Thoracic Surgery, Department of Surgery, University 
Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany). 
The collected specimen and data material will only be shared with PSN coding.  
At a later stage, the pseudonymized samples will be forwarded for genome-wide analysis to 
Prof. Dr. med. C. A. Schmidt, acting director of the Clinic and Polyclinic for Internal Medicine 
C; Hematology and Oncology - Transplant Center, University Medicine Greifswald, 
Sauerbruchstraße, Diagnostic Center, 17475 Greifswald.  
 
11.4  Processing of the obtained samples 
It is planned that freshly frozen tumor material and the ficollated nucleated blood cells of 
primary and secondary AS will be sequenced using the "next generation sequencing" 
technology and, if necessary, checked for mutated genes and altered proteins with regard to 
RNA expression. From the collected tumor material, 5 participants will initially be brought into 
the translational research project. If the results of the 5 tissue samples submitted appear to be 
meaningful for further investigation or confirmation in the context of the questions of this 
research project (see above), further tumor samples and nucleated blood cells from study 
participants who have agreed to the transnational research part will be sequenced. For these 
confirmatory studies and for all further studies, paraffin-embedded material may be sufficient. 
 
11.5 Data protection and traceability of results 
The genetic patient data are stored separately and encrypted in different databases, each with 
controlled access, to protect you. The data can be stored indefinitely until revoked. All genetic 
data is collected, examined and stored only in encrypted form. Only authorized personnel have 
access to this encrypted data. Traceability of the data is only possible via a patient identifier 
(PID) assigned by the study center and via a pseudonym (PSN) assigned by the tumor bank. 
Inference to patient data for unintended purposes should thus be excluded. 
 
 
 
 
 
 
 
 


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12 Quality assurance 
12.1 Monitoring 
Center-specific quality control is performed through regular monitoring visits. Monitoring is only 
performed by clinical monitors who are sufficiently qualified. 
Prior to enrollment of the first study participant, an initiation visit is conducted at each study 
center. A face-to-face initiation visit may be waived if the principal investigator at the study site 
and the study team have extensive study experience. It is up to the study director to decide if 
an initiation visit can be replaced by a telephone initiation at the center. During the study 
initiation, the availability of all essential documents and the requirements for proper study 
conduct are verified. During the regular monitoring visits (including after inclusion of the first 
patients at the study center, during the study, and after the end of the study), the responsible 
monitor checks the entries in the CRFs against the source documents as well as the correct 
dispensing and use of the study medication The investigator must ensure the monitor free 
access to all required documents and the study medication. The investigator must support the 
monitor's work at all times.  
Through frequent contact (letter, telephone, email) between visits, the monitor shall verify that 
the study is being conducted in accordance with the study plan and regulatory requirements.  
Details of the scope of monitoring are described in the Monitoring Manual. 
12.2 Audits and Inspections 
To maintain and enhance quality, the German Interdisciplinary Sarcoma Group reserves the 
right to conduct study-specific ICH GCP audits at the respective study sites.  
The competent authorities may request access to all source documents, CRF and other study 
documents for the purpose of an on-site inspection. The investigator must ensure free access 
to these documents and support the work at all times.  
By signing the protocol, the investigator gives consent to study participation and allows 
inspection of all study specific documents by a person designated by GISG or by a competent 
authority. 
In case of an official inspection, please forward the information to the German Interdisciplinary 
Sarcoma Group at studien@gisg.de. 
 
 
 
 


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13 Agreements 
13.1 Financing of the clinical trial 
The clinical trial is funded by the company Novartis Europharm Ltd. The pazopanib is provided 
by the company Novartis Europharm Ltd. 
13.2 Financial disclosure  
Prior to the initiation of this clinical trial, each investigator will disclose any commercial interests 
related to the sponsoring company, the investigational product, or other commercial 
organizations involved in the trial. The investigators undertake to update this information in the 
event of significant changes 
13.3 Reports  
The study center of the Section of Special Surgical Oncology and Thoracic Surgery and the 
IMBI Heidelberg are preparing the final study report together with the scientific coordinator. 
The preparation of the report will be completed 3 months after database closure. 
13.4 Publication  
All data collected in connection with the clinical trial must be treated confidentially until 
publication. Publication of the study results will be independent of the results. First author of a 
publication of the primary and secondary endpoints and the protocol will be the author of the 
protocol, and senior author of the LKP. The participating biometrician of IMBI will be included 
as an author. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14 SIGNATURES  
This protocol has been critically reviewed by all signatories and approved as presented. The 
data contained therein are consistent with: 
- The current status of the benefit-risk assessment of the investigational product. 
- The moral, ethical and scientific principles of clinical research in accordance with the 
Declaration of Helsinki and in accordance with the principles of GCP. 
Each investigator will be fully informed of any important or new findings, including 
investigational product-related AEs. 
 
 
Date: ________________ Signature: _________________________ 
Name (Print letters): Dr. Angela Kalous 
Function: Chancellor of University Sponsor 
 
Date: ________________ Signature: _________________________ 
Name (Print letters): Prof. Dr. P. Hohenberger 
Function: Member of Medical Faculty Mannheim, Heidelberg University and National 
Coordinator as well as Representative of GISG  
 
Date: ________________ Signature: _________________________ 
Name (Print letters): Dr. Daniel Pink 
Function: Investigator, Medical Coordinator (Author)  
 
Date: ________________ Signature: _________________________ 
Name (Print letters): Dr. Geraldine Rauch 
Function: Biometrician (Institut für Medizinische Biometrie und Informatik Heidelberg) 
 
Date: ________________ Signature: _________________________ 
Name (Print letters): Prof. Dr. Thomas Brodowicz 
Function: National Coordinator for Austria  
 


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15 INVESTIGATOR’s DECLARATION  
 
I have read this protocol and confirm that it contains all the information necessary for the proper 
conduct of the trial. I agree to conduct the clinical trial as specified in this protocol. 
I will not enroll the first study participant in the study until all ethical and legal requirements to 
begin a clinical trial have been met. I agree to obtain written informed consent from all study 
participants to participate in the clinical trial. 
I understand the requirements for proper reporting of serious adverse events and agree to 
document and report such events as required. 
I agree to retain all trial-related documents and source documents as described. I will submit 
a curriculum vitae prior to the start of the clinical trial, which may be submitted to the 
appropriate authorities. 
 
Date: ________________ Signature: _________________________ 
Name (Print letter): _______________________ 
Function: Investigator 
Site (Adress): _________________________ 
_________________________ 
_________________________ 
 
 


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16 Appendix A – Bibliographie 
 
1. 
M.G. Fury, C.R. Antonescu, K.J. Van Zee, M.E. Brennan, R.G. Maki: A 14-year 
retrospective review of angiosarcoma: clinical characteristics, prognostic factors, 
and treatment outcomes with sugery and chemotherapy. Cancer J, 11 (2005), pp. 
241–247 
2. 
N. Penel, B.N. Bui, J.O. Bay et al. Phase II trial of weekly paclitaxel for unresectable 
angiosarcoma: the AngioTax study. J Clin Oncol, 26 (2008), pp. 5269–5274 
3. 
R. Chugh, J.K. Wathen, R.G. Maki et al. Phase II multicenter trial of imatinib in 10 
histologic subtypes of sarcoma using a Bayesian hierarchical statistical model. J 
Clin Oncol, 27 (2009), pp. 3148–3153 
4. 
R.G. Maki, D.R. D’Adamo, M.L. Keohan et al. Phase II study of sorafenib in patients 
with metastatic or recurrent sarcomas. J Clin Oncol, 27 (2009), pp. 3133–3140 
5. 
Park MS, Ravi V, Araujo DM. Inhibiting the VEGF-VEGFR pathway in 
angiosarcoma, 
epithelioid 
hemangioendothelioma, 
and 
hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol. 2010 Jul;22(4):351-
5. doi: 10.1097/CCO.0b013e32833aaad4. 
6. 
Ong P, Greulich S, Schumm J, Backes M, Kaufmann M, Bode-Erdmann S, Ott G, 
Hebart H, Mahrholdt H. Favorable course of pericardial angiosarcoma under 
paclitaxel followed by pazopanib treatment documented by cardiovascular 
magnetic resonance imaging. Circulation. 2012 Oct 30;126(18):e279-81. doi: 
10.1161/CIRCULATIONAHA.112.128348 
7. 
Yoo C, Kim JE, Yoon SK, Kim SC, Ahn JH, Kim TW, Suh C, Lee JL. Angiosarcoma 
of the retroperitoneum: report on a patient treated with sunitinib. Sarcoma. 
2009;2009:360875. doi: 10.1155/2009/360875. Epub 2009 May 20. 
8. 
Agulnik M, Okuno SH, von Mehren M, et al. Bevacizumab for the treatment of 
angiosarcoma: an open label multicenter phase II study [abstract #39250]. 15th 
Connective Tissue Oncologic Society Annual Meeting, Miami, Florida, USA; 2009. 
9. 
van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, 
Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson 
IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, 
Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma 
Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma 
(PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 
2012 May 19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. Epub 
2012 May 16. 
10. 
Lau D, Guo L, Gandara D, Young LJ, Xue L. Is inhibition of cancer angiogenesis 
and growth by paclitaxel schedule dependent? Anticancer Drugs. 2004 
Oct;15(9):871-5. 
11. 
Hingorani P, Eshun F, White-Collins A, Watanabe M. Gemcitabine, docetaxel, and 
bevacizumab in relapsed and refractory pediatric sarcomas. J Pediatr Hematol 
Oncol. 2012 Oct;34(7):524-7. 
12. 
Verschraegen CF, Arias-Pulido H, Lee SJ, Movva S, Cerilli LA, Eberhardt S, Schmit 
B, Quinn R, Muller CY, Rabinowitz I, Purdy M, Snyder D, Bocklage T. Phase IB 
study of the combination of docetaxel, gemcitabine, and bevacizumab in patients 
with advanced or recurrent soft tissue sarcoma: the Axtell regimen. Ann Oncol. 
2012 Mar;23(3):785-90. doi: 10.1093/annonc/mdr299. Epub 2011 Jul 11 
13. 
Park MS, Patel SR, Ludwig JA, Trent JC, Conrad CA, Lazar AJ, Wang WL, 
Boonsirikamchai P, Choi H, Wang X, Benjamin RS, Araujo DM. Activity of 
temozolomide and bevacizumab in the treatment of locally advanced, recurrent, 
and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer. 
2011 Nov 1;117(21):4939-47. doi: 10.1002/cncr.26098. Epub 2011 Apr 8 
14. 
Takano M, Kikuchi Y, Susumu N, Kudoh K, Kita T, Kouta H, Goto T, Furuya K. 
Complete remission of recurrent and refractory uterine epithelioid leiomyosarcoma 


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using weekly administration of bevacizumab and temozolomide. Eur J Obstet 
Gynecol Reprod Biol. 2011 Aug;157(2):236-8. 
15. 
Fuller CK, Charlson JA, Dankle SK, Russell TJ. Dramatic improvement of 
inoperable 
angiosarcoma 
with 
combination 
paclitaxel 
and 
bevacizumab 
chemotherapy. J Am Acad Dermatol. 2010 Oct;63(4):e83-4. 
16. 
D'Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwartz 
GK, Chen H, Maki RG. Phase II study of doxorubicin and bevacizumab for patients 
with metastatic soft-tissue sarcomas. J Clin Oncol. 2005 Oct 1;23(28):7135-42. 
17. 
Tan AR, Dowlati A, Jones SF, Infante JR, Nishioka J, Fang L, Hodge JP, Gainer 
SD, Arumugham T, Suttle AB, Dar MM, Lager JJ, Burris HA 3rd. Phase I study of 
pazopanib in combination with weekly paclitaxel in patients with advanced solid 
tumors. Oncologist. 2010;15(12):1253-61. doi: 10.1634/theoncologist.2010-0095. 
Epub 2010 Dec 8. 
18. 
Penel N, Marréaud S, Robin YM, Hohenberger P. Angiosarcoma: state of the art 
and perspectives. Crit Rev Oncol Hematol. 2011 Nov;80(2):257-63. doi: 
10.1016/j.critrevonc.2010.10.007. Epub 2010 Nov 4. Review. 
19. 
J. Fayette, E. Martin, S. Piperno-Neumann et al. Angiosarcomas, a herogeneous 
group of sarcomas with specific behavior depending on primary site: a retrospective 
study of 161 cases Ann Oncol, 18 (2007), pp. 2030–2036 
20. 
J. Meis-Kindblom, L.G. Kindblom Angiosarcoma of soft tissue: a study of 80 cases. 
Am J Surg Pathol, 22 (1998), pp. 683–697 
21. 
J.A. Abraham, F.J. Hornicek, A.M. Kaufman et al. Treatment and outcome of 82 
patients with angiosarcoma. Ann Surg Oncol, 14 (2007), pp. 1953–1967 
22. 
R.J. Mark, J.C. Poen, L.M. Tran, T.S. Fu, G.F. Juillard: Angiosarcoma. A report of 
67 patients and a review of the literature. Cancer, 77 (1996), pp. 2400–2406  
23. 
Tarkkanen M, Wiklund TA, Virolainen MJ, Larramendy ML, Mandahl N, Mertens F, 
Blomqvist CP, Tukiainen EJ, Miettinen MM, Elomaa AI, Knuutila YS. Comparative 
genomic hybridization of postirradiation sarcomas. Cancer. 2001;92:1992–1998.  
24. 
Mertens F, Larramendy M, Gustavsson A, Gisselsson D, Rydholm A, Brosjo O, 
Mitelman F, Knuutila S, Mandahl N. Radiation-associated sarcomas are 
characterized by complex karyotypes with frequent rearrangements of 
chromosome arm 3p. Cancer Genet Cytogenet. 2000;116:89–96.  
25. 
Nakanishi H, Tomita Y, Myoui A, Yoshikawa H, Sakai K, Kato Y, Ochi T, Aozasa K. 
Mutation of the p53 gene in postradiation sarcoma. Lab Invest. 1998;78:727–733.  
26. 
Brachman DG, Hallahan DE, Beckett MA, Yandell DW, Weichselbaum RR. p53 
gene mutations and abnormal retinoblastoma protein in radiation-induced human 
sarcomas. Cancer Res. 1991;51:6393–6396.  
27. 
Gil-Benso R, Lopez-Gines C, Soriano P, Almenar S, Vazquez C, Llombart-Bosch 
A. Cytogenetic study of angiosarcoma of the breast. Genes Chromosomes Cancer. 
1994;10:210–212.  
28. 
Naka N, Tomita Y, Nakanishi H, Araki N, Hongyo T, Ochi T, Aozasa K. Mutations 
of p53 tumor-suppressor gene in angiosarcoma. Int J Cancer. 1997;71:952–955.  
29. 
Baumhoer D, Gunawan B, Becker H, Fuzesi L. Comparative genomic hybridization 
in four angiosarcomas of the female breast. Gynecol Oncol. 2005;97:348–352.  
30. 
Cerilli LA, Huffman HT, Anand A. Primary renal angiosarcoma: a case report with 
immunohistochemical, ultrastructural, and cytogenetic features and review of the 
literature. Arch Pathol Lab Med. 1998;122:929–935.  
31. 
Schuborg C, Mertens F, Rydholm A, Brosjo O, Dictor M, Mitelman F, Mandahl N. 
Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue. 
Cancer Genet Cytogenet. 1998;100:52–56.  
32. 
Wong KF, So CC, Wong N, Siu LL, Kwong YL, Chan JK. Sinonasal angiosarcoma 
with marrow involvement at presentation mimicking malignant lymphoma: 
cytogenetic analysis using multiple techniques. Cancer Genet Cytogenet. 
2001;129:64–68.  


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33. 
Zu Y, Perle MA, Yan Z, Liu J, Kumar A, Waisman J. Chromosomal abnormalities 
and p53 gene mutation in a cardiac angiosarcoma. Appl Immunohistochem Mol 
Morphol. 2001;9:24–28.  
34. 
Mandahl N, Jin YS, Heim S, Willen H, Wennerberg J, Biorklund A, Mitelman F. 
Trisomy 5 and loss of the Y chromosome as the sole cytogenetic anomalies in a 
cavernous 
hemangioma/angiosarcoma. 
Genes 
Chromosomes 
Cancer. 
1990;1:315–316.  
35. 
Manner J, Radlwimmer B, Hohenberger P, Mössinger K, Küffer S, Sauer C, 
Belharazem D, Zettl A, Coindre JM, Hallermann C, Hartmann JT, Katenkamp D, 
Katenkamp K, Schöffski P, Sciot R, Wozniak A, Lichter P, Marx A, Ströbel P. MYC 
high level gene amplification is a distinctive feature of angiosarcomas after 
irradiation or chronic lymphedema. Am J Pathol. 2010 Jan;176(1):34-9. 
36. 
Italiano A, Chen CL, Thomas R, Breen M, Bonnet F, Sevenet N, Longy M, Maki 
RG, Coindre JM, Antonescu CR. Alterations of the p53 and PIK3CA/AKT/mTOR 
pathways in angiosarcomas: a pattern distinct from other sarcomas with complex 
genomics. Cancer. 2012 Dec 1;118(23):5878-87. doi: 10.1002/cncr.27614. Epub 
2012 May 30 
37. 
ESMO / European Sarcoma Network Working Group. Soft tissue and visceral 
sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and Follow-
Up Ann Oncol. 2012 Oct;23 Suppl 7:vii92-9.  
38. 
Billemont B, Medioni J, Taillade L, Helley D, Meric JB, Rixe O, Oudard S. Blood 
glucose levels in patients with metastatic renal cell carcinoma treated with 
sunitinib.Br J Cancer. 2008 Nov 4;99(9):1380-2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17 Appendix B: CYP3A3/4 influencers of Plasma-Pazopanib-concentrations  
 
CYP3A3/4 Substrates 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 

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Statistical Analysis Plan for Final Analysis 
 
 
Trial title:  
EVA (Evaluation of Votrient in Angiosarcoma) 
This Statistical Analysis Plan (SAP) describes the final analysis. This document is additional 
to the SAP describing the interim analysis.  
 
 
Trial code:  
Novartis Common Code (NCC): CPZP034BDE01T 
EudraCT Number: 2012-005846-39 
 
 
SAP version: 1.0 
SAP Date: 
03.04.2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Name and address of the responsible Biometrician: 
Dr. phil. Marietta Kirchner 
Institut für Medizinische Biometrie und Informatik 
Im Neuenheimer Feld 130.3 
D-69120 Heidelberg 
Email: kirchner@imbi.uni-heidelberg.de  
Phone: +49 6221 56 7784 
 
Name and address of the representative of the Biometrician:  
Dr. Anja Sander 
Institut für Medizinische Biometrie und Informatik 
Im Neuenheimer Feld 130.3 
D-69120 Heidelberg 
Email: sander@imbi.uni-heidelberg.de  
Phone: +49 6221 56 5859 
 
Name and address of the Coordinating Investigator:  
Prof. Dr. med. Peter Hohenberger 
Surgical Clinic, 
University Hospital Mannheim, Medical Faculty Mannheim 
Theodor-Kutzer-Ufer 1-3 
68167 Mannheim 
Email: Peter.Hohenberger@umm.de 
Phone: +49 (0) 621 3832609 
Fax: +49 (0) 621 3831479 
 
 
Name and address of the Sponsor:  
University of Heidelberg, Medical Faculty Mannheim,  
represented by the chancellor of the University of Heidelberg 
Central Administration of the University 
Seminarstr. 2 
69117 Heidelberg 
Email: kanzlerin@zuv.uni-heidelberg.de 
Phone: +49 (0) 6221 54-2100 & -2001 
Fax: +49 (0) 6221 54-2618 
 
 
 
 
 
 
 
 


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Signature 
 
 
Date and signature of the responsible Biometrician 
 
 
Date and signature of the representative of the Biometrician 
 
 
Date and signature of the Coordinating Investigator 
 


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1 
Purpose of the Statistical Analysis Plan of the Final Analysis 
The present Statistical Analysis Plan (SAP) describes the remaining analyses which has not 
already been provided at interim as it was defined that they will only be done at the final 
analysis. This document complements the SAP of the interim analysis. However, some 
sections (Section 2, 3, 5) were copied from the already existing SAP in order to have a better 
overview. This will be indicated in the respective sections. 
The study was stopped for futility at interim. According to the study protocol, the interim 
analysis should have been done after having observed the primary endpoint for the first 14 
patients. Actually, there was an overrunning of 12 patients so that 𝑛= 26 patients were 
included in the full analysis set (FAS) of the interim analysis. In order to guarantee that the 
pre-specified significance level 𝛼=0.05 is kept, the method to handle overrunning by Englert 
and Kieser [1] was applied. This results in the decision rule “If 𝑠1 ≤17 successes are seen 
out of 𝑛1 = 26 patients in the first stage the trial will be stopped for futility”. With 12 
successes observed at interim the study was stopped. However, all analyses at interim were 
already provided for the 𝑛= 26 patients which is the total sample size of the present study. 
Thus, the results of these analyses are already part of the statistical report of the interim 
analysis and are the final results so that there is no need to repeat them here. Instead, 
analysis of secondary endpoints and of subgroup analyses were not part of the interim 
analysis and will be described here and summarized in an additional statistical report for 
publication purposes. 
2 
Objective of the Trial 
Copied from the SAP of the interim analysis. 
The objective of this trial is to evaluate efficacy and safety of the experimental treatment 
given by a combination of Pazopanib with Paclitaxel for patients with advanced or metastatic 
angiosarkoma (AS). Primary endpoint is progression-free survival after 6 months 
(observation).  
3 
Study design 
Copied from the SAP of the interim analysis. 
This is a multicentre, open, prospective, single-armed phase II trial to evaluate efficacy and 
safety of the experimental treatment given by a combination of Pazopanib with Paclitaxel for 
patients with advanced or metastatic angiosarkoma. 
Additional information not written in the SAP of the interim analysis: 
Tumor assessment was scheduled at baseline, every eight weeks (± 7 days) during the 
treatment period (consists of six cycles à four weeks (28 days), combination of Pazopanib 


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with Paclitaxel), 30 days after last study medication (“safety follow-up”), every twelve weeks 
(± 14 days) during “follow-up” until progression. According to the study protocol the follow-up 
period ends when the last patient has reached a follow-up period of 24 weeks. 
4 
Analysis sets 
Full Analysis Set (FAS): Consists of all patients who were included in the trial and received 
the study medication at least once or in parts. The term "ITT analysis" is used for an analysis 
applying ITT principles to all patients of the FAS. 
Note, this is the same definition as in the interim analysis. 
5 
Definitions of endpoints to be analysed 
Copied from the SAP of the interim analysis. 
Primary endpoint: The primary endpoint of the study is 6 months progression-free survival 
(PFS) (assessed at 182 days ± 32 days tolerance region after start of treatment, reference 
date is the date of imaging). Start of therapy will be counted when the patient first gets the 
study treatment. The assessment date which best matches the time point of 182 days will be 
used as the reference. If no follow-up visit matches this time interval, conclusions on the 
disease status at 6 months are made as follows: 
• If the patient has stable disease (SD) at the next documented assessment after the 
time interval specified above, the status at 6 months is SD as well. 
• If the patient has complete remission (CR) or partial remission (PR) at the next 
documented follow-up visit after the time interval specified above, the status at 6 
months is counted as SD. 
• If the patient has progressive disease (PD) at any follow-up visit before the time interval 
specified above, the status at 6 months is counted as PD. 
• If neither of the above cases holds true (that is no information is available that directly 
allows to specify the disease status at 6 months), the status at 6 months is counted as 
PD. 
The diagnosis of progression is based on tumor measurements according to the RECIST 
criteria (version 1.1, [2]) based on a predefined set of target lesions and on non-target 
lesions. 
Secondary endpoints:   
The secondary endpoints according to the study protocol are 
• 
Overall survival (OS) defined as start of therapy (date of first study medication) until 
death (event).  


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• 
Response (R) according to the RECIST criteria (version 1.1, [2]). Here, best overall 
response (BOR) within the study period is of interest. It is defined as the best 
response (categories CR, PR, SD, PD) since the patient is on-treament according to 
the following rules: 1. If CR was documented at least once then BOR=CR, 2. If CR 
was never documented but PR at least once then BOR=PR, 3. If CR and PR were 
never documented but SD at least once then BOR=SD, 4. If CR, PR, and SD were 
never documented but an assessment has taken place then BOR=PD, 5. If a patient 
dies and reason of death is progression/ progressive disease then BOR=PD, 6. If a 
patient dies without progression (e.g. as reason of death) before the first assessment, 
“Response” is not evaluable (NE) and thus  BOR=NE. 
• 
Grading of (Serious) Adverse Events ((S)AE) according to CTCAE version 4.0 (v4.0) 
(these are the safety relevant endpoints) 
Further secondary endpoints not specified in the study protocol but of interest for publication 
purposes: 
• 
3 months PFS (assessed at 90 days ± 30 days tolerance region after start of 
treatment, reference date is the date of imaging). Start of therapy will be counted 
when the patient first gets the study treatment. The assessment date which best 
matches the time point of 90 days will be used as the reference. If no follow-up visit 
matches this time interval, conclusions on the disease status at 3 months are made 
according to the rules defined for the primary endpoint. 
• 
PFS as time-to-event endpoint (TTE) defined as start of therapy (patient first gets the 
study treatment) until first progression (PD) or death whatever comes first. 
 
Subgroup analyses: 
The analysis of the primary endpoint (6 months PFS) and of the secondary endpoints (3 
months PFS, PFS TTE, OS and BOR) are applied to the following subgroups: 
1. Cutaneous vs. visceral AS  (compare Tables 8.1.1.4 and 10.2.4 of the statistical 
report of the interim analysis: 𝑛= 9 visceral, 𝑛= 14 cutaneous, 𝑛= 3 visceral and 
cutaneous; according to the clinical trial team, the three patients with “visceral and 
cutaneous” can be clearly assigned to the subgroup “cutaneous” after checking the 
data entries again so that two distinct subgroups will be given).  
2. Primary vs. secondary AS (compare Table 8.1.1.4 of the statistical report of the 
interim analysis: 𝑛= 13 primary and 𝑛= 13 secondary AS)  
6 
Data handling 
Data were checked for consistency and plausibility throughout study conduct and at the end 
of the study (see also data validation plan). 


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AE term: free text fields in the AE database are categorized into clearly defined AE terms so 
that identical AE have the same term assigned. MedDRA lowest level terms (LLT) are used.  
In comparison to the dataset the interim analysis was based on, the following changes were 
made:  
1. As indicated before (Section 5 “Subgroup analysis”), the grouping of patients into 
visceral vs. cutaneous AS was checked again by the clinical trial team due to the 
occurrence of unclear assignments. Four corrections were made for the present 
analysis: three patients assigned to “visceral and cutaneous” will be corrected to 
“cutaneous” (ID 07, 13, 23) and one patient assigned to “visceral” will be corrected to 
“cutaneous” (ID 09).  
2. In addition, some open queries with respect to AE documentation were resolved. 
Note that these variables were not part of the interim analysis as AEs are only 
analysed in the final analysis. 
3. For one patient (ID 25), three further follow-up visits were documented. Again, these 
additional visits do not influence the interim analysis (6 months PFS was already 
observed before) so that no changes to the interim results of the primary endpoint 
have to be made.  
7 
Statistical methods 
All analyses will be applied to the FAS. All analyses have descriptive character and p-values 
can only be interpreted in descriptive manner. 
7.1 
Primary analysis 
The primary analysis was part of the interim analysis. As the study was stopped at interim, 
these analyses are completed and will not be repeated here (compare Section 1). 
7.2 
Analysis of the secondary endpoints 
The analysis of secondary endpoints is of descriptive nature and generally consists of 
summary statistics and interval estimation.  
OS was defined as the time from start of therapy to death (event status = 1) or last contact 
(censoring, event status = 0), respectively. OS will be analysed using Kaplan-Meier curves. 
The median survival time will be provided alongside two-sided 95% confidence intervals (CI, 
if possible). Censoring events (e.g. early drop-out reasons like withdrawal, administratively 
censoring at the end of the study period) will be summarized using absolute and relative 
frequencies. Additionally, an individual listing will be provided showing information on “event” 
(yes/ no), “overall survival time” (time to death if event=yes or time to drop-out if event=no 
[days]), “reasons for drop-out” if event=no (e.g. withdrawal, lost to follow-up, other reason, 
end of study period).  


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Similarly, PFS TTE defined as the time form start of therapy to first progression (PD) or death 
(whatever comes first) or last contact (censoring), respectively, will be analysed by Kaplan-
Meier curves with median survival time (95% CI). Again, an individual listing will be provided 
showing information on “event” (yes(death)/ yes(PD)/ no), “progression-free survival time” 
(time to death if event=yes(death) or time to PD if event=yes(PD) or time to drop-out if 
event=no), “reasons for drop-out” if event=no (e.g. withdrawal, lost to follow-up, other reason, 
end of study period). 
BOR (categories PD, SD, PR, CR, NE) will be summarized by absolute and relative 
frequencies. 
PFS rate at month 3 will be calculated as number of successes (progression-free = response 
status SD, PR, or CR) divided by number of patients together with exact Clopper-Pearson 
95% CI. 
The secondary endpoints “grading of (S)AEs according to CTCAE v4.0” are safety relevant 
endpoints and will be analysed by descriptive statistical methods: 
1. Adverse Events (AEs – yes/no):  
Frequencies (absolute and relative) will be shown for every AE term (LLT) which 
occurred at least once. Here, a patient is coded “1” (yes) if the respective LLT 
occurred at least once and “0” (no) if it does not occur.  
If yes, grading (grade I-II (category 1), III-IV (category 2), to V (category 3)) according 
to the CTCAEv4.0 will be tabulated for each AE term (absolute and relative 
frequencies for each category). Therefore, the maximal grading for each LLT per 
patient is taken (this is relevant if the respective LLT is observed more than once in a 
patient).  
2. Serious Adverse Events (SAEs - yes/no): due to the low number of SAEs (AE 
classified as SAE), all SAEs will be listed with description of the event, CTCAEv4.0 
grading, and relation to study drug. Additionally, CTCAEv4.0 grades (grade I-II 
(category 1), III-IV (category 2), to V (category 3)) will be summarized by absolute 
and relative frequencies (over all SAES irrespective of the respective LLT). 
7.3 
Subgroup analyses 
The analyses of PFS, OS, and BOR will be applied to the subgroups as defined in Section 5.  
First, summary statistics (absolute and relative frequencies) will be given for each subgroup 
as corrections were applied and thus, deviations to the frequencies provided at the interim 
analysis are given.   
Analysis of OS and PFS TTE as defined above is done by Kaplan-Meier curves stratified by 
subgroup (1. cutaneous vs. visceral AS, 2. primary vs. secondary AS) with median survival 


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time and two-sided 95% CI (if possible) provided for each subgroup. The p-value of the log-
rank test for comparison of two survival curves will be reported. 
Frequencies of BOR will be provided stratified by subgroup (1. cutaneous vs. visceral AS, 2. 
primary vs. secondary AS). Results will be displayed in contingency tables and differences in 
proportions is assessed by exact Pearson chi-square test (exact test preferred due to small 
sample size, compare Section 9). The respective test statistic with the descriptive p-value will 
be reported. Again, NE will be considered as a separate category and will be tabulated.  
PFS rate at month 3 and at month 6 will be given for each subgroup. The point estimate for 
the PFS rate is calculated as number of successes (progression-free = response status SD, 
PR, or CR) divided by number of patients in the respective subgroup. Additionally, 95% exact 
Clopper-Pearson confidence intervals are provided. Difference between two proportions (1. 
cutaneous vs. visceral AS, 2. primary vs. secondary AS) is assessed by Barnard's exact test 
and the respective test statistic with the descriptive p-value will be reported. An exact test is 
used here due to small sample size (compare Section 9). Barnard’s exact test is preferred 
over the more common Fisher’s exact test as it is more powerful (less conservative). 
8 
Software 
All evaluations will be carried out using the software package SAS® System 9.4 (SAS Inc., 
Cary/NC, USA). 
9 
Deviations to the study protocol 
In the study protocol, the chi-square test was proposed for the analysis of differences in 
proportions. However, due to the small sample size (final analysis is based on 𝒏= 𝟐𝟔 
patients due to futility stop at interim and not 𝒏= 𝟒𝟒 as planned in case of proceeding with 
the trial after interim analysis), exact tests retain the nominal alpha level and are therefore 
preferred even in this exploratory analysis. In the PROC FREQ statement in SAS, the exact 
statement requests the exact test as exact barnard; for Barnard’s exact test and exact pchi; 
for exact Pearson chi-square test. 
Response was defined as secondary endpoint in the study protocol without further 
definitions. This was specified as “best overall response” for the present analysis.  
10 References 
 [1] 
S. Englert and M. Kieser (2015). Methods for proper handling of overrunning and 
underrunning in phase ii designs for oncology trials. Statistics in Medicine, 34:2128-
2137. 
[2] 
E.A. Eisenhauer et al. (2009). New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer, 45:228-247.