Randomized Open Label Study to Compare the Efficacy and Safety of Everolimus Followed by Chemotherapy With Streptozotocin- Fluorouracilo (STZ-5FU) Upon Progression or the Reverse Sequence, in Advanced Progressive Pancreatic NETs (pNETs)
Phase: PHASE3
Conditions: Neuroendocrine Tumors
Sponsor: Grupo Espanol de Tumores Neuroendocrinos

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭CLINICAL TRIAL PROTOCOL‬
‭EudraCT number: 2013-000726-66‬
‭NCT02246127‬
‭Randomized open label study to compare the efficacy and safety‬
‭of everolimus followed by chemotherapy with STZ-5FU upon progression or‬
‭the reverse sequence, chemotherapy with STZ-5FU  followed by  everolimus‬
‭upon progression, in advanced progressive pNETs‬
‭(SEQTOR study)‬
‭PROTOCOL CODE: GETNE1206‬
‭Version  4.0 25‬‭th‬‭of June 2018‬
‭Modified on the 7‬‭th‬‭of August 2018‬
‭Sponsor:‬‭GETNE‬
‭Collaborative Groups:‬‭ENETS‬
‭Study Coordinator:‬‭Dr Ramón Salazar‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Protocol approval:‬
‭Title:‬‭Randomized‬‭open‬‭label‬‭study‬‭to‬‭compare‬‭the‬‭efficacy‬‭and‬‭safety‬‭of‬‭everolimus‬‭followed‬‭by‬
‭chemotherapy‬ ‭with‬ ‭STZ-5FU‬ ‭upon‬ ‭progression‬ ‭or‬ ‭the‬ ‭reverse‬ ‭sequence,‬ ‭chemotherapy‬ ‭with‬
‭STZ-5FU‬ ‭followed‬‭by‬‭everolimus‬‭upon‬‭progression,‬‭in‬‭advanced‬‭progressive‬‭pNETs‬‭(SEQTOR‬
‭study).‬
‭EudraCT number:‬‭2013-000726-66‬
‭Protocol code‬‭: GETNE1206‬
‭Version‬‭4.0‬‭Date‬‭:  25‬‭th‬‭of June 2018, Modified on‬‭the 7‬‭th‬‭of August 2018‬
‭Relevant‬‭modification‬‭since‬‭version.0:‬‭,‬‭Change‬‭on‬‭main‬‭variable‬‭and‬‭sample‬‭size.‬‭Also,‬‭the‬‭text‬
‭has been improved (corrections of typing errors, clarifications of the text).‬
‭Modified on the 7‬‭th‬‭of August to add a new sub-study‬‭as Annex VI.‬
‭Summary of changes:‬
‭REVISION HISTORY‬
Version‬
‭Date‬
‭Section‬
‭Change‬
‭1.0‬
12‬‭th‬‭Feb 2013‬
‭Initial version‬‭(EudraCTnumber)‬
‭2.0‬
30‬‭th‬
‭Jan‬
‭2014‬
Amendment 1‬
II. Study coordination‬
V. Institutions‬
3. Randomization‬
5.1 Everolimus & 6.1‬
Treatments allowed‬
‭-All along the protocol‬
‭•‬ ‭Change on translational study coordinator (Section II‬
‭•‬ ‭Blood sampling for future analysis (CTC) is deleted‬
‭•‬ ‭Inclusion‬ ‭of‬ ‭detailed‬ ‭address‬ ‭for‬ ‭central‬ ‭CgA‬ ‭and‬
‭CTScan determination‬
‭•‬ ‭Confusing paragraph is deleted.‬
‭•‬ ‭New information on everolimus (IB ed 12)‬
‭•‬ ‭Correction of typing errors, and text clarification.‬
‭2.01‬
1st‬
‭Sept‬
‭2014‬
Working version‬
Sections‬ ‭2.1,‬ ‭3,‬ ‭7.4.1,‬
7.4.2 and 8‬
‭Clarification‬ ‭of‬ ‭study‬ ‭procedures‬ ‭suggested‬ ‭by‬ ‭Health‬
‭Authorities.‬
‭3.0‬
26‬‭th‬
‭Nov‬ ‭2014‬
Amendment 2‬
V. Institutions‬
VI. Timeliness‬
2. Study objectives‬
3. Study design‬
4. Study population‬
5. Investigational drugs‬
7.4.1 Safety Assessment‬
8. Statistics‬
‭• New Instututions are included.‬
‭•‬ ‭Enlargement‬ ‭of‬ ‭study‬ ‭timing‬ ‭based‬ ‭on‬‭new‬‭information‬
‭available from ENETS 2014.‬
‭•‬ ‭Enlargement‬ ‭on‬ ‭the‬ ‭timing‬ ‭for‬ ‭the‬ ‭primary‬ ‭endpoint.‬
‭Clarification suggested by Health Authorities‬
‭•‬ ‭Enlargement‬‭on‬‭the‬‭timing‬‭for‬‭the‬‭primary‬‭endpoint‬‭and‬
‭clarifications suggested by Health Authorities‬
‭•‬ ‭Timing‬ ‭allowed‬ ‭between‬ ‭randomization‬ ‭and‬‭the‬‭start‬‭of‬
‭treatment‬
‭• Clarification suggested by Health Authorities‬
‭• Information updated with Investigator’s Brochure Ed 13‬
‭•‬ ‭Clarification‬ ‭of‬ ‭study‬ ‭procedures‬ ‭suggested‬ ‭by‬ ‭Health‬
‭Authorities.‬
‭•‬ ‭Enlargement‬ ‭on‬ ‭the‬ ‭timing‬ ‭for‬ ‭the‬ ‭primary‬ ‭endpoint‬‭&‬
‭clarifications suggested by Health Authorities.‬
‭Ver‬‭4.0‬‭7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭4.0‬
General Information‬
1.0 Background‬
2.‬ ‭Study‬ ‭objective‬ ‭and‬
purposes‬
3. Study design‬
4.2.Withdrawal‬
‭of‬
sub-jects and study end‬
7.2.6. Laboratory‬
8. Statistics‬
8.1 Primary endpoint‬
8.4.3‬ ‭Main‬ ‭analysis‬ ‭of‬
efficacy‬
Annex VI‬
‭●‬
‭Update of timelines‬
‭●‬
‭The study rational is updated‬
‭●‬
‭New definition according to feasible sample size.‬
‭●‬‭The‬‭primary‬‭objective‬‭has‬‭been‬‭changed‬‭and‬‭the‬‭old‬‭one‬
‭has been moved to secondary‬
‭●‬ ‭Secondary objective were revised‬
‭●‬‭Period between treatments is adjusted to clinical practice‬
‭●‬‭Follow-up of patients is detailed‬
‭●‬‭Clarification‬ ‭about‬ ‭laboratory‬ ‭determinations‬ ‭(standard‬
‭analytical protocol at site is used).‬
‭●‬‭CTC sampling is deleted (not started)‬
‭●‬‭Updated‬ ‭as‬ ‭per‬ ‭changes‬‭on‬‭point‬‭2‬‭of‬‭this‬‭modification‬
‭(Main analysis and sample size)‬
‭●‬‭Definition of event is included‬
‭●‬‭Inclusion of sensitivity analysis‬
‭●‬‭Deletion‬‭of‬‭an‬‭Ancillary‬‭trial‬‭(CTC,‬‭optional)‬‭that‬‭never‬
‭started‬
‭●‬‭Inclusion of a new sub-study on tumor blocks‬
‭Ver‬‭4.0‬‭7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Sponsor / Coordinating investigator:‬
‭Signed:‬‭Dr Ramón Salazar‬
‭Date‬
‭Biostatistician:‬
‭Signed:‬‭Valenti Navarro Pérez‬
‭Date‬
‭Ver‬‭4.0‬‭7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Coordinating Investigator’s Signature (if applicable):‬
‭Study Title:‬
‭Randomized‬‭open‬‭label‬‭study‬‭to‬‭compare‬‭the‬‭efficacy‬‭and‬‭safety‬‭of‬
‭everolimus‬ ‭followed‬ ‭by‬ ‭chemotherapy‬ ‭with‬ ‭STZ-5FU‬ ‭upon‬
‭progression‬‭or‬‭the‬‭reverse‬‭sequence,‬‭chemotherapy‬‭with‬‭STZ-5FU‬
‭followed‬‭by‬ ‭everolimus‬‭upon‬‭progression,‬‭in‬‭advanced‬‭progressive‬
‭pNETs (SEQTOR study)‬
‭Study Number:‬
‭GETNE1206‬
‭Protocol‬
‭Version:‬
‭Protocol/Date:‬
‭4.0‬
‭07 Aug 2018‬
‭I‬‭have‬‭read‬‭the‬‭protocol‬‭described‬‭above.‬‭I‬‭agree‬‭to‬‭comply‬‭with‬‭all‬‭applicable‬‭regulations‬
‭and to conduct the study as described in all sections of the protocol.‬
‭Signed:‬
‭Date:‬
‭Name:‬
‭Address:‬
‭Investigator’s Signature:‬
‭Study Title:‬
‭Randomized‬‭open‬‭label‬‭study‬‭to‬‭compare‬‭the‬‭efficacy‬‭and‬‭safety‬‭of‬
‭everolimus‬ ‭followed‬ ‭by‬ ‭chemotherapy‬ ‭with‬ ‭STZ-5FU‬ ‭upon‬
‭progression‬‭or‬‭the‬‭reverse‬‭sequence,‬‭chemotherapy‬‭with‬‭STZ-5FU‬
‭followed‬‭by‬ ‭everolimus‬‭upon‬‭progression,‬‭in‬‭advanced‬‭progressive‬
‭pNETs (SEQTOR study)‬
‭Study Number:‬
‭GETNE1206‬
‭Protocol‬
‭Version:‬
‭Protocol/Date:‬
‭4.0‬
‭07 Aug 2018‬
‭I‬‭have‬‭read‬‭the‬‭protocol‬‭described‬‭above.‬‭I‬‭agree‬‭to‬‭comply‬‭with‬‭all‬‭applicable‬‭regulations‬
‭and to conduct the study as described in all sections of the protocol.‬
‭Signed:‬
‭Date:‬
‭Name:‬
‭Address:‬
‭Ver  4.0,‬‭7‬‭th‬‭of August 2018‬
‭Page‬‭6‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭GENERAL INFORMATION‬
‭I.‬
‭SPONSOR AND MONITOR‬
‭Sponsor‬
‭Grupo Español de Tumores Neuroendocrinos (GETNE)‬
‭C/ Velázquez nº 7, piso 3‬
‭28001 Madrid, Spain‬
‭CRO‬‭:‬
‭Kantar Health GmbH‬
‭Landsberger Straße 284‬
‭80687 München, Germany‬
‭Tel: +49 89 5600 1280 ‬
‭Fax: +49 89 5600 1590‬
‭E-mail: mercedes.apecechea@kantarhealth.com‬
‭Statistics:‬
‭Valentí Navarro Pérez‬
‭Unidad de Investigación Clínica‬
‭Institut Català d'Oncologia-L'Hospitalet‬
‭Av. Gran Via, 199-203‬
‭08907 - l'Hospitalet-Barcelona‬
‭Tel: 93.260.78.22/Fax: 93.260.73.34‬
‭E-mail: vnavarro@iconcologia.net‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭7‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭II.‬
‭COORDINATING INVESTIGATOR AND ADDRESS‬
‭Dr. Ramón Salazar (chairman of GETNE & study coordinator)‬
‭Catalan Institute of Oncology‬
‭Av. Gran Vía, 199-203‬
‭08907 L´Hospitalet-Barcelona‬
‭Tel: +34 93 2607739‬
‭Fax: +34 93 2607741‬
‭E-mail: ramonsalazar@iconcologia.ne‬‭t‬
‭Dr. Barbro Ericksson (coordinator of translational studies)‬
‭Uppsala University Hospital‬
‭Uppsala SE-751 85, Sweden‬
‭Telephone: +46-186-11-49-17‬
‭Fax: +46 18 51 01 33‬
‭e-mail: barbro.eriksson@medsci.uu.se‬
‭III. COORDINATING GROUPS‬
‭Grupo Español de Tumores Neuroendocrinos (GETNE)‬
‭C/ Velázquez nº 7, piso 3‬
‭28001 Madrid, Spain‬
‭Secretaría Técnica GETNE‬
‭C/ París, 162 Pral 1ª‬
‭Barcelona 08036, Spain‬
‭tel. + 34 93.451.17.24   fax. + 34 93.451.43.66‬
‭e-mail:‬‭getne@getne.org‬
‭Sponsor‬
‭European Neuroendocrine Tumours Society (ENETS)‬
‭ENETS Coordinating Office Dept. of Gastroenterology‬
‭Charite, Campus Virchow-Klinikum‬
‭Augustenburger Platz 1‬
‭13353 Berlin, Germany‬
‭Tel: +49 (30) 450-553096‬
‭Contact person: Elisabeth Zach (elizabeth.zach@charite.de)‬
‭Collaborative group‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭8‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭V.‬
‭OTHER INSTITUTIONS INVOLVED‬
‭Centre for Applied Research on Cancer ‬
‭University of Verona - Policlinico G.B. Rossi‬
‭c/o Piastra Odontoiatrica - secondo piano‬
‭Piazzale L.A. Scuro, 10, 37134 Verona, Italy‬
‭Telephone:   (+39) 045 812 7431‬
‭Laboratory of Systems and Precision Cancer Medicine |‬
‭Division of Molecular Pathology‬
‭The Institute of Cancer Research‬
‭15 Cotswold Road, Belmont, Sutton, Surrey‬
‭SM2 5NG‬
‭Telephone (+44) 208 915 6631‬
‭Translational Research‬
‭Detection of Predictive‬
‭markers (paraffin blocks)‬
‭UCL Cancer Institute and Royal Free Hospital‬
‭Neuroendocrine Tumour Unit‬
‭Royal Free Hospital‬
‭Pond Street, London‬
‭NW3 2QG‬
‭Telephone: (+44) 020 7794 0500‬
‭Translational Research‬
‭Detection of Predictive‬
‭markers (Blood/serum)‬
‭Service de Radiologie‬
‭Hôpital Beaujon‬
‭100, Boulevard du Général Leclerc‬
‭92118 Clichy Cedex‬
‭France‬
‭Translational Research‬
‭Central review & Analysis of‬
‭ENETS Score‬
‭Institut Gustave-Roussy‬
‭Rue Camille Desmoulins 39‬
‭94805 Villejuif, France‬
‭Telephone: +33 (0)1 42 11 42 11‬
‭Translational Research‬
‭CgA central analysis‬
‭Wren Laboratories‬
‭35 NE Industrial Road‬
‭Branford CT 065405, USA‬
‭Telephone: +12032083464‬
‭Translational Research‬
‭Biomarker of NET response‬
‭VI‬
‭TIMELINES‬
‭The estimated timeliness for the study are:‬
‭First patient in (FPI):‬
‭Third Q 2014‬
‭Last Patient in (LPI):‬
‭Fourth Q 2018‬
‭Data matured for primary endpoint analysis: First Q 2020‬
‭Data base lock for primary endpoint analysis:  Third Q 2020‬
‭Primary endpoint publication: First Q 2021 (assuming ENETS 2021)‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭9‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Last Patient out (LPO):‬
‭Fourth Q 2021‬
‭Final Clinical Study Report:‬
‭Second Q 2022‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭10‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭TABLE OF CONTENTS‬
‭GENERAL INFORMATION‬
‭6‬
‭1.‬
‭BACKGROUND INFORMATION AND RATIONALE‬
‭16‬
‭2.‬
‭STUDY OBJECTIVES AND PURPOSE‬
‭19‬
‭2.1‬
‭P‬‭RIMARY‬‭O‬‭BJECTIVE‬
‭19‬
‭2.2‬
‭S‬‭ECONDARY‬‭O‬‭BJECTIVES‬
‭19‬
‭3.‬
‭STUDY DESIGN‬
‭21‬
‭4.‬
‭STUDY POPULATION‬
‭23‬
‭4.1‬
‭SELECTION OF SUBJECTS‬
‭23‬
‭4.1.1‬
‭Inclusion criteria‬
‭23‬
‭4.1.2‬
‭Exclusion criteria‬
‭24‬
‭4.2‬
‭WITHDRAWAL OF SUBJECTS AND STUDY END‬
‭26‬
‭5.‬
‭INVESTIGATIONAL DRUGS‬
‭26‬
‭5.1‬
‭EVEROLIMUS‬
‭28‬
‭5.1.1‬
‭Dose and administration‬
‭28‬
‭5.1.2‬
‭Modification of dose in case of toxicity‬
‭29‬
‭5.1.3‬
‭Monitoring patients with hepatitis B and prophylactic‬‭treatment for its reactivation‬ ‭35‬
‭5.1.4‬
‭Monitoring patients with hepatitis C‬
‭36‬
‭5.2‬
‭STZ-5FU THERAPY‬
‭37‬
‭5.2.1 Dose and administration‬
‭37‬
‭5.2.2‬
‭Dose modifications in case of toxicity‬
‭38‬
‭5.2.3 Monitoring of Adverse Events‬
‭39‬
‭5.2.4 Adverse Events‬
‭39‬
‭5.3‬
‭TREATMENT WITHDRAWAL AND END OF TREATMENT PERIOD‬
‭41‬
‭5.3.1‬
‭Reasons for treatment discontinuation‬
‭41‬
‭5.3.2‬
‭Discontinuation of treatment due to everolimus‬‭toxicity‬
‭41‬
‭5.3.3‬
‭Discontinuation of treatment due to STZ-5FU‬‭toxicity‬
‭41‬
‭6.‬
‭CONCOMITANT‬‭MEDICATION‬
‭42‬
‭6.1.‬ ‭T‬‭REATMENTS‬‭ALLOWED‬‭WITH‬‭EVEROLIMUS‬
‭42‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭11‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭6.2‬
‭TREATMENTS‬‭NOT‬‭ALLOWED‬‭WITH‬‭EVEROLIMUS‬
‭43‬
‭6.3‬
‭DRUG INTERACTIONS CLINICALLY SIGNIFICANT: SUBSTRATES OF‬
‭CYP3A ISOENZYME/P‬‭G‬‭P.‬
‭44‬
‭7‬
‭TRIAL DEVELOPMENT‬
‭46‬
‭7.1‬
‭STUDY‬‭PERIODS‬
‭46‬
‭7.2‬
‭STUDY‬‭ASSESSMENTS‬
‭47‬
‭7.2.1‬
‭Physical examination and vital signs‬
‭47‬
‭7.2.2‬
‭ECOG Performance status‬
‭47‬
‭7.2.3‬
‭Chest X-ray and pulmonary function tests‬
‭47‬
‭7.2.4‬
‭Electrocardiogram (ECG)‬
‭48‬
‭7.2.5‬
‭Radiological tumor assessment‬
‭48‬
‭7.2.6‬
‭Laboratory‬
‭51‬
‭7.2.7‬
‭Pregnancy test. Male contraception.‬
‭55‬
‭7.2.8‬
‭Quality of Life assessments‬
‭56‬
‭7.2.9‬
‭Assessment of health resources used during‬‭study treatment‬
‭57‬
‭7.2.10‬ ‭Translational research‬
‭57‬
‭7.3‬
‭ASSESSMENTS‬‭’‬‭SCHEDULE‬
‭58‬
‭7.3.1‬
‭Screening period/baseline visit: Baseline information‬‭and assessments‬
‭59‬
‭7.3.2‬
‭Treatment visits‬
‭59‬
‭7.3.3‬
‭Visit at the end of treatment‬
‭64‬
‭7.3.4‬
‭Follow-up visits‬
‭65‬
‭Schema of study assessments‬
‭65‬
‭7.4‬
‭SAFETY‬‭ASSESSMENTS‬
‭69‬
‭7.4.1‬
‭Adverse events‬
‭69‬
‭7.4.2‬
‭Adverse event reporting‬
‭70‬
‭7.4.3‬
‭Pregnancies‬
‭73‬
‭8.‬
‭STATISTICS‬
‭74‬
‭8.1‬
‭PRIMARY‬‭ENDPOINT‬
‭74‬
‭8.2‬
‭SECONDARY‬‭ENDPOINTS‬
‭76‬
‭8.3‬
‭A‬‭NALYSIS‬‭POPULATIONS‬
‭77‬
‭8.4‬
‭S‬‭TATISTICAL‬‭M‬‭ETHODS‬
‭78‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭12‬‭/87‬

‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭8.4.1‬
‭Randomization procedure‬
‭78‬
‭8.4.2‬
‭Main Analysis‬
‭78‬
‭8.4.3‬
‭Main analysis of efficacy‬
‭79‬
‭8.4.4‬
‭Other analysis‬
‭79‬
‭8.4.5‬
‭Pharmacoeconomic analysis‬
‭80‬
‭8.4.6‬
‭Safety analysis‬
‭81‬
‭8.5.‬ ‭P‬‭LANNED‬‭INTERIM‬‭ANALYSES‬
‭81‬
‭8.6‬
‭SAMPLE‬‭SIZE‬‭AND‬‭NUMBER‬‭OF‬‭SUBJECTS‬‭PLANNED‬
‭81‬
‭8.7‬
‭PROCEDURE‬‭FOR‬‭REPORTING‬‭ANY‬‭DEVIATION‬‭FROM‬‭THE‬‭ORIGINAL‬‭STATISTICAL‬‭PLAN‬
‭82‬
‭9.‬
‭STUDY RECORDS AND DATA HANDLING‬
‭82‬
‭9.1‬
‭STUDY‬‭RECORDS‬
‭82‬
‭9.2‬
‭CASE‬‭REPORT‬‭FORM‬
‭83‬
‭9.3‬
‭PUBLICATION‬‭POLICY‬
‭84‬
‭10.‬ ‭ETHICS‬
‭84‬
‭10.1‬ ‭STUDY‬‭IMPLEMENTATION‬
‭84‬
‭10.2‬ ‭PROTOCOL‬‭MODIFICATIONS‬
‭85‬
‭10.3‬ ‭PATIENT‬‭INFORMED‬‭CONSENT‬
‭86‬
‭10.4‬ ‭CONFIDENCIALITY‬
‭86‬
‭10.5‬ ‭ADMINISTRATIVE‬‭RESPONSIBILITIES‬
‭87‬
‭11.  T‬‭RIAL‬‭INSURANCE‬
‭89‬
‭12.‬ ‭REFERENCES‬
‭91‬
‭Annex I: ECOG performance status‬
‭Annex II: CTCAE version 4.0‬
‭Annex III: RECIST criteria version 1.0 and RECIST criteria version 1.1‬
‭Annex IV: Tumour block analysis‬
‭Annex V: Evaluation of a blood-based transcriptional assay – the NETest – as a biomarker of‬
‭neuroendocrine tumour response‬
‭Annex VI:‬ ‭PanNETassigner Molecular Subtypes Assay‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭ABBREVIATIONS‬
‭AE‬
‭Adverse Event‬
‭AEMPS‬
‭Spanish Agency for Medicinal Products and Medical Devices‬
‭ALT‬
‭Alanine aminotransferase/Glutamic-pyruvic transaminase/GPT‬
‭ANC‬
‭Absolute neutrophil count‬
‭AR‬
‭Adverse Reaction‬
‭AST‬
‭Aspartate aminotransferase/Glutamic-oxalacetic transaminase/GOT‬
‭BAL‬
‭Bronchoalveolar Lavage‬
‭BUN‬
‭Blood Urea Nitrogen‬
‭CI‬
‭Confidence Interval‬
‭CPK‬
‭Creatine kinase‬
‭CR‬
‭Complete response‬
‭CRF‬
‭Case Report Form‬
‭CT‬
‭Computed Tomography‬
‭CTC‬
‭Common Toxicity Criteria‬
‭CTCAE‬
‭Common Terminology Criteria for Adverse Events‬
‭DLCO‬
‭Diffusing capacity of the lung for carbon monoxide‬
‭DNA‬
‭Deoxyribonucleic acid‬
‭ECG‬
‭Electro-cardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group‬
‭ENETS‬
‭EMA‬
‭5FU‬
‭FSH‬
‭European Neuro Endocrine Tumor Society‬
‭European Medicines Agency‬
‭5-fluorouracil‬
‭Follicle-stimulating hormone‬
‭HB‬
‭Hepatitis B‬
‭HBcAb‬
‭Hepatitis B Virus Core Antigen Antibody‬
‭HBs Ag‬
‭Hepatitis B Virus Surface Antigen‬
‭HBV‬
‭Hepatitis B virus‬
‭HC‬
‭Hepatitis C‬
‭HCC‬
‭Hepatocellular carcinoma‬
‭HCV‬
‭Hepatitis C virus‬
‭HDL‬
‭High-Density Lipoprotein‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭HIV‬
‭Human Immunodeficiency Virus‬
‭HR‬
‭HT‬
‭Hazard Ratio‬
‭Hormonal therapy‬
‭i.m.‬
‭intramuscular‬
‭ICH‬
‭ICER‬
‭International Conference of Harmonisation‬
‭Incremental Cost-effectiveness Ratio‬
‭IDTF‬
‭INN‬
‭Image Data Transmittal Form‬
‭International Non-Proprietary Name‬
‭INR‬
‭International Normalized Ratio‬
‭ITT‬
‭Intention to treat‬
‭IUD‬
‭Intrauterine Device‬
‭LAR‬
‭Long Acting Release‬
‭LDH‬
‭Lactate Dehydrogenase‬
‭LDL‬
‭Low-Density Lipoprotein‬
‭mOS‬
‭MRI‬
‭Median overall survival‬
‭Magnetic resonance imaging‬
‭mRNA‬
‭Messenger ribonucleic acid‬
‭MTOR‬
‭Mammalian Target of Rapamycin‬
‭NCI‬
‭National Cancer Institute‬
‭NET‬
‭Neuroendocrine tumour‬
‭ORR‬
‭OS‬
‭Overall response rate‬
‭Overall survival‬
‭PFS‬
‭Progression-free survival‬
‭PFS1‬
‭First Progression-free survival‬
‭PFS2‬
‭Second Progression-free survival‬
‭PNET‬
‭Pancreatic neuroendocrine tumour‬
‭PP‬
‭Per-Protocol‬
‭PR‬
‭Partial response‬
‭PT‬
‭Prothrombin Time‬
‭RECIST‬
‭Response Evaluation Criteria in Solid Tumours‬
‭RT‬
‭RR‬
‭Radiation therapy‬
‭Response Rate‬
‭SAE‬
‭Serious Adverse Event‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭SD‬
‭Stable Disease‬
‭SS‬
‭STZ‬
‭SUSAR‬
‭Sandostatin analogue‬
‭Streptozotocin‬
‭Suspected Unexpected Serious Adverse Reaction‬
‭TTP‬
‭Time To Progression‬
‭ULN‬
‭Upper limit of normal‬
‭WHO‬
‭World Health Organisation‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭1.‬
‭BACKGROUND INFORMATION AND RATIONALE‬
‭The‬ ‭first‬ ‭randomized‬ ‭phase‬ ‭III‬ ‭trial‬ ‭in‬ ‭pancreatic‬ ‭neuroendocrine‬ ‭tumours‬ ‭(pNETs)‬ ‭was‬
‭performed‬ ‭by‬ ‭Moertel‬ ‭in‬ ‭1980.‬ ‭84‬ ‭patients‬ ‭with‬ ‭pNETs‬ ‭were‬ ‭randomized‬ ‭to‬ ‭receive‬ ‭the‬
‭combination‬ ‭of‬ ‭streptozocin‬ ‭(STZ)‬ ‭and‬ ‭5-fluorouracil‬ ‭(5FU)‬ ‭or‬ ‭STZ‬ ‭as‬ ‭a‬ ‭single‬ ‭agent.‬ ‭The‬
‭combination‬ ‭arm‬ ‭demonstrated‬ ‭superior‬ ‭results‬ ‭to‬ ‭those‬ ‭of‬ ‭the‬ ‭monotherapy‬ ‭arm‬‭in‬‭terms‬‭of‬
‭overall‬‭response‬‭rate‬‭(ORR)‬‭(63%‬‭vs‬‭36%‬‭respectively)‬‭and‬‭median‬‭overall‬‭survival‬‭(mOS)‬‭(26‬
‭versus 16.5 months), although the difference in mOS was not statistically significant‬‭1‬‭.‬
‭A‬‭Swedish‬‭study‬‭2‬ ‭tested‬‭STZ‬‭in‬‭combination‬‭with‬‭5FU‬‭or‬‭doxorubicin‬‭as‬‭first-line‬‭treatment‬‭and‬
‭produced‬‭overall‬‭objective‬‭responses‬‭in‬‭20‬‭out‬‭of‬‭44‬‭(45%)‬‭patients‬‭with‬‭a‬‭median‬‭duration‬‭of‬
‭response of 27.5 months.‬
‭In‬‭1992,‬‭Moertel‬‭et‬‭al,‬‭published‬‭the‬‭results‬‭of‬‭another‬‭randomized‬‭phase‬‭III‬‭trial‬‭sponsored‬‭by‬
‭the‬ ‭Eastern‬ ‭Cooperative‬ ‭Oncology‬ ‭Group‬ ‭(ECOG),‬ ‭where‬ ‭105‬ ‭patients‬ ‭with‬ ‭pNETs‬‭received‬
‭STZ‬‭plus‬‭doxorubicin‬‭or‬‭STZ‬‭plus‬‭5FU,‬‭or‬‭with‬‭chlorozotocin‬‭as‬‭a‬‭single‬‭agent.‬‭The‬‭STZ‬‭plus‬
‭doxorubicin‬‭arm‬‭was‬‭superior‬‭to‬‭STZ‬‭plus‬‭5FU‬‭in‬‭terms‬‭of‬‭ORR‬‭(69%‬‭versus‬‭45%;‬‭p‬‭0.05),‬‭in‬
‭time‬ ‭to‬ ‭tumour‬ ‭progression‬ ‭(median‬ ‭20‬ ‭versus‬ ‭6.9‬ ‭months,‬ ‭p‬ ‭0.001),‬ ‭and‬ ‭in‬ ‭median‬ ‭overall‬
‭survival‬ ‭(26.4‬‭versus‬‭16.8‬‭months,‬‭p‬‭0.004).‬‭However,‬‭the‬‭combination‬‭arm‬‭with‬‭doxorubicin‬
‭was‬ ‭associated‬ ‭with‬ ‭more‬ ‭noteworthy‬ ‭drug-related‬ ‭toxicity,‬ ‭mainly‬ ‭leukopenia‬ ‭and‬
‭nephrotoxicity.‬‭Chlorozotocin‬‭alone‬‭produced‬‭a‬‭30‬‭%‬‭regression‬‭rate,‬‭with‬‭the‬‭length‬‭of‬‭time‬‭to‬
‭tumor‬ ‭progression‬ ‭and‬ ‭the‬ ‭survival‬ ‭time‬ ‭equivalent‬ ‭to‬ ‭those‬ ‭observed‬ ‭with‬ ‭streptozocin‬ ‭plus‬
‭fluorouracil‬‭3‬‭.‬
‭Also‬ ‭in‬ ‭1992,‬ ‭Bukowski‬ ‭et‬ ‭al‬ ‭reported‬ ‭that‬ ‭chlorozotocin‬ ‭plus‬ ‭5FU‬ ‭tested‬ ‭by‬ ‭the‬‭Southwest‬
‭Oncology‬ ‭Group‬ ‭(SWOG)‬‭4‬ ‭in‬ ‭44‬ ‭patients‬ ‭with‬ ‭pNETs‬ ‭showing‬ ‭36%‬ ‭partial‬ ‭responses;‬ ‭side‬
‭effects‬‭were‬‭moderate‬‭to‬‭severe‬‭and‬‭13‬‭patients‬‭developed‬‭renal‬‭toxicity,‬‭which‬‭was‬‭severe‬‭or‬
‭life-threatening‬ ‭in‬ ‭5‬ ‭patients.‬ ‭This‬ ‭important‬ ‭toxicity‬ ‭has‬ ‭limited‬ ‭the‬ ‭use‬ ‭of‬ ‭chlorozotocin‬‭in‬
‭subsequent trials.‬
‭In‬‭1993,‬‭Eriksson‬‭and‬‭Oberg‬‭5‬ ‭reported‬‭their‬‭experience‬‭with‬‭31‬‭patients‬‭treated‬‭with‬‭STZ‬‭plus‬
‭5FU.‬‭STZ‬‭plus‬‭5FU‬‭produced‬‭objective‬‭responses‬‭in‬‭17‬‭(54%)‬‭patients‬‭with‬‭a‬‭median‬‭duration‬‭of‬
‭response of 23 months.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Retrospective‬ ‭reports‬ ‭of‬ ‭the‬ ‭use‬ ‭of‬ ‭STZ‬ ‭and‬ ‭doxorubicin‬ ‭have‬ ‭been‬ ‭published.‬ ‭In‬ ‭2004,‬ ‭a‬
‭retrospective‬‭review‬‭of‬‭84‬‭patients‬‭treated‬‭with‬‭combinations‬‭of‬‭5FU,‬‭doxorubicin‬‭and‬‭STZ‬‭at‬
‭the‬ ‭MD‬ ‭Anderson‬ ‭Cancer‬ ‭Centre‬ ‭has‬ ‭reported‬ ‭an‬ ‭overall‬ ‭response‬ ‭rate‬ ‭of‬ ‭39%,‬ ‭and‬ ‭disease‬
‭stabilization‬‭in‬‭50%‬‭of‬‭the‬‭patients.‬‭The‬‭median‬‭response‬‭duration‬‭was‬‭9.3‬‭months.‬‭The‬‭2-year‬
‭progression‬ ‭free‬ ‭survival‬ ‭(PFS)‬ ‭rate‬ ‭was‬ ‭41%,‬ ‭and‬‭the‬‭2-year‬‭overall‬‭survival‬‭rate‬‭was‬‭74%.‬
‭Multivariate‬‭analysis‬‭showed‬‭that‬‭replacement‬‭of‬‭more‬‭than‬‭75%‬‭of‬‭the‬‭liver‬‭was‬‭independently‬
‭associated‬‭with‬‭inferior‬‭PFS‬‭6‬‭.‬‭In‬‭1999‬‭and‬‭2004,‬‭the‬‭Memorial‬‭Sloan‬‭Kettering‬‭Cancer‬‭Center‬‭7‬
‭and‬‭the‬‭Dana‬‭Farber‬‭Cancer‬‭Institute‬‭8‬ ‭respectively,‬ ‭reported‬‭their‬‭experience,‬‭with‬‭16‬‭patients‬
‭each,‬‭with‬‭the‬‭use‬‭of‬‭this‬‭combination,‬‭obtaining‬‭response‬‭rates‬‭of‬‭6%,‬‭which‬‭is‬‭much‬‭lower‬‭than‬
‭previous reports.‬
‭The‬‭disparity‬‭of‬‭these‬‭results‬‭could‬‭be‬‭explained‬‭by‬‭the‬‭fact‬‭that‬‭the‬‭methodology‬‭used‬‭to‬‭assess‬
‭response‬ ‭in‬ ‭older‬ ‭studies‬ ‭was‬ ‭not‬ ‭standardized.‬ ‭It‬ ‭could‬ ‭also‬ ‭be‬ ‭explained‬ ‭by‬ ‭tumour‬
‭heterogeneity‬‭in‬‭terms‬‭of‬‭biological‬‭behaviour‬‭and‬‭responsiveness‬‭to‬‭chemotherapy.‬‭Another‬‭fact‬
‭to‬‭be‬‭taken‬‭into‬‭account‬‭which‬‭could‬‭also‬‭influence‬‭these‬‭results‬‭is‬‭the‬‭introduction‬‭of‬‭biological‬
‭therapies‬‭as‬‭first-‬‭or‬‭second-line‬‭treatment,‬‭starting‬‭chemotherapy‬‭only‬‭after‬‭the‬‭progression‬‭to‬
‭those therapies‬‭9‬‭.‬
‭Temozolomide‬‭has‬‭also‬‭been‬‭tried‬‭in‬‭combination‬‭with‬‭capecitabine‬‭with‬‭encouraging‬‭results.‬‭In‬
‭vitro‬ ‭data‬ ‭indicate‬ ‭that‬ ‭the‬ ‭combination‬ ‭of‬ ‭capecitabine‬ ‭and‬ ‭temozolomide‬ ‭is‬ ‭synergistic‬ ‭for‬
‭induction‬‭of‬‭apoptosis‬‭in‬‭neuroendocrine‬‭tumor‬‭cell‬‭lines.‬ ‭A‬‭retrospective‬‭study‬‭in‬‭17‬‭patients‬
‭with‬ ‭pNETs‬ ‭showed‬ ‭1‬ ‭complete‬ ‭response‬ ‭(6%)‬ ‭and‬ ‭9‬ ‭partial‬ ‭responses‬ ‭(54%)‬ ‭by‬ ‭RECIST‬
‭criteria,‬‭with‬‭a‬‭median‬‭duration‬‭of‬‭partial‬‭response‬‭of‬‭284‬‭days.‬‭All‬‭of‬‭the‬‭patients‬‭had‬‭failed‬
‭first-line‬ ‭treatment‬ ‭with‬ ‭escalating‬ ‭doses‬ ‭of‬ ‭sandostatin‬ ‭LAR‬ ‭and‬ ‭11‬ ‭patients‬ ‭had‬ ‭failed‬
‭multiagent chemotherapy (range 1-5 regimens)‬‭10‬‭.‬
‭In‬‭another‬‭recent‬‭trial‬‭reported‬‭by‬‭Strosberg‬‭et‬‭al‬‭in‬‭2011,‬‭30‬‭patients‬‭with‬‭progressive‬‭metastatic‬
‭pNETs‬‭who‬‭had‬‭not‬‭received‬‭prior‬‭systemic‬‭chemotherapy‬‭were‬‭treated‬‭with‬‭capecitabine‬‭(750‬
‭mg/m2‬‭twice‬‭daily,‬‭days‬‭1-14)‬‭and‬‭temozolomide‬‭(200‬‭mg/m2‬‭once‬‭daily,‬‭days‬‭10-14)‬‭every‬‭28‬
‭days.‬ ‭70%‬ ‭patients‬ ‭achieved‬ ‭an‬ ‭objective‬ ‭radiographic‬ ‭response,‬ ‭the‬‭median‬‭progression-free‬
‭survival‬‭was‬‭18‬‭months,‬‭the‬‭rate‬‭of‬‭survival‬‭at‬‭two‬‭years‬‭was‬‭92%‬‭and‬‭only‬‭4‬‭patients‬‭(12%)‬
‭experienced‬‭grade‬‭3‬‭or‬‭4‬‭adverse‬‭events‬‭11‬‭.‬‭Therefore,‬‭this‬‭combination‬‭has‬‭a‬‭promising‬‭activity‬
‭that should be evaluated in further studies.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Other‬‭combinations‬‭with‬‭STZ‬‭were‬‭reported‬‭in‬‭2008.‬‭Treatment‬‭with‬‭combined‬‭streptozotocin‬
‭and‬ ‭liposomal‬ ‭doxorubicin‬ ‭in‬ ‭30‬‭patients‬‭achieved‬‭an‬‭objective‬‭radiological‬‭response‬‭of‬‭40%‬
‭with‬ ‭a‬ ‭median‬ ‭duration‬ ‭of‬ ‭9‬ ‭months.‬ ‭The‬ ‭efficacy‬ ‭seems‬ ‭comparable‬ ‭to‬ ‭that‬ ‭of‬ ‭combined‬
‭streptozotocin‬‭and‬‭doxorubicin,‬‭avoiding‬‭cardiac‬‭toxicity‬‭12‬‭(2008).‬‭Chemotherapy‬‭regimens‬‭with‬
‭triple‬ ‭combinations‬ ‭have‬ ‭also‬ ‭been‬ ‭administered‬ ‭in‬ ‭intent‬ ‭to‬ ‭improve‬ ‭efficacy,‬ ‭but‬ ‭none‬ ‭has‬
‭demonstrated to be superior to doublets and there was an increase in toxicity.‬
‭Well‬ ‭differentiated‬ ‭nets‬ ‭(WDNETs)‬ ‭are‬ ‭a‬ ‭subset‬ ‭of‬ ‭tumors‬ ‭with‬ ‭slow‬ ‭growth‬ ‭and‬ ‭relatively‬
‭indolent‬ ‭behaviour.‬ ‭Recently‬ ‭the‬ ‭mTOR‬ ‭inhibitor,‬‭everolimus,‬‭has‬‭shown‬‭to‬‭be‬‭efficacious‬‭in‬
‭WD-‬ ‭NETS.‬ ‭Everolimus‬ ‭10mg/day,‬ ‭as‬ ‭compared‬ ‭with‬ ‭placebo,‬ ‭significantly‬ ‭prolonged‬
‭progression-free‬‭survival‬‭among‬‭patients‬‭with‬‭progressive‬‭advanced‬‭pancreatic‬‭neuroendocrine‬
‭tumors‬‭and‬‭was‬‭associated‬‭with‬‭a‬‭low‬‭rate‬‭of‬‭severe‬‭adverse‬‭events‬‭(RADIANT-3‬‭study).‬‭Results‬
‭published‬ ‭from‬ ‭this‬ ‭study‬ ‭showed‬‭a‬‭median‬‭progression-free‬‭survival‬‭of‬‭11.0‬‭months‬‭13‬‭.‬‭This‬
‭study‬‭included‬‭patients‬‭with‬‭advanced,‬‭low-grade‬‭or‬‭intermediate‬‭grade‬‭pNET‬‭with‬‭radiologic‬
‭progression within the previous 12 months.‬
‭STZ‬‭based‬‭chemotherapy,‬‭STZ-5FU,‬‭is‬‭the‬‭actual‬‭standard‬‭of‬‭care‬‭for‬‭advanced‬‭pNETS‬‭in‬‭the‬
‭European‬‭Union‬‭(ENETS‬‭guidelines;‬‭Neuroendocrinology‬‭2012)‬‭14‬‭.‬‭Everolimus‬‭has‬‭been‬‭recently‬
‭approved‬‭for‬‭its‬‭use‬‭in‬‭advanced‬‭pNETs‬‭by‬‭the‬‭FDA‬‭and‬‭in‬‭Europe‬‭by‬‭the‬‭EMA‬‭(see‬‭section‬
‭5.1).‬‭A‬‭randomized‬‭study‬‭is‬‭needed‬‭to‬‭have‬‭a‬‭clear‬‭knowledge‬‭about‬‭the‬‭best‬‭sequence‬‭for‬‭its‬
‭administration;‬ ‭this‬ ‭is,‬ ‭before‬ ‭or‬‭after‬‭palliative‬‭chemotherapy.‬‭There‬‭may‬‭or‬‭may‬‭not‬‭be‬‭any‬
‭benefits‬‭from‬‭giving‬‭first‬‭each‬‭other‬‭treatment‬‭of‬‭the‬‭study.‬‭The‬‭information‬‭obtained‬‭from‬‭this‬
‭study will help the physician improve the treatment and management of patients with pNET.‬
‭Variation‬ ‭of‬ ‭treatment‬ ‭choices‬ ‭will‬ ‭still‬ ‭depend‬ ‭on‬‭physician‬‭expertise,‬‭the‬‭complexity‬‭of‬‭the‬
‭treatment‬ ‭center‬ ‭and,‬ ‭access‬ ‭to‬ ‭novel‬ ‭treatments‬ ‭(ENETS‬ ‭guidelines,‬ ‭Neuroendocrinology‬
‭2016)‬‭26‬‭.‬ ‭There‬ ‭are‬ ‭not‬ ‭randomized‬ ‭trials‬ ‭comparing‬ ‭Progression‬ ‭Free‬ ‭Survival‬ ‭(PFS)‬‭of‬‭STZ‬
‭based chemotherapy versus Everolimus.‬
‭This‬‭study‬‭was‬‭planned‬‭to‬‭compare‬‭STZ-5FU‬‭chemotherapy‬‭followed‬‭by‬‭everolimus‬‭10‬‭mg/day‬
‭upon‬‭progression‬‭versus‬‭the‬‭reverse‬‭sequence.‬‭However‬‭sequential‬‭studies‬‭with‬‭pNETs‬‭are‬‭hard‬
‭to‬‭be‬‭managed‬‭in‬‭terms‬‭of‬‭time‬‭and‬‭costs.‬‭Therefore‬‭we‬‭propose‬‭to‬‭have‬‭PFS1‬‭(progression‬‭free‬
‭survival‬‭after‬‭course‬‭1)‬‭as‬‭primary‬‭endpoint‬‭and‬‭PFS2‬‭(i.e.‬‭progression‬‭free‬‭survival‬‭after‬‭both‬
‭STZ‬ ‭based‬ ‭chemotherapy‬ ‭and‬ ‭Everolimus‬ ‭or‬ ‭the‬ ‭reverse‬ ‭order)‬‭as‬‭secondary‬‭endpoint.‬ ‭This‬
‭information will be extremely valuable for the day to day clinical practice of NET oncologists.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭2.‬
‭STUDY OBJECTIVES AND PURPOSE‬
‭The‬‭purpose‬‭of‬‭this‬‭study‬‭is‬‭to‬‭compare‬‭STZ‬‭vs‬‭everolimus‬‭as‬‭first‬‭line‬‭treatment‬‭for‬‭advanced‬
‭pNET‬ ‭and‬ ‭elucidate‬ ‭which‬ ‭sequence‬ ‭of‬ ‭STZ‬ ‭based‬ ‭chemotherapy‬ ‭and‬ ‭the‬ ‭mTOR‬ ‭inhibitor,‬
‭everolimus,‬‭gives‬‭better‬‭results‬‭in‬‭terms‬‭of‬‭PFS‬‭in‬‭well‬‭differentiated‬‭and‬‭advanced‬‭pancreatic‬
‭NETs  assessed by local investigator using RECIST criteria 1.0.‬
‭2.1‬
‭P‬‭RIMARY‬‭O‬‭BJECTIVE‬
‭To‬ ‭compare‬ ‭the‬ ‭progression‬ ‭free‬ ‭survival‬ ‭rate‬ ‭at‬ ‭12‬ ‭months‬ ‭which‬ ‭is‬ ‭the‬ ‭proportion‬ ‭of‬
‭patients‬‭who‬‭are‬‭alive‬‭without‬‭progression‬‭to‬‭Course‬‭1‬‭therapy‬‭at‬‭12‬‭months‬‭from‬‭the‬‭date‬‭of‬
‭randomization in STZ based CT vs Everolimus arms.‬
‭PNET‬ ‭lesions‬ ‭are‬ ‭usually‬ ‭multiple‬ ‭and‬ ‭difficult‬ ‭and‬ ‭therefore‬ ‭a‬ ‭measurement‬ ‭of‬ ‭a‬ ‭lower‬
‭number‬‭of‬‭lesions,‬‭as‬‭suggested‬‭in‬‭version‬‭1.1‬‭of‬‭the‬‭RECIST‬‭criteria,‬‭not‬‭validated‬‭for‬‭this‬
‭disease, could be misleading.‬
‭Primary endpoint:‬
‭Proportion‬‭of‬‭patients‬‭who‬‭are‬‭alive‬‭without‬‭progression‬‭to‬‭Course‬‭1‬‭therapy‬‭at‬‭12‬‭months‬
‭from the date of randomization in STZ based CT vs Everolimus arms.‬
‭2.2‬
‭S‬‭ECONDARY‬‭O‬‭BJECTIVES‬
‭The following secondary objectives considered for this study are listed below:‬
‭o‬ ‭To‬‭compare‬‭the‬‭efficacy‬‭of‬‭the‬‭combination‬‭STZ-5FU‬‭chemotherapy‬‭followed‬‭by‬
‭Everolimus‬ ‭10‬ ‭mg/day‬ ‭upon‬ ‭progression‬ ‭versus‬ ‭the‬ ‭reverse‬ ‭sequence‬ ‭in‬ ‭the‬
‭treatment‬ ‭of‬ ‭advanced‬ ‭pancreatic‬ ‭neuroendocrine‬ ‭tumours‬ ‭(pNET),‬ ‭in‬‭terms‬‭of‬
‭rate‬ ‭of‬ ‭patients‬ ‭with‬ ‭second‬ ‭progression‬ ‭free‬ ‭survival‬ ‭at‬ ‭140±8‬ ‭weeks‬ ‭of‬
‭treatment, assessed by local investigator using RECIST criteria 1.0.‬
‭o‬ ‭To‬ ‭describe‬ ‭the‬ ‭efficacy‬ ‭of‬ ‭the‬ ‭two‬ ‭sequences‬ ‭of‬ ‭treatment‬ ‭STZ-5FU‬ ‭and‬
‭everolimus‬‭10‬‭mg/day,‬‭as‬‭a‬‭continuous‬‭variable‬‭Hazard‬‭Ratio‬‭(HR),‬‭in‬‭advanced‬
‭pNETs at 12 months (main analysis time point) and 140+/-8 weeks‬‭.‬
‭o‬ ‭To‬‭determine‬‭whether‬‭the‬‭overall‬‭survival‬‭of‬‭patients‬‭with‬‭advanced‬‭pNETs‬‭could‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭be‬‭modified‬‭by‬‭the‬‭upfront‬‭administration‬‭of‬‭each‬‭other‬‭treatment,‬‭STZ-5FU‬‭and‬
‭everolimus 10 mg/day, upon progression.‬
‭o‬
‭To‬‭compare‬‭the‬‭clinical‬‭activity‬‭of‬‭STZ-5FU‬‭and‬‭everolimus‬‭10‬‭mg/day‬‭treatment‬
‭given‬‭in‬‭1‬‭st‬ ‭or‬‭2‬‭nd‬ ‭place‬‭in‬‭advanced‬‭pNETS,‬‭in‬‭terms‬‭of‬‭time‬‭to‬‭first‬‭and‬‭second‬
‭progression,‬ ‭response‬ ‭rate‬ ‭(RR),‬ ‭and‬ ‭early‬ ‭biochemical‬‭response‬‭(4‬‭week‬‭CgA‬
‭levels),‬ ‭Quality‬ ‭of‬ ‭Life‬ ‭and‬ ‭Cost-effectiveness‬ ‭of‬ ‭each‬ ‭sequence,‬ ‭and‬ ‭to‬
‭investigate‬ ‭the‬ ‭criteria‬ ‭for‬ ‭measuring‬ ‭progression‬ ‭free‬ ‭survival‬ ‭(RECIST‬ ‭1.0,‬
‭RECIST‬‭1.1,‬‭composite‬‭RECIST‬‭1.0‬‭and‬‭composite‬‭RECIST‬‭1.1)‬‭that‬‭correlates‬
‭better with overall survival.‬
‭o‬
‭To‬‭compare‬‭the‬‭safety‬‭and‬‭tolerability‬‭of‬‭treatment‬‭with‬‭STZ-5FU‬‭and‬‭everolimus‬
‭10‬‭mg/day,‬‭given‬‭upfront‬‭each‬‭other‬‭upon‬‭progression,‬‭in‬‭patients‬‭with‬‭advanced‬
‭pNET.‬
‭o‬ ‭To‬‭compare‬‭the‬‭Cost-effectiveness‬‭of‬‭treatment‬‭with‬‭STZ-5FU‬‭and‬‭everolimus‬‭10‬
‭mg/day, given upfront each other upon progression, in advanced pNET patients.‬
‭Secondary endpoints:‬
‭o‬
‭Second‬‭progression‬‭free‬‭survival‬‭defined‬‭as‬‭PFS‬‭of‬‭Course‬‭1‬‭+‬‭interval‬‭between‬
‭treatments‬‭+‬‭PFS‬‭of‬‭Course‬‭2,‬‭where‬‭PFS1‬‭represents‬‭progression‬‭free‬‭survival‬‭of‬
‭Course 1 and PFS2 represents progression free survival of Course 2.‬
‭It‬ ‭will‬ ‭be‬ ‭expressed‬ ‭as‬ ‭the‬ ‭rate‬ ‭of‬‭second‬‭progression‬‭free‬‭survival;‬‭this‬‭is‬‭the‬
‭proportion of patients which are free of second progression at 140±8 weeks.‬
‭o‬
‭Second‬‭progression‬‭free‬‭survival‬‭(PFS‬‭of‬‭Course‬‭1‬‭+‬‭interval‬‭between‬‭treatments‬
‭+ PFS of course 2) as a continuous time variable.‬
‭o‬
‭Time‬‭to‬‭first‬‭progression‬‭of‬‭STZ-5FU‬‭and‬‭Everolimus‬‭10‬‭mg/day‬‭or‬‭the‬‭reverse‬
‭sequence in advanced pNETs.‬
‭o‬
‭Time‬‭to‬‭second‬‭progression‬‭of‬‭STZ-5FU‬‭and‬‭Everolimus‬‭10‬‭mg/day‬‭or‬‭the‬‭reverse‬
‭sequence in advanced pNETs.‬
‭o‬
‭Time‬‭from‬‭first‬‭progression‬‭to‬‭second‬‭progression‬‭of‬‭STZ-5FU‬‭and‬‭Everolimus‬‭10‬
‭mg/day or the reverse sequence in advanced pNETs.‬
‭o‬
‭Response‬‭rate‬‭of‬‭STZ-5FU‬‭and‬‭Everolimus‬‭10‬‭mg/day‬‭or‬‭the‬‭reverse‬‭sequence‬‭in‬
‭advanced pNETs assessed every 12 weeks.‬
‭o‬
‭Quality‬‭of‬‭life‬‭score‬‭at‬‭baseline,‬‭upon‬‭progression‬‭and‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬
‭of study treatment (both sequences).‬
‭o‬
‭CgA levels at baseline and at 4 weeks of treatment start.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭o‬
‭Correlation‬ ‭between‬ ‭the‬ ‭four‬ ‭criteria‬ ‭for‬ ‭second‬ ‭progression‬ ‭free‬ ‭survival‬
‭(RECIST‬‭1.0,‬‭RECIST‬‭1.1,‬‭composite‬‭RECIST‬‭1.0‬‭and‬‭composite‬‭RECIST‬‭1.1)‬
‭and Kendall tau variables.‬
‭o‬
‭Overall‬ ‭survival‬ ‭(OS)‬ ‭of‬ ‭patients‬ ‭on‬ ‭treatment‬ ‭with‬ ‭the‬‭combination‬‭STZ-5FU‬
‭chemotherapy‬‭followed‬‭by‬‭Everolimus‬‭10‬‭mg/day‬‭upon‬‭progression‬‭or‬‭the‬‭reverse‬
‭sequence,‬ ‭in‬ ‭the‬ ‭treatment‬ ‭of‬ ‭advanced‬ ‭pancreatic‬ ‭neuroendocrine‬ ‭tumours‬
‭(pNET).‬
‭o‬
‭Number‬ ‭of‬ ‭adverse‬ ‭events,‬ ‭dose‬ ‭reductions,‬ ‭and‬ ‭total‬ ‭dose‬ ‭administered‬ ‭on‬
‭patients‬‭treated‬‭with‬‭STZ-5FU‬‭followed‬‭by‬‭everolimus‬‭10‬‭mg/day‬‭or‬‭the‬‭reverse‬
‭sequence, in advanced pNETs.‬
‭o‬
‭Cost‬ ‭per‬ ‭progression‬ ‭free‬‭survival‬‭gained:‬ ‭Incremental‬‭Cost-effectiveness‬‭ratio‬
‭(ICER)‬‭of‬‭the‬‭differential‬‭of‬‭costs‬‭incurred‬‭on‬‭by‬‭each‬‭treatment‬‭arm‬‭(A‬‭and‬‭B):‬
‭ICER= (Arm A costs – Arm B costs)/(Arm A 2nd PFS – Arm B 2nd PFS).‬
‭3.‬
‭STUDY DESIGN‬
‭Randomized‬ ‭phase‬ ‭III‬ ‭open‬‭label‬‭and‬‭cross-over‬‭treatment‬‭study‬‭to‬‭compare‬‭the‬‭efficacy‬‭and‬
‭safety‬ ‭of‬ ‭everolimus‬ ‭followed‬ ‭by‬ ‭chemotherapy‬‭upon‬‭progression‬‭or‬‭the‬‭reverse‬‭sequence,‬‭in‬
‭advanced progressive pNETs.‬
‭Study periods‬‭:‬
‭●‬
‭Screening period:‬‭<‬‭28 days‬
‭●‬
‭Treatment period: Estimated length,‬‭up to‬‭140‬‭±‬‭8  weeks‬
‭o‬ ‭Arm A‬‭: Everolimus+STZ-5FU.‬
‭o‬ ‭An‬‭interval‬‭period‬‭of‬‭time‬‭between‬‭the‬‭end‬‭of‬‭first‬‭regime‬ ‭and‬‭the‬‭start‬‭of‬‭second‬‭regimen‬
‭≤‬‭to‬‭4‬‭weeks‬‭approximately‬‭during‬‭which‬‭no‬‭active‬‭systemic‬‭treatment‬‭is‬‭given‬‭before‬‭the‬
‭start of 2nd treatment.‬
‭o‬ ‭Arm B‬‭: STZ-5FU+Everolimus.‬
‭●‬ ‭Safety Follow-up: 30 days after last dose intake (can be a face to face or telephone contact).‬
‭●‬
‭Survival‬ ‭follow-up‬ ‭period:‬ ‭All‬ ‭patients‬ ‭will‬ ‭be‬ ‭followed-up‬ ‭for‬ ‭survival‬ ‭purposes,‬‭up‬‭to‬
‭patient’s‬‭death,‬‭up‬‭to‬‭140±8‬ ‭weeks‬‭+‬‭30‬‭days,‬‭or‬‭study‬‭end‬‭(this‬‭is,‬‭last‬‭visit‬‭of‬‭last‬‭patient‬
‭included), whatever comes first.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Study schema‬‭:‬
‭Arm A‬‭: Everolimus (10 mg)‬
‭Everolimus (10mg)‬
‭daily (oral)‬
‭daily (oral)‬
‭Arm B‬‭:  STZ-5FU (see below)‬
‭STZ-5FU (see below)‬
‭every 6 or 3 weeks                                                                         every 6 or 3 weeks‬
‭Screening‬
‭Treatment visits‬
‭Resting period‬
‭Treatment visits‬
‭Visit at end of‬
‭treatment‬
‭<28 days‬
‭(up to first progression or‬
‭unacceptable toxicity or study end)‬
‭(approximately 4‬
‭weeks after end of‬
‭first regime)‬
‭(up to second progression,‬
‭unacceptable toxicity‬
‭or at 140±8  weeks or‬
‭study end)‬
‭(30 days after last‬
‭study dose)‬
‭Treatment plan‬‭:‬
‭STZ-5FU‬‭(ENETS guidelines; Neuroendocrinology 2012):‬
‭o‬ ‭STZ 0.5 g/m2 days 1–5 and 5-FU 400 mg/m2 days 1–5 every 6 weeks (Moertel)‬
‭or,‬
‭o‬ ‭0.5 g/m2 STZ on days 1–5 and 400mg/m2 5-FU on days 1-3 and then,‬
‭1-day‬‭treatment‬‭with‬‭1g/m2‬‭STZ‬‭and‬‭1‬‭day‬‭treatment‬‭with‬‭400mg/m2‬‭5-FU‬‭every‬
‭3 weeks (Uppsala).‬
‭Everolimus‬‭: 10mg per day (Prescription information‬‭on technical sheet).‬
‭This study includes a fixed-dose regime of treatment (see 5.1.1)‬
‭Randomization‬‭:‬
‭Assignment‬‭to‬‭treatment‬‭arms‬‭A‬‭and‬‭B‬‭is‬‭going‬‭to‬‭be‬‭done‬‭at‬‭random‬‭by‬‭an‬‭equal‬‭distribution‬
‭algorithm‬‭automatically‬‭assigned‬‭by‬‭the‬‭EDC‬‭system.‬‭Study‬‭groups‬‭will‬‭be‬‭stratified‬‭according‬
‭to‬‭ECOG‬‭Performance‬‭Status‬‭(PS):‬‭0‬‭versus‬‭1‬‭or‬‭2.‬‭The‬‭size‬‭of‬‭randomization‬‭blocks‬‭will‬‭be‬
‭reported on the Statistical Analysis Plan.‬
‭The‬‭analysis‬‭of‬‭the‬‭best‬‭option‬‭for‬‭radiological‬‭assessment‬‭(RECIST‬‭criteria‬‭and‬‭New‬‭Composite‬
‭Score,‬‭and‬‭its‬‭versions‬‭1.0‬‭&1.1),‬‭will‬‭be‬‭done‬‭retrospectively.‬‭An‬‭ENETS‬‭Central‬‭Radiological‬
‭Commission will be set up for a centralized evaluation of Computed Tomography (CTs).‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Sites‬‭should‬‭have‬‭a‬‭copy‬‭of‬‭patient’s‬‭CTs‬‭available‬‭for‬‭central‬‭radiological‬‭assessment.‬‭CTs‬‭will‬
‭be‬‭collected‬‭and‬‭sent‬‭using‬‭electronic‬‭transfer/CD,‬‭to‬‭the‬‭Central‬‭Radiological‬‭Commission‬‭in‬
‭Paris, France.‬
‭4.‬
‭STUDY POPULATION‬
‭About‬ ‭140‬ ‭adult‬ ‭patients‬ ‭with‬ ‭a‬ ‭diagnosis‬ ‭of‬ ‭advanced‬ ‭pancreatic‬ ‭Neuroendocrine‬ ‭Tumour‬
‭(pNET)‬‭will‬‭be‬‭recruited‬‭in‬‭approximately‬‭8‬‭countries‬‭all‬‭around‬‭Europe‬‭(136‬‭patients‬‭already‬
‭included).‬
‭4.1‬
‭SELECTION OF SUBJECTS‬
‭4.1.1‬‭Inclusion criteria‬
‭1.‬ ‭Adult patients ≥ 18 years old.‬
‭2.‬ ‭Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.‬
‭3.‬ ‭Documented‬ ‭confirmation‬ ‭of‬ ‭pancreatic‬ ‭NET‬ ‭G1‬ ‭or‬ ‭G2‬ ‭as‬ ‭per‬ ‭ENETS‬ ‭classification‬
‭system:‬
‭G1: <2 mitoses per 2 mm‬‭2‬‭and/or Ki-67 index ≤ 2%‬
‭G2: 2–20 mitoses per 2 mm‬‭2‬‭and/or Ki-67 index >2%‬‭and ≤ 20%‬
‭4.‬ ‭Patients‬‭from‬‭whom‬‭a‬‭paraffin-embedded‬‭primary‬‭tumour‬‭or‬‭metastasis‬‭block‬‭is‬‭available‬
‭to‬‭be‬‭sent‬‭by‬‭courier‬‭(Section‬‭7.2.10).‬‭Patient‬‭should‬‭give‬‭RECISThis/her‬‭consent‬‭for‬‭its‬
‭use in future investigations.‬
‭5.‬ ‭Before‬‭study‬‭inclusion‬‭,‬‭patients‬‭must‬‭show‬‭progressive‬‭disease‬‭documented‬‭by‬‭radiology‬
‭within‬‭12‬‭months‬‭prior‬‭to‬‭study‬‭inclusion.‬‭If‬‭patient‬‭received‬‭anti-tumour‬‭therapy‬‭during‬
‭the‬‭past‬‭12‬‭months,‬‭he/she‬‭must‬‭have‬‭radiological‬‭documentation‬‭of‬‭progressive‬‭disease‬
‭while‬‭on‬‭or‬‭after‬‭receiving‬‭that‬‭anti-tumour‬‭therapy.‬‭Treatment‬‭naive‬‭patients‬‭can‬‭be‬‭also‬
‭included‬‭if,‬‭under‬‭investigator’s‬‭judgment,‬‭the‬‭patient‬‭needs‬‭active‬‭treatment‬‭with‬‭either‬
‭chemotherapy or everolimus.‬
‭6.‬ ‭Before‬‭starting‬‭with‬‭the‬‭second‬‭treatment‬‭in‬‭sequence‬‭,‬‭patients‬‭must‬‭show‬‭documented‬
‭disease‬‭progression‬‭by‬‭RECIST‬‭1.0‬‭(local‬‭assessment)‬‭while‬‭on‬‭anti-tumour‬‭therapy‬‭or‬‭in‬
‭case of toxicity caused by the first treatment period.‬
‭7.‬ ‭ECOG Performance status score 0 - 2.‬
‭8.‬ ‭Life expectancy > 12 months.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭9.‬ ‭Presence‬‭of‬‭measurable‬‭disease‬‭as‬‭per‬‭RECIST‬‭criteria‬‭1.0,‬‭documented‬‭by‬‭a‬‭Triphasic‬
‭Computed Tomography (CT) scan or multiphase MRI radiological assessment.‬
‭10.‬‭Previous‬‭treatment‬‭with‬‭somatostatin‬‭(SS)‬‭analogues‬‭is‬‭allowed.‬‭Only‬‭those‬‭patients‬‭with‬
‭active functioning syndrome at entry can continue with SS analogues during the study.‬
‭11.‬‭Adequate‬‭bone‬‭marrow‬‭function,‬‭documented‬‭by‬‭ANC‬‭>‬‭1.5‬‭x‬‭10‬‭9‬‭/L,‬‭platelets‬‭>‬‭100‬‭x‬
‭10‬‭9‬‭/L, haemoglobin > 9 g/dL.‬
‭12.‬‭Adequate‬‭liver‬‭function‬‭documented‬‭by:‬‭serum‬‭bilirubin‬‭≤‬‭2.0‬‭mg/dL,‬‭INR‬‭≤‬‭2,‬‭ALT‬‭and‬
‭AST‬‭≤‬‭2.5 x ULN (‬‭≤‬‭5 x ULN in patients with liver‬‭metastasis).‬
‭13.‬‭Adequate renal function documented by: serum creatinine < 1.5 x ULN.‬
‭14.‬‭Fasting‬‭serum‬‭cholesterol‬‭<‬‭300‬‭mg/dL‬‭or‬‭<‬‭7.75‬‭mmol/L‬‭and‬‭fasting‬‭triglycerides‬‭<‬‭2.5‬
‭x‬‭ULN.‬‭If‬‭one‬‭or‬‭both‬‭thresholds‬‭are‬‭exceeded,‬‭the‬‭patient‬‭may‬‭only‬‭be‬‭included‬‭after‬
‭starting treatment with an adequate lipid-lowering agent.‬
‭15.‬‭Women‬‭with‬‭child-bearing‬‭potential‬‭must‬‭have‬‭a‬‭negative‬‭serum‬‭pregnancy‬‭test‬‭within‬‭14‬
‭days‬‭prior‬‭to‬‭enrollment‬‭and/or‬‭a‬‭urine‬‭pregnancy‬‭test‬‭48‬‭hours‬‭before‬‭the‬‭administration‬
‭of the first study treatment.‬
‭16.‬‭Written Informed Consent obtained according to local regulations.‬
‭4.1.2‬‭Exclusion criteria‬
‭1.‬ ‭Patients‬‭with‬‭poorly‬‭differentiated‬‭pancreatic‬‭neuroendocrine‬‭tumor;‬‭this‬‭is,‬‭pNET‬‭G3‬‭as‬
‭per ENETS classification system:‬
‭G3: 21 or more mitoses per 2 mm‬‭2‬‭and/or Ki-67 index‬‭>20%‬
‭2.‬ ‭Previous‬‭treatment‬‭with‬‭chemotherapy‬‭and/or‬‭mTOR‬‭inhibitors‬‭(sirolimus,‬‭temsirolimus,‬
‭everolimus,‬ ‭deforolimus)‬ ‭or‬ ‭tirosyne‬ ‭kinase‬ ‭inhibitors‬ ‭(sunitinib,‬ ‭sorafenib,‬ ‭axitinib,‬
‭pazopanib, regerafenib).‬
‭3.‬ ‭Immune‬ ‭therapy‬ ‭or‬ ‭radiation‬ ‭therapy‬ ‭within‬ ‭4‬ ‭weeks‬ ‭prior‬ ‭to‬ ‭the‬ ‭patient‬‭entering‬‭the‬
‭study.‬
‭4.‬ ‭Hepatic‬‭artery‬‭embolization‬‭within‬‭the‬‭last‬‭6‬‭months‬‭(1‬‭month‬‭if‬‭there‬‭are‬‭other‬‭sites‬‭of‬
‭measurable‬‭disease),‬‭or‬‭cryoablation/radiofrequency‬‭ablation‬‭of‬‭hepatic‬‭metastasis‬‭within‬
‭2 months of enrolment.‬
‭5.‬ ‭Previous‬‭treatment‬‭with‬‭Peptide-Receptor‬‭Radionuclide‬‭Therapy‬‭(PRRT)‬‭within‬‭the‬‭last‬‭6‬
‭months and/or without progression following PRRT.‬
‭6.‬ ‭Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5 x ULN.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭7.‬ ‭Patients with any severe and/or uncontrolled medical conditions such as:‬
‭a.‬ ‭unstable‬ ‭angina‬ ‭pectoris,‬ ‭symptomatic‬ ‭congestive‬ ‭heart‬ ‭failure,‬ ‭myocardial‬
‭infarction‬ ‭≤‬ ‭6‬ ‭months‬ ‭prior‬ ‭to‬ ‭randomization,‬ ‭serious‬ ‭uncontrolled‬ ‭cardiac‬
‭arrhythmia,‬
‭b.‬ ‭active or uncontrolled severe infection,‬
‭c.‬ ‭severe‬ ‭hepatic‬ ‭impairment‬ ‭(Child‬ ‭Pugh‬ ‭C)‬ ‭is‬ ‭not‬ ‭allowed;‬ ‭moderate‬ ‭hepatic‬
‭impairment‬ ‭(Child‬‭Pugh‬‭B‬‭and‬‭A)‬‭requires‬‭a‬‭reduced‬‭dose‬‭of‬‭everolimus‬‭(5mg‬
‭and‬ ‭7.5‬ ‭mg‬ ‭daily‬ ‭respectively).‬ ‭Positive‬‭HBV-DNA‬‭and‬‭or‬‭HBsAg‬‭patients‬‭at‬
‭screening should receive prophylaxis treatment.‬
‭d.‬ ‭severely‬ ‭impaired‬ ‭lung‬ ‭function‬ ‭(spirometry‬‭and‬‭DLCO‬‭50%‬‭or‬‭less‬‭of‬‭normal‬
‭and O‬‭2‬‭saturation 88% or less at rest on room air),‬
‭e.‬ ‭active, bleeding diathesis‬
‭8.‬ ‭Treatment‬‭with‬‭potent‬‭inhibitors‬‭or‬‭inducers‬‭of‬‭CYP3A‬‭isoenzyme‬‭(rifabutin,‬‭rifampicin,‬
‭clarithromycin,‬‭ketoconazole,‬‭itraconazole,‬‭voriconazole,‬‭ritonavir,‬‭telithromycin)‬‭within‬
‭5‬ ‭days‬ ‭immediately‬ ‭before‬ ‭the‬ ‭start‬ ‭of‬ ‭treatment‬ ‭(a‬ ‭list‬ ‭of‬ ‭clinically‬ ‭significant‬ ‭drug‬
‭interactions is shown in section 6. Concomitant Medication).‬
‭9.‬ ‭Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.‬
‭10.‬‭Patients known to be HIV seropositive.‬
‭11.‬‭Known‬‭intolerance‬‭or‬‭hypersensitivity‬‭to‬‭everolimus‬‭or‬‭its‬‭excipients‬‭or‬‭other‬‭rapamycin‬
‭analogues.‬‭Patients‬‭with‬‭rare‬‭hereditary‬‭problems‬‭of‬‭galactose‬‭intolerance,‬‭Lapp‬‭lactase‬
‭deficiency or glucose-galactose malabsorption should not take this medicinal product.‬
‭12.‬‭Known‬‭intolerance‬‭or‬‭hypersensitivity‬‭to‬‭5FU‬‭or‬‭STZ‬‭or‬‭its‬‭excipients‬‭(notice‬‭that‬‭this‬
‭criterion‬ ‭includes‬ ‭patients‬ ‭with‬ ‭known‬ ‭deficit‬ ‭of‬ ‭dihydropyrimidine‬ ‭dehydrogenase‬
‭deficiency –DPD-).‬
‭13.‬‭Participation‬ ‭in‬ ‭any‬ ‭other‬ ‭clinical‬ ‭trial‬ ‭or‬ ‭concomitant‬ ‭treatment‬ ‭with‬ ‭any‬ ‭other‬
‭investigational drug.‬
‭14.‬‭No‬‭other‬‭prior‬‭or‬‭concurrent‬‭malignancy‬‭is‬‭allowed‬‭except‬‭for‬‭the‬‭following:‬‭adequately‬
‭treated‬‭basal‬‭cell‬‭or‬‭squamous‬‭cell‬‭skin‬‭cancer,‬‭or‬‭other‬‭adequately‬‭treated‬‭in‬‭situ‬‭cancer,‬
‭or any other cancer from which the patient has been disease free for ≥ 3 years.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭15.‬‭Pregnant,‬‭lactating‬‭women‬‭or‬‭fertile‬‭adults‬‭not‬‭using‬‭effective‬‭birth‬‭control‬‭methods.‬‭If‬
‭barrier‬‭contraceptives‬‭are‬‭used,‬‭these‬‭must‬‭be‬‭continued‬‭to‬‭be‬‭used‬‭throughout‬‭the‬‭trial‬‭by‬
‭both sexes and for up to 8 weeks after the end of treatment.‬
‭16.‬‭For administrative matters (insurance) patients‬‭≥‬‭95 are not allowed during the trial.‬
‭Only‬ ‭those‬ ‭patients‬ ‭coming‬ ‭from‬ ‭the‬ ‭hospital‬ ‭pool‬ ‭will‬ ‭be‬ ‭included‬ ‭in‬ ‭SEQTOR‬ ‭trial‬ ‭(e.g.‬
‭persons detained in an institution as a result of an official or court order are excluded).‬
‭4.2‬
‭WITHDRAWAL OF SUBJECTS AND STUDY END‬
‭All‬‭patients‬‭receiving‬‭treatment‬‭will‬‭be‬‭followed‬‭at‬‭least‬‭until‬‭14‬‭months‬‭(60‬‭weeks‬‭which‬
‭is‬‭the‬‭first‬ ‭radiological‬‭evaluation‬‭from‬‭12‬‭months)‬‭of‬‭the‬‭start‬‭of‬‭course‬‭1‬‭of‬‭last‬‭patient‬‭in‬
‭(LPI). .‬
‭Patients will be taken‬‭off treatment‬‭if any of the‬‭following situations occurs:‬
‭- Disease progression of pNET‬
‭-‬ ‭Unacceptable‬ ‭toxicity‬ ‭(see‬ ‭next‬ ‭section)‬ ‭even‬‭with‬‭optimal‬‭supportive‬‭care,‬‭following‬
‭investigator’s judgement.‬
‭- Patient withdraws her/his consent to continue with study treatment.‬
‭- Patient dies.‬
‭In‬ ‭case‬ ‭of‬ ‭treatment‬ ‭discontinuation,‬ ‭the‬ ‭patient‬ ‭will‬ ‭continue‬ ‭in‬ ‭the‬ ‭study‬ ‭for‬‭survival‬
‭follow-up, up to last visit of last patient.‬
‭Patients will be considered‬‭off study‬‭if any of the‬‭following occurs:‬
‭- Patient is lost to follow-up.‬
‭- Patient withdraws his/her consent for survival data collection.‬
‭- Patient dies.‬
‭- Study ends (up to last visit of last patient as defined above).‬
‭The study can be finished for administrative reasons.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭5.‬
‭INVESTIGATIONAL DRUGS‬
‭Interventional‬‭treatment‬‭consists‬‭on‬‭the‬‭administration‬‭of‬‭everolimus‬‭and‬‭a‬‭streptozotocin‬‭based‬
‭therapy given upfront each other upon progression.‬
‭Physicians‬ ‭will‬ ‭prescribe‬ ‭the‬ ‭Study‬ ‭Drug‬ ‭in‬ ‭accordance‬ ‭with‬ ‭medical‬ ‭guidelines‬ ‭and‬ ‭in‬
‭accordance with licensed indications of the Study Drug.‬
‭Drug substance 1‬
‭INN:‬‭Everolimus‬
‭Therapeutic group:‬‭L01X E10.‬
‭Trade name:‬‭Afinitor‬
‭Name used in the study:‬‭Everolimus‬
‭Pharmaceutical form:‬‭Elongated white to off-white‬‭tablets.‬
‭Route of Administration:‬‭Oral‬
‭Dose and method of administration:‬‭10 mg/day‬
‭Storage temperature:‬‭Room temperature (up to 25ºC).‬‭Protect from light and moisture.‬
‭Drug substance 2‬
‭INN:‬‭Streptozotocin‬
‭Trade name: Zanosar‬
‭Therapeutic group:‬‭L01AD04‬
‭Name used in the study:‬‭Streptozotocin‬
‭Pharmaceutical form:‬‭Powder for solution‬
‭Route of Administration:‬‭inyectable‬
‭Dose‬‭and‬‭method‬‭of‬‭administration‬‭:‬‭0,5g/m²‬‭days‬‭1-5‬‭in‬‭combination‬‭with‬‭5FU‬‭(according‬‭to‬
‭Moertel‬‭or‬‭Uppsala).‬‭STZ‬‭is‬‭administered‬‭as‬‭a‬‭short‬‭(30–60‬‭min)‬‭infusion‬‭or‬‭rapid‬‭intravenous‬
‭push.‬
‭Storage temperature:‬‭2-8 ºC.‬‭P‬‭rotect from light (preferably‬‭stored in carton).‬
‭Drug substance 3‬
‭INN:‬‭Fluorouracil‬
‭Therapeutic group:‬‭L01BC02‬
‭Name used in the study:‬‭5-Fluorouracil (5FU)‬
‭Pharmaceutical form:‬‭Vial‬
‭Route of Administration:‬‭intravenous infusion or injection‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Dose‬‭and‬‭method‬‭of‬‭administration‬‭:‬‭400‬‭mg/m²‬‭5FU‬‭(according‬‭to‬‭Moertel‬‭or‬‭Uppsala).‬‭5FU‬
‭is given as intravenous bolus injection.‬
‭Administration should be completed before 24 hours of preparation.‬
‭Storage temperature:‬‭8 ºC to 25ºC (Do not refrigerate).‬‭Protect from light.‬
‭All the patients enrolled in the study will follow two treatments in sequence:‬
‭Treatment 1:‬‭Everolimus‬
‭Treatment 2:‬‭STZ-5FU‬
‭Or the reverse sequence.‬
‭Supply and storage of study drugs‬
‭Commercial‬‭drugs‬‭will‬‭be‬‭used‬‭in‬‭this‬‭study.‬‭No‬‭drug‬‭will‬‭be‬‭supplied‬‭by‬‭the‬‭sponsor‬‭since‬‭this‬
‭is‬‭just‬‭a‬‭comparative‬‭study‬‭of‬‭the‬‭effect‬‭of‬‭sequencial‬‭order‬‭of‬‭two‬‭accepted‬‭therapies‬‭used‬‭in‬
‭clinical‬‭practice‬‭from‬‭which‬‭there‬‭is‬‭no‬‭clinical‬‭evidence‬‭about‬‭its‬‭efficacy‬‭when‬‭given‬‭upfront‬
‭each other.‬
‭Labelling‬
‭Commercial‬ ‭drug‬ ‭is‬ ‭going‬ ‭to‬ ‭be‬ ‭used‬ ‭in‬ ‭this‬ ‭trial.‬ ‭There‬ ‭is‬ ‭no‬ ‭labelling‬ ‭but‬ ‭commercial‬
‭packaging.‬‭Pharmacy‬‭Service‬‭should‬‭annotate‬‭patient‬‭numbers‬‭and‬‭patient‬‭visit‬‭on‬‭the‬‭box.‬‭This‬
‭information should be tracked separately per patient.‬
‭For documentation of everolimus intake patients will receive a patient diary‬
‭5.1‬
‭EVEROLIMUS‬
‭Everolimus‬ ‭obtained‬ ‭approval‬ ‭from‬ ‭the‬ ‭US‬ ‭and‬ ‭EU‬ ‭for‬ ‭the‬ ‭treatment‬ ‭of‬ ‭patients‬ ‭with‬
‭advanced‬‭pNETs‬‭in‬‭2011.‬‭In‬‭Europe,‬‭everolimus‬‭has‬‭been‬‭approved‬‭,‬‭on‬‭the‬‭following‬‭dates:‬
‭Germany:‬‭Q3‬‭2011,‬‭Sweden:‬‭Q3‬‭2011,‬‭UK:‬‭Q3‬‭2011,‬‭Denmark:‬‭Q3‬‭2011,‬‭The‬‭Netherlands:‬
‭Q3 2011, Scotland: Q2 2012, France: Q4 2012, Italy: Q4 2012, and Spain: Q2 2013.‬
‭5.1.1‬‭Dose and administration‬
‭The‬ ‭recommended‬ ‭dose‬ ‭for‬ ‭everolimus‬ ‭is‬ ‭10‬ ‭mg‬ ‭once‬ ‭a‬ ‭day‬ ‭while‬‭a‬‭clinical‬‭benefit‬‭is‬
‭observed‬‭or‬‭until‬‭unacceptable‬‭toxicity‬‭occurs.‬‭Everolimus‬‭length‬‭of‬‭cycles‬‭is‬‭4‬‭weeks‬‭(28‬
‭days).‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Recommended‬ ‭dose‬ ‭for‬ ‭patients‬ ‭with‬ ‭mild‬ ‭hepatic‬ ‭impairment‬ ‭Child-Pugh‬‭A‬‭is‬‭7,5‬‭mg‬
‭daily.‬‭Child-Pugh‬‭B‬‭patients‬‭(moderate‬‭impairment)‬‭should‬‭start‬‭at‬‭a‬‭reduced‬‭dose‬‭(5‬‭mg‬
‭daily)‬‭and‬‭the‬‭dose‬‭may‬‭be‬‭decreased‬‭to‬‭2.5‬‭if‬‭not‬‭well‬‭tolerated‬‭Dose‬‭adjustments‬‭should‬
‭be made if a patient’s hepatic (Child-Pugh) status changes during treatment.‬
‭Everolimus‬ ‭must‬ ‭be‬ ‭administered‬ ‭every‬ ‭day‬ ‭at‬ ‭the‬ ‭same‬ ‭time‬ ‭and‬ ‭under‬ ‭the‬ ‭same‬
‭conditions,‬‭immediately‬‭after‬‭meals.‬‭The‬‭tablets‬‭must‬‭not‬‭be‬‭chewed‬‭or‬‭crushed,‬‭but‬‭taken‬
‭whole‬ ‭with‬ ‭a‬ ‭glass‬ ‭of‬ ‭water.‬ ‭The‬ ‭blisters‬ ‭will‬ ‭only‬ ‭be‬ ‭opened‬ ‭when‬ ‭at‬ ‭the‬ ‭time‬ ‭of‬
‭administration, since they are hygroscopic and sensitive to light.‬
‭If a dose is missed, an extra dose‬‭must not be taken‬‭;‬‭patient must wait until the next dose.‬
‭Recommendations‬‭stated‬‭on‬‭the‬‭Summary‬‭of‬‭Product‬‭Characteristics‬‭(Technical‬‭Sheet)‬‭and‬
‭its‬‭updates‬‭is‬‭going‬‭to‬‭be‬‭followed‬‭in‬‭case‬‭of‬‭everolimus‬‭toxicity‬‭and‬‭should‬‭be‬‭consulted‬‭in‬
‭case‬‭of‬‭AE.‬‭Summary‬‭of‬‭Product‬‭Characteristics‬‭of‬‭everolimus,‬‭STZ‬‭and‬‭5-FU‬‭will‬‭be‬‭part‬
‭of the Investigator’s file as recommended on ICH guidelines.‬
‭Patient should document regularly the administration of everolimus on a patient diary.‬
‭5.1.1.1 Summary of Adverse Drug Reactions‬
‭The‬‭most‬‭common‬‭ADRs‬‭(incidence‬‭≥1/10‬‭and‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭treatment‬‭by‬‭the‬
‭investigator)‬ ‭from‬ ‭the‬ ‭pooled‬ ‭safety‬ ‭data‬ ‭were‬ ‭(in‬ ‭decreasing‬ ‭order):‬ ‭stomatitis,‬ ‭rash,‬
‭fatigue,‬ ‭diarrhea,‬ ‭infections,‬‭nausea,‬‭decreased‬‭appetite,‬‭anemia,‬‭dysgeusia,‬‭pneumonitis,‬
‭hyperglycemia,‬
‭weight‬
‭decreased,‬
‭pruritus,‬
‭asthenia,‬
‭peripheral‬
‭edema,‬
‭hypercholesterolemia, epistaxis, and headache.‬
‭The‬‭most‬‭common‬‭grade‬‭3/4‬‭ADRs‬‭(incidence‬‭≥1/100‬‭to‬‭<1/10‬‭and‬‭suspected‬‭to‬‭be‬‭related‬
‭to‬ ‭treatment‬ ‭by‬ ‭the‬ ‭investigator)‬ ‭were‬ ‭stomatitis,‬ ‭anemia,‬ ‭hyperglycemia,‬ ‭fatigue,‬
‭infections,‬ ‭pneumonitis,‬ ‭diarrhea,‬ ‭asthenia,‬ ‭thrombocytopenia,‬ ‭neutropenia,‬ ‭dyspnea,‬
‭lymphopenia,‬ ‭proteinuria,‬ ‭hemorrhage,‬ ‭hypophosphatemia,‬ ‭rash,‬ ‭hypertension,‬ ‭aspartate‬
‭aminotransferase‬ ‭(AST)‬ ‭increased,‬ ‭alanine‬ ‭aminotransferase‬ ‭(ALT)‬ ‭increased‬ ‭and‬
‭pneumonia.‬
‭5.1.2‬‭Modification of dose in case of toxicity‬
‭This‬ ‭study‬ ‭includes‬ ‭a‬‭fixed-dose‬‭regime‬‭of‬‭treatment.‬‭For‬‭adverse‬‭reactions‬‭of‬‭Grade‬‭1,‬
‭dose‬ ‭adjustment‬ ‭is‬ ‭usually‬ ‭not‬ ‭required.‬ ‭However,‬ ‭if‬ ‭the‬ ‭patient‬ ‭experiences‬ ‭any‬
‭treatment-related‬ ‭adverse‬ ‭event,‬ ‭Everolimus‬ ‭therapy‬ ‭may‬ ‭require‬ ‭temporary‬ ‭dose‬
‭interruption (with or without dose reduction) or discontinuation.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭The following dose reductions (also shown in Table I) are recommended:‬
‭If‬‭dose‬‭reduction‬‭is‬‭required,‬‭the‬‭suggested‬‭dose‬‭is‬‭aproximately‬‭50%‬‭lower‬‭than‬‭the‬‭daily‬
‭dose‬ ‭previously‬ ‭administrated.‬ ‭For‬ ‭dose‬ ‭reductions‬ ‭below‬ ‭the‬ ‭lowest‬ ‭dose‬ ‭available,‬
‭alternate day dosing should be considered.‬
‭●‬
‭Dose reduction to 5 mg a day.‬
‭●‬
‭Dose reduction to 5 mg every other day.‬
‭Clinical‬ ‭judgement‬ ‭of‬ ‭the‬ ‭treating‬ ‭clinician‬ ‭should‬ ‭guide‬ ‭the‬ ‭management‬ ‭plan‬ ‭of‬‭each‬
‭patient based on individual benefit/risk assessment.‬
‭Hepatic impairement‬
‭Dose‬‭adjustements‬‭should‬‭be‬‭made‬‭if‬‭a‬‭patient’s‬‭hepatic‬‭status‬‭changes‬‭during‬‭treatment.‬‭The‬
‭recommended‬‭dose‬‭for‬‭patients‬‭with‬‭moderate‬‭hepatic‬‭impairement‬‭(Child-Pugh‬‭B)‬‭is‬‭5‬‭mg‬
‭daily;‬ ‭the‬ ‭dose‬ ‭may‬ ‭be‬ ‭decreased‬ ‭to‬ ‭2.5mg‬ ‭daily‬ ‭if‬ ‭not‬ ‭well‬ ‭tolerated.‬ ‭Treatment‬ ‭with‬
‭everolimus on a patient with severe hepatic impairement (Child-Pugh C) is not recommended.‬
‭Table‬‭I.-‬‭Guidelines‬‭for‬‭dose‬‭modification‬‭in‬‭case‬‭of‬‭suspected‬‭toxicity‬‭to‬‭everolimus‬
‭and restart of treatment with everolimus‬
‭TOXICITY‬
‭ACTIONS‬
‭Stomatitis‬
‭Grade 1‬
‭Minimal symptoms, normal diet‬
‭No dose adjustment required. Manage with non-alcoholic or salt‬
‭water (0.9%) mouthwash several times a day.‬
‭Grade 2‬
‭Symptomatic but can eat and‬
‭swallow modified diet‬
‭Temporary dose interruption until recovery to Grade ≤1.‬
‭Re-initiate Everolimus at the same dose. If stomatitis recurs at‬
‭Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate‬
‭Everolimus at a lower dose (see section 6.1).‬
‭Grade 3‬
‭Symptomatic and unable to‬
‭adequately eat or hydrate orally‬
‭Temporary dose interruption until recovery to Grade ≤1.‬
‭Re-initiate Everolimus at a lower dose (see section 6.1) .‬
‭Grade 4‬
‭Symptoms associated with‬
‭life-threatening consequences‬
‭Discontinue everolimus and treat with appropriate medical‬
‭therapy.‬
‭Other non haematologic toxicities (excluding metabolic events)‬
‭Grade 1‬
‭Asymptomatic, radiographic findings‬
‭only‬
‭If toxicity is tolerable, no dose adjustemnt required.‬
‭Initiate appropriate medical therapy and monitor.‬
‭Grade 2‬
‭Symptomatic, not interfering with‬
‭ADL‬
‭If toxicity is tolerable, maintain the same dose. Initiate‬
‭appropriate medical therapy and monitor.‬
‭If toxicity becomes intolerable for the patient, discontinue‬
‭everolimus until recovery to grade ≤1. Then restart everolimus at‬
‭the same dose. If the event returns to grade 2, discontinue‬
‭everolimus until it recovers to grade ≤1. Then restart everolimus‬
‭at a lower dose.‬
‭Grade 3‬
‭Discontinue everolimus until recovery to grade ≤1. Initiate‬
‭appropriate medical therapy and monitor. Consider restart‬
‭everolimus at a lower dose. If toxicity recurs to grade 3, consider‬
‭discontinuation.‬
‭Grade 4‬
‭Remove everolimus, and treat with appropriate medical therapy‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Metabolic events (e.g. hyperglycemia, dyslipemia)‬
‭Grade 1 and grade 2‬
‭No dose adjustment is required. . Initiate appropriate medical‬
‭therapy and monitor.‬
‭Grade 3‬
‭Interrupt everolimus temporary. Re-initiate at a lower dose.‬
‭Mange with appropriate medical therapy and monitor.‬
‭Grade 4‬
‭Remove everolimus, and treat with appropriate medical therapy‬
‭Haematologic toxicity‬
‭Grade 2 thrombocytopoenia‬
‭(platelets <75, ≥50x10‬‭9‬‭/L)‬
‭Discontinue everolimus until recovery to grade ≤1 (>75 x10‬‭9‬‭/L).‬
‭Then restart everolimus at the same dose. If thrombocytopoenia‬
‭returns to grade 2, discontinue everolimus until it recovers to‬
‭grade ≤1. Then restart everolimus at the next lower dose.‬
‭Grade 3 and 4 thrombocytopoenia‬
‭(platelets <50x10‬‭9‬‭/L)‬
‭Discontinue everolimus until recovery to grade ≤1 (platelets‬‭>‬‭75‬
‭x10‬‭9‬‭/L). Then restart everolimus at a lower dose.‬‭If grade 3‬
‭thrombocytopoenia recurs, remove everolimus.‬
‭Grade 2 neutropoenia‬
‭(neutrophils ( ≥1 x10‬‭9‬‭/L)‬
‭No dose adjustment is required.‬
‭Grade 3 neutropoenia‬
‭(neutrophils (<1, ≥0.5 x10‬‭9‬‭/L)‬
‭Discontinue everolimus until recovery to grade ≤2 (neutrophils‬
‭>‬‭1 x10‬‭9‬‭/L). Then restart everolimus at the same dose.‬
‭Grade 4 neutropoenia‬
‭(neutrophils (< 0.5 x10‬‭9‬‭/L)‬
‭Discontinue everolimus until recovery to grade ≤2 (neutrophils‬
‭>‬‭1 x10‬‭9‬‭/L). Then restart everolimus at the next lower‬‭dose level.‬
‭Grade 3 febrile neutropoenia‬
‭(not life-threatening)‬
‭Discontinue everolimus until fever and neutropoenia subside to‬
‭grade ≤2 (neutrophils‬‭>‬‭1,25 x10‬‭9‬‭/L) and no fever.‬‭Then restart‬
‭everolimus at a lower dose.‬
‭Grade 4 febrile neutropoenia‬
‭(life-threatening)‬
‭Discontinue everolimus.‬
‭For‬ ‭the‬ ‭treatment‬ ‭of‬ ‭other‬ ‭toxicities‬ ‭such‬ ‭as‬ ‭stomatitis/mucositis,‬ ‭diarrhoea,‬
‭hyperlipidaemia‬‭and‬‭hyperglycaemia,‬‭see‬‭Allowed‬‭and‬‭Prohibited‬‭concomitant‬‭medications‬
‭Section 6 in the protocol.‬
‭Stomatitis‬‭or‬‭oral‬‭mucositis‬‭will‬‭be‬‭adequately‬‭classified‬‭using‬‭the‬‭functional‬‭classification‬
‭for adverse events provided in the NCI-CTCAE scale, version 4.0.‬
‭Cases‬ ‭of‬ ‭hyperglycaemia‬ ‭have‬ ‭been‬ ‭reported‬ ‭in‬ ‭patients‬ ‭taking‬ ‭Everolimus.‬ ‭It‬ ‭is‬
‭recommended‬ ‭to‬ ‭measure‬ ‭fasting‬ ‭glucose‬ ‭serum‬ ‭levels‬ ‭before‬ ‭starting‬ ‭treatment‬ ‭with‬
‭everolimus‬ ‭and‬ ‭then‬‭monitor‬‭them‬‭regularly.‬‭More‬‭frequent‬‭monitoring‬‭is‬‭recommended‬
‭when everolimus is co-administrated with other drugs that may induce hyperglycemia.‬
‭Dyslipemia‬ ‭(including‬ ‭hypercholesterolemia‬ ‭and‬ ‭hyprtriglyceridemia)‬‭has‬‭been‬‭reported.‬
‭Monitoring‬ ‭of‬ ‭cholesterol‬ ‭and‬ ‭triglycerides‬ ‭prior‬ ‭to‬ ‭start‬ ‭and‬ ‭periodically‬ ‭thereafter‬ ‭is‬
‭recommended.‬
‭Cases‬‭of‬‭non-infectious‬‭neumonitis‬‭(including‬‭interstitial‬‭lung‬‭disease)‬‭have‬‭been‬‭described‬
‭in‬‭patients‬‭taking‬‭Everolimus.‬‭Some‬‭of‬‭these‬‭have‬‭been‬‭severe‬‭and‬‭on‬‭rare‬‭occasions,‬‭fatal‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭outcome‬ ‭was‬ ‭observed.‬ ‭In‬ ‭case‬ ‭of‬ ‭non-infectious‬‭pneumonitis‬‭with‬‭moderate‬‭symptoms‬
‭(this is, grade 2), treatment interruption should be considered until the symptoms improve.‬
‭If‬‭the‬‭patient‬‭experiences‬‭grade‬‭3‬‭pneumonitis‬‭the‬‭treatment‬‭should‬‭be‬‭interrupted‬‭and‬‭the‬
‭patient‬‭treated‬‭clinically‬‭following‬‭the‬‭standard‬‭procedures.‬‭A‬‭pulmonary‬‭function‬‭test‬‭and‬
‭bronchoscopy‬‭with‬‭biopsy‬‭(and‬‭BAL)‬‭will‬‭be‬‭performed‬‭if‬‭considered‬‭clinically‬‭necessary.‬
‭The‬‭use‬‭of‬‭corticosteroids‬‭may‬‭be‬‭indicated‬‭until‬‭symptoms‬‭subside.‬‭The‬‭treatment‬‭may‬‭be‬
‭restarted at a reduced dose .‬
‭A‬‭diagnosis‬‭of‬‭non-infectious‬‭pneumonitis‬‭should‬‭be‬‭considered‬‭in‬‭patients‬‭with‬‭unspecific‬
‭respiratory‬ ‭signs‬ ‭or‬ ‭symptoms,‬ ‭such‬ ‭as‬ ‭hypoxia,‬ ‭pleural‬ ‭effusion,‬ ‭cough,‬ ‭or‬ ‭dyspnoea.‬
‭Therefore,‬ ‭assessment‬ ‭by‬ ‭a‬ ‭pneumologist‬ ‭should‬ ‭be‬ ‭considered‬ ‭if‬ ‭non-infectious‬
‭pneumonitis‬‭is‬‭diagnosed,‬‭as‬‭well‬‭as‬‭in‬‭cases‬‭where‬‭the‬‭causes‬‭of‬‭infectious,‬‭neoplastic‬‭and‬
‭non-pharmacological‬ ‭origin‬ ‭have‬ ‭been‬ ‭ruled‬ ‭out‬ ‭after‬ ‭performing‬ ‭the‬ ‭relevant‬
‭investigations.‬‭Opportunistic‬‭infections‬‭such‬‭as‬‭PJP‬‭should‬‭be‬‭ruled‬‭out‬‭in‬‭the‬‭differential‬
‭diagnosis of non-infectious pneumonitis.‬
‭For‬ ‭patients‬ ‭who‬ ‭required‬ ‭corticosteroids‬ ‭for‬ ‭treatment‬ ‭of‬ ‭non-infectious‬ ‭pneumonitis,‬
‭prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be considered.‬
‭The‬ ‭patients‬ ‭must‬‭be‬‭instructed‬‭to‬‭notify‬‭immediately‬‭any‬‭new‬‭or‬‭worsening‬‭respiratory‬
‭symptom.‬ ‭Patients‬ ‭participating‬‭in‬‭this‬‭study‬‭will‬‭be‬‭asked‬‭regularly‬‭for‬‭the‬‭presence‬‭or‬
‭changes in pulmonary symptoms indicating pulmonary toxicity.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Table II. Schedule of the management of non-infectious pneumonitis‬
‭Worst grade‬
‭Assessments needed‬
‭Treatment‬
‭Dose adjustment  of‬
‭everolimus‬
‭Grade 1‬
‭asymptomatic‬
‭radiographic‬
‭findings only‬
‭Initiate appropiate monitoring‬
‭CT with pulmonary window.‬
‭Repeat at least every three‬
‭cycles until return to normal‬
‭limits.‬
‭No specific treatment is‬
‭required.‬
‭Administer 100% of the‬
‭everolimus dose.‬
‭Grade 2,‬
‭symptomatic; does‬
‭not interfere with‬
‭activities of daily‬
‭life.‬
‭CT with pulmonary window‬
‭and pulmonary function tests,‬
‭including: spirometry, DLCO‬
‭and O2 saturation at rest with‬
‭ambient air; Repeat in each‬
‭cycle until return to baseline‬
‭values. Consider the possibility‬
‭of performing a bronchoscopy.‬
‭Only symptomatic‬
‭treatment. Consider‬
‭corticosteroids if‬
‭coughing that is‬
‭uncomfortable for the‬
‭patient is observed.‬
‭Consider interruption of‬
‭therapy, rule out infection‬
‭and consider treatment‬
‭with corticoesteroids until‬
‭symptoms improve to‬
‭grade ≤ 1. Reinitiate at a‬
‭lower dose.‬
‭Patients will be removed‬
‭from treatment if they do‬
‭not recover to ≤ grade 1‬
‭within 4 weeks.‬
‭Grade 3,‬
‭symptomatic; does‬
‭not interfere with‬
‭activities of daily‬
‭life. Oxygen‬
‭therapy is‬
‭indicated.‬
‭Rule out infection. CT with‬
‭pulmonary window and‬
‭pulmonary function tests,‬
‭including: spirometry, DLCO‬
‭and O2 saturation at rest with‬
‭ambient air; Repeat in each‬
‭cycle until return to baseline‬
‭values. Bronchoscopy‬
‭recommended.‬
‭Consider treatment with‬
‭corticosteroids if an‬
‭infectious origin is ruled‬
‭out. Titrate the dose‬
‭according to medical‬
‭indication.‬
‭Interrupt treatment until‬
‭resolution to grade‬‭<‬‭1.‬
‭Rule out infection and‬
‭consider treatment with‬
‭corticoesteroids .The‬
‭treatment may be restarted‬
‭s at a reduced dose (by‬
‭one level).‬
‭If toxicity recurse at grade‬
‭3, consider‬
‭discontinutaion.‬
‭Life-threatening,‬
‭grade 4; assisted‬
‭ventilation‬
‭indicated.‬
‭Rule out infection. CT with‬
‭pulmonary window and‬
‭pulmonary function tests,‬
‭including: spirometry, DLCO‬
‭and O2 saturation at rest with‬
‭ambient air. Repeat at least‬
‭every two cycles until return to‬
‭normal limits. If possible,‬
‭bronchoscopy with biopsy and‬
‭BAL are recommended.*‬
‭Consider the possibility of‬
‭using corticosteroids if an‬
‭infectious origin is ruled‬
‭out. Titrate the dose‬
‭according to medical‬
‭indication.‬
‭Discontinue treatment.‬
‭Rule out infection and‬
‭consider treatment with‬
‭corticoesteroids .‬
‭* When a bronchoscopy is performed, a biopsy or bronchoalveolar lavage (BAL) should be also done.‬
‭In‬ ‭the‬ ‭event‬ ‭of‬ ‭localised‬ ‭or‬ ‭systemic‬ ‭infections‬ ‭(everolimus‬ ‭has‬ ‭immunosuppressive‬
‭properties),‬ ‭including‬ ‭pneumonia,‬ ‭other‬ ‭bacterial,‬ ‭fungal,‬ ‭viral‬ ‭or‬ ‭protozoan‬ ‭infections‬
‭including‬ ‭infections‬ ‭with‬ ‭opportunistic‬ ‭pathogens‬ ‭(PJP),‬ ‭including‬ ‭reactivation‬ ‭of‬ ‭the‬
‭hepatitis‬‭B‬‭virus‬‭(some‬‭of‬‭these‬‭infections‬‭have‬‭been‬‭severe‬‭leeding‬‭to‬‭sepsis,‬‭respiratory‬‭or‬
‭hepatic‬‭failure)‬‭and‬‭occasionally‬‭had‬‭a‬‭fatal‬‭outcome.‬‭Both‬‭physicians‬‭and‬‭patients‬‭must‬
‭be‬‭aware‬‭that‬‭everolimus‬‭is‬‭associated‬‭with‬‭an‬‭increased‬‭risk‬‭of‬‭infection‬‭.‬‭Therefore,‬
‭any‬‭existing‬‭infections‬‭must‬‭be‬‭treated‬‭appropriately‬‭and‬‭should‬‭have‬‭been‬‭resolved‬‭fully‬
‭before‬ ‭starting‬ ‭treatment‬ ‭with‬ ‭everolimus.‬ ‭During‬ ‭treatment‬ ‭with‬ ‭everolimus,‬ ‭special‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭attention‬‭will‬‭be‬‭paid‬‭to‬‭symptoms‬‭and‬‭signs‬‭of‬‭infection;‬‭if‬‭any‬‭infections‬‭are‬‭diagnosed,‬
‭the‬‭site‬‭should‬‭immediately‬‭provide‬‭the‬‭appropriate‬‭treatment‬‭and‬‭consider‬‭temporary‬‭or‬
‭definitive‬ ‭discontinuation‬ ‭of‬ ‭everolimus‬‭.‬ ‭Should‬ ‭the‬ ‭patient‬ ‭require‬ ‭erythromycin,‬
‭verapamil‬ ‭or‬ ‭oral‬ ‭cyclosporine,‬ ‭reducing‬ ‭the‬ ‭dose‬ ‭to‬ ‭5‬ ‭mg‬ ‭should‬ ‭be‬ ‭considered‬ ‭(see‬
‭Section 6 Treatments Allowed).‬
‭In‬ ‭case‬ ‭of‬ ‭fungal‬ ‭invasive‬ ‭systemic‬ ‭infection‬‭,‬ ‭treatment‬ ‭with‬ ‭everolimus‬ ‭should‬ ‭be‬
‭discontinued immediately and permanently‬‭.‬
‭Pneumocystis‬ ‭jirovecii‬ ‭pneumonia‬ ‭(PJP)‬ ‭cases,‬ ‭some‬ ‭with‬ ‭fatal‬ ‭outcome,‬ ‭have‬ ‭been‬
‭reported‬‭in‬‭patients‬‭who‬‭received‬‭everolimus.‬‭PJP‬‭may‬‭be‬‭associated‬‭with‬‭concomitant‬‭use‬
‭of‬ ‭corticosteroids‬ ‭or‬ ‭other‬ ‭immunosuppressive‬ ‭agents.‬ ‭Prophylaxis‬ ‭for‬ ‭PJP‬ ‭should‬ ‭be‬
‭considered‬‭when‬‭concomitant‬‭use‬‭of‬‭corticosteroids‬‭or‬‭other‬‭immunosuppressive‬‭agents‬‭are‬
‭required.‬
‭No‬‭dose‬‭adjustment‬‭is‬‭required‬‭for‬‭renal‬‭impairment‬‭.‬‭Everolimus‬‭has‬‭been‬‭associated‬‭with‬
‭renal‬ ‭failure‬ ‭events‬ ‭(including‬ ‭fatal‬ ‭ones)‬ ‭and‬ ‭proteinuria.‬ ‭Renal‬ ‭function‬ ‭should‬ ‭be‬
‭monitored‬‭particularly‬‭where‬‭patients‬‭have‬‭additional‬‭risk‬‭factors‬‭that‬‭may‬‭further‬‭impair‬
‭renal function.‬
‭Hypersensitivity‬ ‭reactions‬ ‭manifested‬ ‭by‬ ‭symptoms‬ ‭including,‬ ‭but‬ ‭not‬ ‭limited‬ ‭to,‬
‭anaphylaxis,‬‭dyspnoea,‬‭flushing,‬‭chest‬‭pain‬‭or‬‭angioedema‬‭(e.g.‬‭swelling‬‭of‬‭the‬‭airways‬‭or‬
‭tongue,‬ ‭with‬ ‭or‬ ‭without‬ ‭respiratory‬ ‭impairment)‬ ‭have‬ ‭been‬ ‭observed‬ ‭with‬ ‭everolimus.‬
‭Patients‬‭with‬‭rare‬‭hereditary‬‭problems‬‭of‬‭galactose‬‭intolerance,‬‭Lapp‬‭lactase‬‭deficiency‬‭or‬
‭glucose-galactose malabsorption should not take this medicinal product.‬
‭Angioedema‬
‭(rare‬
‭adverse‬
‭drug‬
‭reaction):‬
‭Patients‬
‭taking‬
‭concomitant‬
‭angiotensin-converting‬ ‭enzyme‬ ‭(ACE)‬ ‭inhibitor‬ ‭therapy‬ ‭may‬ ‭be‬ ‭at‬ ‭increased‬ ‭risk‬ ‭for‬
‭angioedema‬ ‭(e.g.‬ ‭swelling‬ ‭of‬ ‭the‬ ‭airways‬ ‭or‬ ‭tongue,‬ ‭with‬ ‭or‬ ‭without‬ ‭respiratory‬
‭impairment).‬
‭Based on non-clinical findings,‬‭male and female fertility‬‭may be compromised by treatment‬
‭with‬‭everolimus.‬‭Everolimus‬‭may‬‭have‬‭an‬‭impact‬‭on‬‭female‬‭fertility‬‭and‬‭may‬‭affect‬‭male‬
‭fertility‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭For‬‭the‬‭full‬‭list‬‭of‬‭all‬‭side‬‭effects‬‭reported‬‭with‬‭everolimus,‬‭see‬‭the‬‭Summary‬‭of‬‭Product‬
‭Characteristics leaflet in the Investigator’s file.‬
‭5.1.3‬‭Monitoring‬ ‭patients‬ ‭with‬ ‭hepatitis‬ ‭B‬ ‭and‬ ‭prophylactic‬
‭treatment for its reactivation‬
‭In‬‭patients‬‭with‬‭cancer‬‭and‬‭hepatitis‬‭B,‬‭whether‬‭carriers‬‭of‬‭virus‬‭or‬‭if‬‭they‬‭have‬‭developed‬
‭chronic‬ ‭hepatitis,‬ ‭it‬ ‭has‬ ‭been‬ ‭shown‬ ‭that‬ ‭the‬ ‭use‬ ‭of‬ ‭antivirals‬ ‭during‬ ‭cancer‬ ‭treatment‬
‭reduces‬‭the‬‭risk‬‭of‬‭reactivation‬‭of‬‭the‬‭hepatitis‬‭B‬‭virus‬‭(HBV)‬‭as‬‭well‬‭as‬‭the‬‭morbidity‬‭and‬
‭mortality associated with this virus‬‭15,16‬‭.‬
‭Everolimus‬ ‭has‬ ‭been‬ ‭associated‬ ‭with‬ ‭serious‬‭cases‬‭of‬‭hepatitis‬‭B‬‭reactivation,‬‭including‬
‭fatal‬ ‭outcome.‬ ‭Reactivation‬ ‭of‬ ‭infections‬ ‭is‬ ‭an‬ ‭expected‬ ‭event‬ ‭during‬ ‭periods‬ ‭of‬
‭immunosuppression.‬
‭Lab‬ ‭Samples‬ ‭for‬ ‭detection‬‭of‬‭Hepatitis‬‭Viremia‬‭have‬‭to‬‭be‬‭taken‬‭at‬‭screening‬‭+‬‭at‬‭each‬
‭examination during everolimus therapy whether carriers of hepatitis B (see tables below).‬
‭A/‬ ‭Screening‬ ‭period‬‭:‬ ‭If‬ ‭hepatitis‬ ‭tests‬ ‭are‬ ‭performed‬ ‭before‬‭including‬‭the‬‭patient‬‭in‬‭the‬
‭study, the following measures should be adopted based on the outcome obtained:‬
‭Table III. Detection of HBV‬
‭Test‬
‭Result‬
‭Result‬
‭Result‬
‭Result‬
‭Result‬
‭HBV-DNA‬
‭+‬
‭+ o -‬
‭-‬
‭-‬
‭-‬
‭HBs Ag‬
‭+ o -‬
‭+‬
‭-‬
‭-‬
‭-‬
‭Anti-HBs Ab‬
‭+ o -‬
‭+ o -‬
‭+‬
‭and no previous‬
‭vaccination for‬
‭HBV‬
‭+ o -‬
‭o +‬
‭with previous‬
‭vaccination for‬
‭HBV‬
‭Anti-HBc Ab‬
‭+ o -‬
‭+ o -‬
‭+ o -‬
‭+‬
‭-‬
‭Recommendation‬
‭Administered prophylactic‬
‭treatment between 1 and 2‬
‭weeks before administration‬
‭of the first dose of the study‬
‭drug;* monitor HBV-DNA‬
‭approximately every 6‬
‭months.‬
‭No prophylaxis is required;‬
‭monitor HBV-DNA‬
‭approximately every 3 months.‬
‭No specific‬
‭action is required.‬
‭*‬‭Administration of the prophylactic antiviral treatment‬‭will be continued until at least 4 weeks‬
‭following the last administration of the study drug.‬
‭B/ On-treatment period:‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭In‬‭the‬‭event‬‭of‬‭reactivation‬‭of‬‭hepatitis‬‭B‬‭during‬‭the‬‭study‬‭treatment,‬‭the‬‭following‬‭should‬
‭be performed:‬
‭Table‬ ‭IV.‬ ‭Treatment‬ ‭of‬ ‭HBV‬ ‭reactivation*‬ ‭(with‬ ‭or‬ ‭without‬ ‭clinical‬ ‭signs‬ ‭or‬
‭symptoms)‬
‭Patients‬ ‭with‬ ‭baseline‬
‭results:‬
‭Positive HBV-DNA‬
‭OR‬
‭Positive HBsAg‬
‭----------------------------------‬
‭Reactivation‬ ‭is‬ ‭defined‬ ‭as:‬
‭[increase‬
‭of‬
‭1‬
‭log‬
‭in‬
‭HBV-DNA‬
‭from‬
‭the‬
‭baseline‬
‭value‬
‭of‬
‭new‬
‭measurable‬ ‭HBV-DNA‬ ‭OR‬
‭HBV-DNA]‬
‭AND‬
‭increase of ALT 5 x ULN‬
‭Start treatment with a second antiviral drug;‬
‭AND‬
‭discontinue administration of the study drug until it subsides:‬
‭>ALT ≤ grade 1 (or baseline ALT, if > grade 1); and‬
‭HBV-DNA ≤ baseline values‬
‭If the episode subsides within ≤ 28 days, administration of the study drug‬
‭should be restarted with a lower dose, if possible (see Table I. Guidelines‬
‭for changing the dose of everolimus). If the patient already receives the‬
‭lowest dose of the study drug established in this protocol, the treatment will‬
‭be restarted at the same dosage after it subsides. Administration of both‬
‭antiviral treatments should be continued until at least 4 weeks following the‬
‭last administration of the study drug.‬
‭If‬ ‭the‬ ‭episode‬ ‭subsides‬ ‭within‬‭>‬‭28‬‭days,‬‭administration‬‭of‬‭the‬‭study‬‭drug‬
‭should‬ ‭be‬ ‭definitively‬ ‭discontinued‬ ‭and‬ ‭administration‬ ‭of‬ ‭both‬ ‭antiviral‬
‭treatments‬‭will‬‭continue‬‭until‬‭at‬‭least‬‭4‬‭weeks‬‭after‬‭the‬‭last‬‭administration‬‭of‬
‭the study drug.‬
‭Patients with baseline‬
‭results:‬
‭Negative HBV-DNA and‬
‭HBsAg‬
‭AND‬
‭[Positive‬‭anti-HBs‬‭Ab‬‭(with‬
‭no‬ ‭history‬ ‭of‬ ‭vaccination‬
‭for HBV) or anti-HBc Ab]‬
‭----------------------------------‬
‭---‬
‭Reactivation‬ ‭is‬ ‭defined‬ ‭as‬
‭new‬
‭measurable‬
‭HBV-DNA.‬
‭Start treatment with a first antiviral drug;‬
‭AND‬
‭discontinue administration of the study drug until it subsides:‬
‭HBV-DNA ≤ baseline values‬
‭If‬ ‭the‬ ‭episode‬‭subsides‬‭within‬‭≤‬‭28‬‭days,‬‭administration‬‭of‬‭the‬‭study‬‭drug‬
‭will‬‭be‬‭restarted‬‭with‬‭a‬‭lower‬‭dose,‬‭if‬‭possible‬‭(see‬‭Table‬‭I.‬‭Guidelines‬‭for‬
‭changing‬‭the‬‭dose‬‭of‬‭everolimus).‬‭If‬‭the‬‭patient‬‭already‬‭receives‬‭the‬‭lowest‬
‭dose‬ ‭of‬ ‭the‬ ‭study‬ ‭drug‬ ‭established‬ ‭in‬ ‭this‬ ‭protocol,‬ ‭the‬ ‭treatment‬ ‭will‬ ‭be‬
‭restarted‬ ‭at‬ ‭the‬ ‭same‬ ‭dosage‬ ‭after‬ ‭it‬ ‭subsides.‬ ‭Administration‬ ‭should‬ ‭be‬
‭continued‬ ‭until‬ ‭at‬ ‭least‬ ‭4‬ ‭weeks‬ ‭after‬ ‭the‬ ‭last‬ ‭administration‬‭of‬‭the‬‭study‬
‭drug.‬
‭If‬ ‭the‬ ‭episode‬ ‭subsides‬ ‭within‬‭>‬‭28‬‭days,‬‭administration‬‭of‬‭the‬‭study‬‭drug‬
‭should‬ ‭be‬ ‭definitively‬ ‭discontinued‬ ‭and‬ ‭administration‬ ‭of‬ ‭the‬ ‭antiviral‬
‭treatment‬‭will‬‭continue‬‭until‬‭at‬‭least‬‭4‬‭weeks‬‭after‬‭the‬‭last‬‭administration‬‭of‬
‭the study drug.‬
‭*‬ ‭All‬ ‭hepatitis‬ ‭B‬ ‭reactivations‬ ‭will‬ ‭be‬ ‭noted‬ ‭as‬ ‭grade‬ ‭3‬ ‭(according‬ ‭to‬ ‭CTCAE,‬ ‭version‬ ‭4.0,‬
‭Metabolic/Laboratory/Other:‬ ‭viral‬ ‭reactivation),‬ ‭unless‬ ‭they‬‭are‬‭considered‬‭potentially‬‭life-threatening‬
‭in‬‭the‬‭investigator’s‬‭opinion,‬‭in‬‭which‬‭case‬‭they‬‭will‬‭be‬‭noted‬‭as‬‭grade‬‭4‬‭(according‬‭to‬‭CTCAE,‬‭version‬‭4.0,‬
‭Metabolic/Laboratory/Other:‬‭viral‬‭reactivation).‬‭The‬‭viral‬‭reactivation‬‭date‬‭will‬‭be‬‭considered‬‭as‬‭the‬‭date‬
‭when‬‭both‬‭the‬‭criteria‬‭for‬‭DNA‬‭and‬‭the‬‭ALT‬‭value‬‭are‬‭met‬‭(for‬‭instance,‬‭if‬‭a‬‭patient‬‭had‬‭positive‬‭results‬‭in‬
‭the‬‭HBV-DNA‬‭analysis‬‭on‬‭1‬‭January,‬‭2010)‬‭and‬‭reached‬‭a‬‭value‬‭of‬‭ALT‬‭≥‬‭5‬‭x‬‭ULN‬‭on‬‭1‬‭April,‬‭2010,‬‭this‬
‭will be the last date of viral reactivation).‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭5.1.4‬‭Monitoring patients with hepatitis C‬
‭HCV reactivation should be monitored every 6 weeks in the following patients:‬
‭●‬
‭Patients‬‭with‬‭known‬‭history‬‭of‬‭infection‬‭by‬‭HCV,‬‭despite‬‭having‬‭negative‬‭results‬‭in‬
‭the‬ ‭viremia‬ ‭analysis‬ ‭at‬ ‭baseline‬ ‭(also‬ ‭in‬ ‭patients‬ ‭receiving‬ ‭treatment‬ ‭and‬ ‭considered‬
‭"cured").‬
‭Guidelines for the treatment of hepatitis C are detailed below:‬
‭Table V. Treatment of HCV reactivation*‬
‭In patients with the following baseline‬
‭results:‬
‭Detectable HCV-RNA,‬
‭Reactivation is defined as:‬
‭increase of ALT 5 x ULN‬
‭Definitively discontinue the study drug.‬
‭In patients with the following baseline‬
‭results:‬
‭known history of infection by HCV with no‬
‭detectable HCV-RNA,‬
‭Reactivation is defined as‬‭:‬
‭new detectable HCV-RNA‬
‭Definitively discontinue the study drug.‬
‭* All hepatitis C reactivations will be noted as grade 3 (according to CTCAE, version 4.0,‬
‭Metabolic/Laboratory/Other: viral reactivation), unless they are considered life-threatening in the‬
‭investigator’s opinion, in which case they will be noted as grade 4 (according to CTCAE, version 4.0,‬
‭Metabolic/Laboratory/Other: viral reactivation).‬
‭5.2‬
‭STZ-5FU THERAPY‬
‭5.2.1 Dose and administration‬
‭Treatment‬‭recommendations‬‭on‬‭ENETS‬‭guidelines‬‭(Moertel’s‬‭or‬‭Uppsala‬‭regimens)‬‭should‬
‭be followed for STZ-5FU dosage/regime‬‭14‬‭, this is:‬
‭Moertel:‬
‭●‬ ‭STZ 0.5 g/m‬‭2‬‭on days 1–5‬
‭●‬ ‭5FU 400 mg/m‬‭2‬‭on days 1–5‬
‭every 6 weeks.‬
‭Uppsala:‬
‭●‬ ‭STZ 0.5 g/m‬‭2‬‭on days 1–5‬
‭5FU 400 mg/m‬‭2‬‭on days 1-3‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭and then every 3 weeks,‬
‭●‬ ‭1-day treatment with 1g/m‬‭2‬‭STZ‬
‭1-day treatment with 400mg/m‬‭2‬‭5-FU‬
‭STZ‬‭is‬‭administered‬‭as‬‭a‬‭short‬‭(30–60‬‭min)‬‭infusion‬‭or‬‭rapid‬‭intravenous‬‭push‬‭and‬‭5FU‬‭is‬
‭given as intravenous bolus injection.‬
‭5.2.2‬‭Dose modifications in case of toxicity‬
‭Dosage adjustments or discontinuance of STZ may be indicated, depending upon the‬
‭degree of toxicity noted:‬
‭-‬ ‭Renal impairment: dose reductions of STZ should be‬‭considered when creatinine‬
‭clearance is <60 ml/min and should not be given below 30 ml/min.‬
‭-‬‭Liver impairment: reduction of doses should be considered.‬
‭-‬‭Oral ulceration/GI side effects: Treatment with 5-FU should be discontinued at the first‬
‭sign such as stomatitis, diarrhoea or bleeding from the G.I. tract.‬
‭Fluorouracil‬‭has‬‭a‬‭narrow‬‭margin‬‭of‬‭safety‬‭and‬‭is‬‭a‬‭highly‬‭toxic‬‭drug.‬‭Fluorouracil‬‭therapy‬
‭should‬‭be‬‭discontinued‬‭promptly‬‭whenever‬‭one‬‭of‬‭the‬‭following‬‭signs‬‭of‬‭toxicity‬‭appears:‬
‭leucopenia,‬ ‭thrombocytopenia,‬ ‭stomatitis,‬ ‭oesophagopharyngitis,‬ ‭intractable‬ ‭vomiting,‬
‭diarrhoea,‬‭melena‬‭haemorrhage,‬‭oral‬‭ulceration,‬‭evidence‬‭of‬‭gastrointestinal‬‭ulceration‬‭or‬
‭bleeding.‬‭The‬‭ratio‬‭between‬‭effective‬‭and‬‭toxic‬‭dose‬‭is‬‭small‬‭and‬‭therapeutic‬‭response‬‭is‬
‭unlikely‬‭without‬‭some‬‭degree‬‭of‬‭toxicity.‬‭Care‬‭must‬‭be‬‭taken,‬‭therefore,‬‭in‬‭the‬‭selection‬‭of‬
‭patients and adjustment of dosage.‬
‭Cytotoxic‬ ‭agents,‬ ‭including‬ ‭fluorouracil,‬ ‭may‬ ‭produce‬ ‭myelosuppression‬ ‭(including,‬‭but‬
‭not‬ ‭limited‬ ‭to,‬ ‭leucopenia,‬ ‭granulocytopenia,‬ ‭pancytopenia‬ ‭and‬ ‭thrombocytopenia).‬
‭Leucopenia‬‭and‬‭thrombocytopenia‬‭commonly‬‭follow‬‭treatment‬‭with‬‭fluorouracil.‬‭Clinical‬
‭consequences‬‭of‬‭sever‬‭myelosuppression‬‭include‬‭infections.‬‭Viral,‬‭bacterial,‬‭fungal‬‭and/or‬
‭parasitic‬ ‭infections,‬ ‭either‬ ‭localized‬ ‭or‬ ‭systemic,‬ ‭may‬ ‭be‬ ‭associated‬ ‭with‬ ‭the‬ ‭use‬ ‭of‬
‭fluorouracil‬ ‭alone‬ ‭or‬ ‭in‬ ‭combination‬ ‭with‬ ‭other‬ ‭immunosuppressive‬ ‭agents.‬ ‭These‬
‭infections may be mild, but can be severe and at times fatal.‬
‭Rarely,‬ ‭severe‬ ‭toxicity‬ ‭(e.g.,‬ ‭stomatitis,‬ ‭diarrhoea,‬ ‭neutropenia,‬ ‭and‬ ‭neurotoxicity)‬
‭associated‬ ‭with‬ ‭fluorouracil‬ ‭has‬ ‭been‬ ‭attributed‬ ‭to‬ ‭deficiency‬ ‭of‬ ‭dihydropyrimidine‬
‭dehydrogenase‬‭(DPD)‬‭activity.‬‭Fatal‬‭outcome‬‭has‬‭been‬‭reported‬‭in‬‭some‬‭cases.‬‭Absence‬‭of‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭this‬ ‭catabolic‬ ‭enzyme‬ ‭appears‬ ‭to‬ ‭result‬ ‭in‬ ‭prolonged‬ ‭clearance‬ ‭of‬ ‭fluorouracil.‬ ‭Special‬
‭attention‬ ‭should‬ ‭be‬ ‭given‬ ‭to‬ ‭DPD‬ ‭status‬ ‭when‬ ‭evaluating‬ ‭patients‬ ‭experiencing‬
‭fluorouracil-related toxicities.‬
‭Recommendations‬‭stated‬‭on‬‭the‬‭Summary‬‭of‬‭Product‬‭Characteristics‬‭(Technical‬‭Sheet)‬‭is‬
‭going to be followed in case of CT toxicity.‬
‭5.2.3 Monitoring of Adverse Events‬
‭-‬
‭Check for extravasation.‬
‭-‬
‭Before‬ ‭each‬ ‭course‬ ‭it‬ ‭is‬ ‭recommended‬ ‭checking:‬ ‭creatinine‬ ‭clearance,‬ ‭blood‬ ‭counts,‬
‭transaminases,‬ ‭bilirubin,‬ ‭albumin,‬‭blood‬‭glucose,‬‭serial‬‭urinalysis,‬‭blood‬‭urea‬‭nitrogen,‬
‭plasma creatinine, serum electrolytes.‬
‭Fluorouracil‬‭should‬‭be‬‭used‬‭with‬‭caution‬‭in‬‭elderly‬‭patients.‬‭Age‬‭70‬‭years‬‭or‬‭older‬‭and‬
‭the‬ ‭female‬ ‭gender‬ ‭are‬ ‭reported‬ ‭independent‬ ‭risk‬ ‭factors‬ ‭for‬ ‭severe‬ ‭toxicity‬ ‭from‬
‭fluorouracil‬ ‭based‬ ‭chemotherapy.‬ ‭Close‬ ‭monitoring‬ ‭for‬ ‭multiple‬ ‭organ‬ ‭toxicities‬ ‭and‬
‭vigorous supportive care of those with toxicity are necessary.‬
‭Renal‬ ‭function‬ ‭must‬ ‭be‬ ‭monitored‬ ‭before‬ ‭and‬ ‭after‬ ‭each‬ ‭course‬‭of‬‭therapy‬‭with‬‭STZ.‬
‭Serial‬‭urinalysis,‬‭blood‬‭urea‬‭nitrogen,‬‭plasma‬‭creatinine,‬‭serum‬‭electrolytes‬‭and‬‭creatinine‬
‭clearance‬ ‭should‬‭be‬‭obtained‬‭prior‬‭to,‬‭at‬‭least‬‭weekly‬‭during,‬‭and‬‭for‬‭four‬‭weeks‬‭after‬
‭drug‬‭administration.‬‭Serial‬‭urinalysis‬‭is‬‭particularly‬‭important‬‭for‬‭the‬‭early‬‭detection‬‭of‬
‭proteinuria‬ ‭and‬ ‭should‬ ‭be‬ ‭quantitated‬ ‭with‬ ‭a‬ ‭24‬ ‭hour‬ ‭collection‬ ‭when‬ ‭proteinuria‬ ‭is‬
‭detected.‬‭Mild‬‭proteinuria‬‭is‬‭one‬‭of‬‭the‬‭first‬‭signs‬‭of‬‭renal‬‭toxicity‬‭and‬‭may‬‭herald‬‭further‬
‭deterioration‬ ‭of‬ ‭renal‬ ‭function.‬ ‭Reduction‬ ‭of‬ ‭the‬ ‭dose‬ ‭of‬ ‭STZ‬ ‭or‬ ‭discontinuation‬ ‭of‬
‭treatment‬ ‭is‬‭suggested‬‭in‬‭the‬‭presence‬‭of‬‭significant‬‭renal‬‭toxicity.‬‭Adequate‬‭hydration‬
‭may‬‭help‬‭reduce‬‭the‬‭risk‬‭of‬‭nephrotoxicity‬‭to‬‭renal‬‭tubular‬‭epithelium‬‭by‬‭decreasing‬‭renal‬
‭and urinary concentration of the drug and its metabolites.‬
‭Fluorouracil‬ ‭is‬ ‭contraindicated‬ ‭in‬ ‭patients‬ ‭who‬ ‭are‬‭debilitated,‬‭who‬‭are‬‭suffering‬‭from‬
‭bone‬ ‭marrow‬ ‭depression‬ ‭following‬ ‭radiotherapy‬ ‭or‬ ‭therapy‬ ‭with‬ ‭other‬ ‭antineoplastic‬
‭agents,‬‭and‬‭in‬‭patients‬‭who‬‭are‬‭pregnant.‬‭Fluorouracil‬‭should‬‭not‬‭be‬‭readministered‬‭after‬
‭a‬‭documented‬‭cardiovascular‬‭reaction‬‭(arrhythmia,‬‭angina,‬‭ST‬‭segment‬‭changes)‬‭as‬‭there‬
‭is‬‭a‬‭risk‬‭of‬‭sudden‬‭death.‬‭Any‬‭form‬‭of‬‭therapy‬‭which‬‭adds‬‭to‬‭the‬‭stress‬‭of‬‭the‬‭patient,‬
‭interferes‬ ‭with‬ ‭nutritional‬ ‭uptake‬‭or‬‭depresses‬‭bone‬‭marrow‬‭function,‬‭will‬‭increase‬‭the‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭toxicity‬‭of‬‭fluorouracil.‬‭Fluorouracil‬‭should‬‭be‬‭used‬‭with‬‭caution‬‭in‬‭patients‬‭with‬‭reduced‬
‭renal or liver function or jaundice.‬
‭5.2.4 Adverse Events‬
‭-‬‭Nausea – try another 5-HT 3 -receptor blocker or add a prepitant.‬
‭-‬‭Renal impairment – dose reductions of STZ should be considered when creatinine‬
‭clearance is <60 ml/min and should not be given below 30 ml/min.‬
‭-‬‭Liver impairment – reduction of doses should be considered.‬
‭-‬‭Stomatitis – frequent mouth care.‬
‭-‬‭Photosensitivity – avoid direct sunlight.‬
‭Many‬‭patients‬‭treated‬‭with‬‭STZ‬‭have‬‭experienced‬‭renal‬‭toxicity,‬‭as‬‭evidenced‬‭by‬‭azotemia,‬
‭anuria,‬ ‭hypophosphatemia,‬ ‭glycosuria‬ ‭and‬ ‭renal‬ ‭tubular‬ ‭acidosis.‬ ‭Such‬ ‭toxicity‬ ‭is‬
‭dose-related‬ ‭and‬ ‭cumulative‬ ‭and‬ ‭may‬ ‭be‬ ‭severe‬ ‭or‬ ‭fatal.‬ ‭Use‬ ‭of‬ ‭STZ‬ ‭in‬‭patients‬‭with‬
‭preexisting‬ ‭renal‬ ‭disease‬ ‭requires‬ ‭a‬ ‭judgment‬ ‭by‬ ‭the‬ ‭physician‬ ‭of‬ ‭potential‬ ‭benefit‬ ‭as‬
‭opposed‬ ‭to‬ ‭the‬ ‭known‬ ‭risk‬ ‭of‬ ‭serious‬ ‭renal‬ ‭damage.‬ ‭This‬ ‭drug‬ ‭should‬ ‭not‬ ‭be‬ ‭used‬ ‭in‬
‭combination with or concomitantly with other potential nephrotoxins.‬
‭Most‬‭patients‬‭treated‬‭with‬‭STZ‬‭have‬‭experienced‬‭severe‬‭nausea‬‭and‬‭vomiting,‬‭occasionally‬
‭requiring‬‭discontinuation‬‭of‬‭drug‬‭therapy.‬‭Some‬‭patients‬‭experienced‬‭diarrhea.‬‭A‬‭number‬
‭of‬ ‭patients‬ ‭have‬ ‭experienced‬ ‭hepatic‬‭toxicity,‬‭as‬‭characterized‬‭by‬‭elevated‬‭liver‬‭enzyme‬
‭(SGOT‬ ‭and‬ ‭LDH)‬ ‭levels‬ ‭and‬ ‭hypoalbuminemia.‬ ‭Hematological‬ ‭toxicity‬ ‭has‬ ‭been‬ ‭rare,‬
‭most‬ ‭often‬ ‭involving‬ ‭mild‬‭decreases‬‭in‬‭hematocrit‬‭values.‬‭However,‬‭fatal‬‭hematological‬
‭toxicity with substantial reductions in leukocyte and platelet count has been observed.‬
‭Mild‬ ‭to‬ ‭moderate‬ ‭abnormalities‬ ‭of‬ ‭glucose‬ ‭tolerance‬ ‭have‬ ‭been‬ ‭noted‬ ‭in‬ ‭some‬‭patients‬
‭treated‬ ‭with‬ ‭STZ.‬ ‭These‬ ‭have‬ ‭generally‬ ‭been‬ ‭reversible,‬ ‭but‬ ‭insulin‬ ‭shock‬ ‭with‬
‭hypoglycemia‬‭has‬‭been‬‭observed.‬‭Two‬‭cases‬‭of‬‭nephrogenic‬‭diabetes‬‭insipidus‬‭following‬
‭therapy‬ ‭with‬ ‭STZ‬ ‭have‬ ‭been‬ ‭reported.‬ ‭One‬ ‭had‬ ‭spontaneous‬ ‭recovery‬ ‭and‬ ‭the‬ ‭second‬
‭responded‬‭to‬‭indomethacin.‬‭Spontaneous‬‭reports‬‭have‬‭been‬‭received‬‭of‬‭local‬‭inflammation‬
‭(i.e.,‬ ‭edema,‬ ‭erythema,‬ ‭burning,‬ ‭tenderness)‬ ‭following‬ ‭extravasation‬ ‭of‬ ‭the‬ ‭product.‬ ‭In‬
‭most cases, these events resolved the same day or within a few days.‬
‭For‬‭the‬‭full‬‭list‬‭of‬‭all‬‭side‬‭effects‬‭reported‬‭with‬‭STZ-5FU‬‭based‬‭regime,‬‭see‬‭the‬‭respective‬
‭Summary of Product Characteristics leaflet in the Investigator’s file.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭5.3‬
‭T‬‭REATMENT‬‭WITHDRAWAL AND END OF TREATMENT PERIOD‬
‭5.3.1‬‭Reasons for treatment discontinuation‬
‭Patients‬ ‭will‬ ‭discontinue‬ ‭treatment‬‭with‬‭STZ-5FU‬‭or‬‭everolimus‬‭if‬‭any‬‭of‬‭the‬‭following‬
‭situations occurs:‬
‭-‬
‭First or second disease progression of pNET respectively.‬
‭-‬
‭Unacceptable‬ ‭toxicity‬ ‭even‬ ‭with‬ ‭optimal‬ ‭supportive‬ ‭care,‬ ‭following‬ ‭investigator’s‬
‭judgement.‬
‭-‬
‭Patient withdraws her/his consent.‬
‭-‬
‭Patient dies.‬
‭5.3.2‬‭Discontinuation of treatment due to everolimus toxicity‬
‭Treatment with‬‭everolimus‬‭will be discontinued in‬‭the following cases:‬
‭-‬
‭Any grade 4 non haematological toxicity (see Table I)‬
‭-‬
‭Grade 3 thrombocytopenia after everolimus restart (see Table I)‬
‭-‬
‭Grade 4 thrombocytopenia (see Table I)‬
‭-‬
‭Recurrent grade 3 and 4 neutropenia, see Table I‬
‭-‬
‭Grade 4 febrile neutropenia (life-threatening for the patient).‬
‭-‬
‭Life-threatening, grade 4, non-infectious pneumonitis (see Table I).‬
‭-‬
‭Reactivation of hepatitis C  (see Table V)‬
‭-‬
‭Any‬‭toxicity‬‭that‬‭can‬‭not‬‭be‬‭reversed‬‭with‬‭a‬‭maximum‬‭of‬‭21‬‭days‬‭of‬‭discontinuation‬
‭with‬ ‭study‬ ‭treatment‬ ‭(28‬ ‭days‬ ‭in‬ ‭case‬ ‭of‬ ‭prophylactic‬ ‭treatment‬ ‭with‬ ‭antivirals‬‭for‬
‭HBV)‬ ‭without‬ ‭a‬ ‭justified‬ ‭reason‬ ‭(adverse‬ ‭event‬ ‭that‬ ‭allows‬ ‭restart‬ ‭after‬ ‭recovery,‬
‭urgent‬‭surgery,‬‭or‬‭toxicity‬‭that‬‭can‬‭be‬‭resolved‬‭with‬‭a‬‭restart‬‭at‬‭a‬‭lower‬‭dose)‬‭as‬‭per‬
‭investigator’s judgement.‬
‭In‬‭the‬‭event‬‭of‬‭discontinuation‬‭due‬‭to‬‭AEs‬‭or‬‭abnormal‬‭laboratory‬‭values‬‭,‬‭the‬‭patient‬‭will‬
‭be monitored weekly until the adverse event disappears or decreases to grade 1.‬
‭If‬‭the‬‭patient‬‭was‬‭receiving‬‭prophylactic‬‭antiviral‬‭treatment‬‭,‬‭this‬‭will‬‭be‬‭continued‬‭until‬‭at‬
‭least 4 weeks following the last administration of study drug.‬
‭5.3.3‬‭Discontinuation of treatment due to STZ-5FU toxicity‬
‭-‬
‭Renal impairment: STZ should not be given below 30 ml/min creatinine clearance.‬
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‭Treatment‬ ‭with‬ ‭STZ-5FU‬ ‭will‬ ‭be‬ ‭discontinued‬ ‭as‬ ‭per‬ ‭recommendations‬ ‭stated‬ ‭on‬ ‭the‬
‭Summary of Product Characteristics (Technical Sheet) and section 5.2 in this protocol.‬
‭6.‬
‭CONCOMITANT‬‭MEDICATION‬
‭6.1.‬ ‭TREATMENTS ALLOWED WITH EVEROLIMUS‬
‭In‬ ‭case‬ ‭of‬ ‭diarrhoea‬ ‭attributed‬ ‭to‬ ‭everolimus‬ ‭treatment,‬ ‭the‬ ‭patient‬ ‭can‬ ‭be‬ ‭treated‬ ‭with‬
‭loperamide.‬‭When‬‭required,‬‭other‬‭drugs‬‭may‬‭be‬‭used‬‭for‬‭diarrhoea,‬‭such‬‭as‬‭pancrealipase‬‭for‬
‭the‬‭treatment‬‭of‬‭steatorrhoea‬‭due‬‭to‬‭the‬‭use‬‭of‬‭somatostatin‬‭analogues,‬‭or‬‭cholestyramine‬‭for‬
‭the management of diarrhoea associated with short bowel syndrome.‬
‭In‬‭case‬‭of‬‭stomatitis/oral‬‭mucositis‬‭of‬‭grade‬‭1-2‬‭according‬‭to‬‭the‬‭CTCAE‬‭version‬‭4.0‬‭due‬‭to‬
‭everolimus‬ ‭(if‬‭the‬‭examination‬‭shows‬‭mouth‬‭ulcers‬‭and‬‭not‬‭a‬‭general‬‭inflammation‬‭of‬‭the‬
‭mouth)‬ ‭local‬ ‭support‬ ‭care‬ ‭should‬ ‭be‬ ‭given‬ ‭with‬ ‭mouth‬ ‭washes‬ ‭or‬ ‭rinses‬ ‭with‬ ‭salt‬ ‭water‬
‭(0.9%)‬‭several‬‭times‬‭a‬‭day‬‭until‬‭they‬‭subside;‬‭avoid‬‭those‬‭containing‬‭alcohol‬‭or‬‭peroxides,‬
‭iodine‬‭or‬‭thyme‬‭derivatives,‬‭since‬‭they‬‭can‬‭worsen‬‭mouth‬‭ulcers.‬‭For‬‭more‬‭severe‬‭toxicities‬
‭(grade‬‭2‬‭when‬‭the‬‭patients‬‭experience‬‭pain‬‭but‬‭can‬‭maintain‬‭adequate‬‭intake,‬‭or‬‭grade‬‭3‬‭when‬
‭the‬ ‭patients‬ ‭cannot‬ ‭maintain‬ ‭adequate‬ ‭intake),‬ ‭the‬ ‭recommended‬ ‭treatment‬ ‭is‬ ‭topical‬
‭analgaesics‬ ‭(i.e.,‬ ‭local‬ ‭anaesthetics,‬ ‭such‬ ‭as‬ ‭benzocaine,‬ ‭butyl‬ ‭aminiobenzoate,‬ ‭tetracaine‬
‭hydrochloride,‬ ‭menthol‬ ‭or‬ ‭phenol).‬ ‭The‬ ‭use‬ ‭of‬ ‭highly‬ ‭active‬ ‭topical‬ ‭steroids‬‭such‬‭as‬‭oral‬
‭triamcinolone‬‭paste‬‭at‬‭0.1%‬‭(Kenalog‬‭in‬‭Orabase)‬‭is‬‭permitted.‬‭Use‬‭antifungal‬‭agents‬‭only‬
‭after fungal infection has been diagnosed.‬
‭In‬‭case‬‭of‬‭hyperlipidaemia‬‭the‬‭patient‬‭condition‬‭will‬‭be‬‭considered‬‭before‬‭starting‬‭treatment,‬
‭as‬‭well‬‭as‬‭his‬‭dietary‬‭habits.‬‭Blood‬‭tests‬‭for‬‭monitoring‬‭hyperlipidaemia‬‭should‬‭be‬‭performed‬
‭under‬‭fasting‬‭conditions.‬‭Grade‬‭2‬‭hypercholesterolaemia‬‭(>300‬‭mg/dL‬‭or‬‭7.75‬‭mmol/L)‬‭or‬
‭grade‬‭2‬‭hypertriglyceridaemia‬‭(>2.5‬‭x‬‭upper‬‭limit‬‭of‬‭normal)‬‭should‬‭be‬‭treated‬‭with‬‭a‬‭statin‬
‭(HMG-CoA‬ ‭reductase‬ ‭inhibitor)‬‭or‬‭with‬‭an‬‭appropriate‬‭lipid-lowering‬‭drug,‬‭in‬‭addition‬‭to‬
‭taking‬ ‭care‬ ‭of‬ ‭diet.‬ ‭The‬ ‭patients‬ ‭should‬ ‭be‬ ‭monitored‬ ‭clinically‬ ‭and‬ ‭through‬ ‭serum‬
‭biochemistry‬ ‭to‬ ‭monitor‬ ‭the‬ ‭development‬ ‭of‬ ‭rhabdomyolysis‬ ‭and‬ ‭other‬ ‭adverse‬ ‭events‬
‭described in the package leaflet of the HMG-CoA reductase inhibitors.‬
‭Note:‬‭Concomitant‬‭therapy‬‭with‬‭fibrates‬‭and‬‭a‬‭HMG-CoA‬‭reductase‬‭inhibitor‬‭is‬‭associated‬
‭with‬ ‭an‬ ‭increased‬ ‭risk‬ ‭of‬ ‭uncommon‬ ‭but‬ ‭severe‬ ‭musculoskeletal‬ ‭toxicity,‬ ‭evidenced‬ ‭as‬
‭rhabdomyolysis,‬‭marked‬‭increase‬‭in‬‭the‬‭levels‬‭of‬‭creatine‬‭kinase‬‭(CPK)‬‭and‬‭myoglobinuria,‬
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‭acute‬ ‭renal‬ ‭failure‬ ‭and‬ ‭sometimes‬ ‭death.‬ ‭The‬ ‭risk/benefit‬ ‭of‬ ‭using‬‭this‬‭therapy‬‭should‬‭be‬
‭evaluated individually based on the risk of cardiovascular complications of hyperlipidaemia.‬
‭Patients‬‭taking‬‭concomitant‬‭angiotensin-converting‬‭enzyme‬‭(ACE)‬‭inhibitor‬‭therapy‬‭may‬‭be‬
‭at‬ ‭increased‬ ‭risk‬ ‭for‬ ‭angioedema‬ ‭(e.g.‬ ‭swelling‬ ‭of‬‭the‬‭airways‬‭or‬‭tongue,‬‭with‬‭or‬‭without‬
‭respiratory impairment).‬
‭Prophylaxis‬‭for‬‭PJP‬‭should‬‭be‬‭considered‬‭when‬‭concomitant‬‭use‬‭of‬‭corticosteroids‬‭or‬‭other‬
‭immunosuppressive agents are required.‬
‭6.2‬
‭TREATMENTS NOT ALLOWED WITH EVEROLIMUS‬
‭Patients‬ ‭should‬ ‭be‬ ‭warned‬ ‭to‬ ‭avoid‬ ‭bitter‬ ‭oranges,‬ ‭grapefruit‬ ‭and‬ ‭their‬ ‭juices,‬ ‭since‬ ‭they‬
‭affect‬‭the‬‭activity‬‭of‬‭the‬‭P450‬‭cytochrome‬‭and‬‭Pgp;‬‭preparations‬‭containing‬‭St.‬‭John’s‬‭wort‬
‭should not be used.‬
‭Use‬‭of‬‭live‬‭vaccines‬‭should‬‭be‬‭avoided‬‭during‬‭treatment‬‭with‬‭everolimus,‬‭since‬‭it‬‭may‬‭affect‬
‭the‬‭response‬‭to‬‭vaccines‬‭and‬‭vaccination‬‭can‬‭be‬‭less‬‭effective.‬‭Examples‬‭of‬‭live‬‭vaccines‬‭are:‬
‭intranasal‬ ‭influenza,‬ ‭mumps,‬ ‭rubella,‬‭oral‬‭polio,‬‭BCG,‬‭yellow‬‭fever,‬‭varicella,‬‭and‬‭TY21a‬
‭thyphoid vaccines.‬
‭Agents that may increase everolimus blood concentrations‬
‭Concurrent‬‭treatment‬‭with‬‭strong‬‭CYP3A4‬‭inhibitors‬‭should‬‭be‬‭avoided‬‭(including‬‭but‬‭not‬
‭limited‬‭to‬‭clarithromycin‬‭and‬‭telythromycin;‬‭see‬‭table‬‭in‬‭next‬‭section‬‭6.3).‬‭Antifungal‬‭agents‬
‭should‬ ‭not‬ ‭be‬ ‭used‬ ‭without‬ ‭a‬ ‭diagnosis‬ ‭of‬ ‭fungal‬ ‭infection.‬ ‭In‬ ‭particular,‬ ‭systemic‬
‭antimycotic‬ ‭agents‬ ‭based‬ ‭on‬ ‭imidazole‬ ‭(including‬ ‭but‬ ‭not‬ ‭limited‬ ‭to‬ ‭ketoconazole,‬
‭fluconazole,‬‭itraconazole)‬‭should‬‭be‬‭avoided‬‭in‬‭all‬‭patients‬‭due‬‭to‬‭their‬‭strong‬‭inhibition‬‭of‬
‭the‬ ‭everolimus‬ ‭metabolism,‬ ‭which‬ ‭involves‬ ‭a‬ ‭higher‬ ‭exposure‬ ‭to‬ ‭everolimus.‬ ‭Therefore,‬
‭topical‬ ‭antimycotic‬ ‭agents‬ ‭are‬ ‭preferred‬ ‭if‬ ‭a‬ ‭fungal‬ ‭infection‬ ‭is‬ ‭diagnosed.‬ ‭Furthermore,‬
‭antiviral agents, such as acyclovir, should be avoided, unless a viral infection is diagnosed.‬
‭Concomitant‬ ‭treatment‬ ‭with‬ ‭moderate‬ ‭inhibitors‬ ‭of‬ ‭CYP3A4‬ ‭including‬ ‭but‬ ‭not‬ ‭limited‬‭to‬
‭erythromycin,‬‭verapamil,‬‭cyclosporin,‬‭fluconazole,‬‭diltiazem,‬‭amprenavir,‬‭fosamprenavir,‬‭or‬
‭aprepitant)‬ ‭and‬ ‭PgP‬ ‭inhibitors‬ ‭requires‬ ‭caution.‬ ‭Reduce‬ ‭the‬ ‭everolimus‬ ‭dose‬ ‭if‬
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‭coadministered‬ ‭with‬ ‭moderate‬ ‭CYP3A4/PgP‬ ‭inhibitors.‬ ‭Everolimus‬ ‭can‬ ‭affect‬ ‭the‬
‭bioavailability‬‭of‬‭drugs‬‭administered‬‭concomitantly‬‭and‬‭substrates‬‭of‬‭CYP34A‬‭and/or‬‭Pgp.‬
‭Should‬‭the‬‭patient‬‭require‬‭moderate‬‭CYP3A4/PgP‬‭inhibitors‬‭(e.g.‬‭erythromycin,‬‭verapamil‬‭or‬
‭oral cyclosporine etc.), reducing the dose to 5 mg should be considered.‬
‭In‬ ‭patients‬ ‭receiving‬ ‭a‬ ‭CYP3A‬ ‭inhibitor,‬ ‭a‬ ‭low‬ ‭starting‬ ‭dose‬ ‭of‬ ‭5‬ ‭mg/day‬ ‭of‬ ‭everolimus‬
‭should‬‭be‬‭considered,‬‭and‬‭if‬‭it‬‭is‬‭well‬‭tolerated‬‭at‬‭two‬‭weeks,‬‭the‬‭dose‬‭of‬‭everolimus‬‭may‬‭be‬
‭increased to 10 mg/day.‬
‭Agents that may decrease everolimus blood concentrations‬
‭Avoid‬ ‭the‬ ‭use‬ ‭of‬ ‭potent‬ ‭CYP3A4‬ ‭inducers‬‭.‬ ‭Concomitant‬ ‭use‬ ‭of‬ ‭potent‬ ‭CYP3A4‬ ‭or‬ ‭PgP‬
‭inducers‬ ‭such‬ ‭as‬ ‭rifampicin‬ ‭and‬ ‭ririfabutin,‬ ‭carbamazepine,‬ ‭phenobarbital‬ ‭or‬ ‭phenytoin‬
‭should‬‭be‬‭avoided,‬‭unless‬‭the‬‭use‬‭of‬‭the‬‭drug‬‭is‬‭essential‬‭and‬‭then,‬‭it‬‭may‬‭be‬‭necessary‬‭to‬
‭adjuste‬‭the‬‭dose.‬‭If‬‭the‬‭patient‬‭requires‬‭co-administration‬‭of‬‭potent‬‭CYP3A4‬‭inducers‬‭(i.e.,‬
‭phenytoin,‬ ‭carbamazepine,‬ ‭rifampin,‬ ‭rifabutine,‬ ‭phenobarbital,‬ ‭St.‬ ‭John’s‬ ‭wort),‬ ‭a‬ ‭dose‬
‭increase‬‭of‬‭everolimus‬‭should‬‭be‬‭considered‬‭of‬‭up‬‭to‬‭double‬‭the‬‭daily‬‭dose‬‭or‬‭a‬‭5‬‭mg‬‭increase‬
‭of current dose.‬
‭No‬‭dose‬‭changes‬‭are‬‭required‬‭in‬‭patients‬‭receiving‬‭a‬‭CYP3A‬‭substrate.‬‭If‬‭everolimus‬‭is‬‭taken‬
‭with‬‭orally‬‭administered‬‭drugs‬‭with‬‭a‬‭narrow‬‭therapeutic‬‭index‬‭which‬‭are‬‭CYP3A‬‭substrates‬
‭however, then patients should be monitored accurately for toxicity.‬
‭6.3‬
‭DRUG‬
‭INTERACTIONS‬
‭CLINICALLY‬
‭SIGNIFICANT:‬
‭SUBSTRATES OF CYP3A ISOENZYME/P‬‭G‬‭P.‬
‭Investigator‬‭will‬‭instruct‬‭the‬‭patient‬‭to‬‭notify‬‭the‬‭intake‬‭of‬‭any‬‭new‬‭medicine‬‭he/she‬‭takes‬
‭after the start with‬‭everolimus‬‭.‬
‭Avoid‬‭the‬‭use‬‭of‬‭potent‬‭CYP3A4‬‭inducers.‬‭If‬‭the‬‭patient‬‭requires‬‭co-administration‬‭of‬‭potent‬
‭CYP3A4‬ ‭inducers‬ ‭(i.e.,‬ ‭phenytoin,‬ ‭carbamazepine,‬ ‭rifampin,‬ ‭rifabutine,‬ ‭phenobarbital,‬‭St.‬
‭John’s‬‭wort),‬‭a‬‭dose‬‭increase‬‭of‬‭everolimus‬‭should‬‭be‬‭considered‬‭of‬‭up‬‭to‬‭double‬‭the‬‭daily‬
‭dose or a 5 mg increase of current dose.‬
‭Enzyme‬‭induction‬‭usually‬‭occurs‬‭at‬‭7-10‬‭days,‬‭so‬‭the‬‭dose‬‭of‬‭everolimus‬‭should‬‭be‬‭increased‬
‭by‬‭one‬‭dose‬‭level‬‭7‬‭days‬‭after‬‭starting‬‭treatment‬‭with‬‭inducers.‬‭If‬‭there‬‭are‬‭no‬‭safety‬‭concerns‬
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‭in‬‭the‬‭next‬‭7‬‭days,‬‭before‬‭starting‬‭treatment‬‭with‬‭potent‬‭CYP3A4‬‭inducers,‬‭the‬‭dose‬‭may‬‭be‬
‭increased up to a maximum of a dose twice a day.‬
‭This‬‭dose‬‭adjustment‬‭of‬‭everolimus‬‭intends‬‭to‬‭reach‬‭an‬‭AUC‬‭similar‬‭to‬‭the‬‭range‬‭observed‬
‭without‬‭inducers.‬‭However,‬‭no‬‭clinical‬‭data‬‭are‬‭available‬‭for‬‭this‬‭dose‬‭adjustment‬‭in‬‭patients‬
‭receiving‬‭potent‬‭CYP3A4‬‭inducers.‬‭If‬‭treatment‬‭with‬‭potent‬‭inducers‬‭is‬‭removed,‬‭the‬‭dose‬‭of‬
‭everolimus used before starting treatment with potent CYP3A4/Pgp should be restored.‬
‭Summary‬ ‭of‬ ‭inhibitors‬ ‭and‬ ‭inducers‬ ‭of‬ ‭CYP3A4/PgP‬ ‭as‬ ‭of‬ ‭Summary‬ ‭of‬ ‭Product‬
‭Characteristics January 2014‬
‭Table 2 Effects of other active substances on everolimus‬
‭ACTIVE SUBSTANCE BY INTERACTION‬
‭RECOMMENDATIONS‬
‭CONCERNING‬
‭CO-ADMINISTRATION‬
‭Potent‬‭CYP3A4/PgP inhibitors‬
‭Ketoconazole‬
‭Concomitant‬ ‭treatment‬ ‭of‬‭everolimus‬‭and‬‭potent‬‭inhibitors‬
‭is not recommended.‬
‭Itraconazole, posaconazole, voriconazole‬
‭Telithromycin,‬ ‭clarithromycin,‬ ‭troleandamycin,‬
‭cobicistat, conivaptan,‬
‭Nefazodone‬
‭Ritonavir,‬ ‭,‬ ‭saquinavir,‬ ‭indinavir,‬ ‭nelfinavir,‬
‭tripanavir‬‭,‬
‭telaprevir,‬
‭lopinavir,‬ ‭boceprevir,‬
‭elvitegravir‬
‭Moderate‬‭CYP3A4/PgP inhibitors‬
‭Erythromycin,‬
‭aprepitant,‬
‭casopitant,‬
‭cimetidine, tofisopam‬
‭Use‬ ‭caution‬ ‭when‬ ‭co-administration‬ ‭of‬ ‭moderate‬‭CYP3A4‬
‭inhibitors‬ ‭or‬ ‭PgP‬ ‭inhibitors‬ ‭cannot‬ ‭be‬ ‭avoided.‬ ‭If‬ ‭patients‬
‭require‬ ‭co-administration‬ ‭of‬ ‭a‬ ‭moderate‬ ‭CYP3A4‬ ‭or‬ ‭PgP‬
‭inhibitor,‬‭dose‬‭reduction‬‭to‬‭5‬‭mg‬‭daily‬‭or‬‭2.5‬‭mg‬‭daily‬‭may‬
‭be‬‭considered.‬‭However,‬‭there‬‭are‬‭no‬‭clinical‬‭data‬‭with‬‭this‬
‭dose‬ ‭adjustment.‬ ‭Due‬ ‭to‬ ‭between‬ ‭subject‬ ‭variability‬ ‭the‬
‭recommended‬ ‭dose‬ ‭adjustments‬ ‭may‬ ‭not‬ ‭be‬ ‭optimal‬ ‭in‬ ‭all‬
‭individuals,‬ ‭therefore‬ ‭close‬ ‭monitoring‬ ‭of‬ ‭side‬ ‭effects‬ ‭is‬
‭recommended.‬ ‭If‬ ‭the‬ ‭moderate‬ ‭inhibitor‬ ‭is‬ ‭discontinued,‬
‭consider‬ ‭a‬ ‭washout‬ ‭period‬ ‭of‬ ‭at‬ ‭least‬ ‭2‬‭to‬‭3‬‭days‬‭(average‬
‭elimination‬ ‭time‬ ‭for‬ ‭most‬ ‭commonly‬ ‭used‬ ‭moderate‬
‭inhibitors)‬‭before‬‭the‬‭everolimus‬‭dose‬‭is‬‭returned‬‭to‬‭the‬‭dose‬
‭used prior to initiation of the co-administration.‬
‭Imatinib, Verapamil , Ciclosporin‬
‭Fluconazole,‬
‭Diltiazem,‬
‭Dronedarone,‬
‭Amprenavir,‬
‭fosamprenavir,‬
‭atazanavir,‬
‭darunavir‬
‭Grapefruit‬ ‭juice‬ ‭or‬ ‭other‬
‭food‬
‭affecting‬
‭CYP3A4/PgP‬
‭Schisandra sphenanthrea‬
‭Combination should be avoided.‬
‭Potent‬‭CYP3A4 inducers‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Rifampicin‬
‭Carbamazepine,‬ ‭Phenobarbital,‬ ‭Phenytoin,‬
‭Avasimibe, Mitotane, Rifabutin‬
‭Avoid‬ ‭the‬ ‭use‬ ‭of‬ ‭concomitant‬‭potent‬‭CYP3A4‬‭inducers.‬‭If‬
‭patients‬ ‭require‬ ‭co-administration‬ ‭of‬ ‭a‬ ‭potent‬ ‭CYP3A4‬
‭inducer,‬ ‭an‬ ‭everolimus‬ ‭dose‬ ‭increase‬‭from‬‭10‬‭mg‬‭daily‬‭up‬
‭to‬‭20‬‭mg‬‭daily‬‭should‬‭be‬‭considered‬‭using‬‭5‬‭mg‬‭increments‬
‭or‬ ‭less‬ ‭applied‬ ‭on‬ ‭Day‬ ‭4‬ ‭and‬ ‭8‬ ‭following‬ ‭start‬ ‭of‬ ‭the‬
‭inducer.‬ ‭This‬ ‭dose‬ ‭of‬ ‭everolimus‬ ‭is‬‭predicted‬‭to‬‭adjust‬‭the‬
‭AUC‬ ‭to‬ ‭the‬ ‭range‬ ‭observed‬ ‭without‬ ‭inducers.‬ ‭However,‬
‭there‬ ‭are‬ ‭no‬ ‭clinical‬ ‭data‬ ‭with‬ ‭this‬ ‭dose‬ ‭adjustment.‬ ‭If‬
‭treatment‬ ‭with‬ ‭the‬ ‭inducer‬ ‭is‬ ‭discontinued,‬ ‭consider‬ ‭a‬
‭washout‬ ‭period‬‭of‬‭at‬‭least‬‭3‬‭to‬‭5‬‭days‬‭(reasonable‬‭time‬‭for‬
‭significant‬ ‭enzyme‬ ‭de-induction),‬ ‭before‬ ‭the‬ ‭everolimus‬
‭dose‬ ‭is‬ ‭returned‬ ‭to‬ ‭the‬ ‭dose‬ ‭used‬ ‭prior‬ ‭to‬ ‭initiation‬‭of‬‭the‬
‭co-administration.‬
‭St John’s Wort (Hypericum perforatum)‬
‭Preparations‬ ‭containing‬ ‭St‬ ‭John’s‬ ‭Wort‬ ‭should‬‭not‬‭be‬‭used‬
‭during treatment with everolimus‬
‭Moderate‬‭CYP3A4 inducers‬
‭Bosentan,‬
‭efavirenz,‬
‭etravine,‬
‭genistein,‬
‭modafinil,‬
‭nafcilin,‬
‭ritonavir,‬
‭[talviradine],‬
‭thioridazine, tiprnavir‬
‭Weak CYP3A4 inducers‬
‭Amprenavir,‬‭aprepitant,‬‭amodafinil‬‭(R-amodafinil),‬‭bexarotene,‬‭clobazam,‬‭danshen,‬‭dexamethasone,‬‭Echinacea,‬
‭garlic‬ ‭(allium‬ ‭sativum),‬ ‭gingko‬ ‭(gingko‬ ‭biloba),‬ ‭glycyrrhizin,‬ ‭methylprednisolone,‬‭nevirapine,‬‭oxcarbazepine,‬
‭pioglitazone,‬ ‭prednisone,‬ ‭[pleconaril],‬ ‭primidone,‬ ‭raltegravir,‬ ‭rufinamide,‬ ‭sorafenib,‬ ‭telaprevir,‬ ‭terbinafine,‬
‭topiramate, [troglitazone], vinblastine.‬
‭Investigator‬‭will‬‭instruct‬‭the‬‭patient‬‭to‬‭notify‬‭the‬‭intake‬‭of‬‭any‬‭new‬‭medicine‬‭he/she‬‭takes‬
‭after the start with‬‭everolimus‬‭.‬
‭All‬ ‭treatments,‬ ‭including‬ ‭non-drug‬ ‭therapies‬ ‭(i.e.‬ ‭herbal‬ ‭therapy‬ ‭and‬ ‭blood‬ ‭transfusions)‬
‭administered‬‭after‬‭the‬‭patient‬‭starts‬‭with‬‭study‬‭treatment‬‭will‬‭be‬‭reported‬‭in‬‭the‬‭CRF‬‭in‬‭the‬
‭relevant section.‬
‭7‬‭.‬
‭TRIAL DEVELOPMENT‬
‭7.1‬
‭STUDY PERIODS‬
‭The study will have an approximate duration of‬‭6‬‭years,‬‭distributed as follows:‬
‭●‬
‭A screening of up to‬‭28 days‬‭.‬
‭●‬
‭Recruitment period estimated in 30 months.‬
‭●‬
‭Treatment‬‭period‬‭finishes‬‭upon‬‭second‬‭progression‬‭unacceptable‬‭toxicity‬‭or‬‭the‬‭end‬
‭of the study.‬
‭●‬
‭Safety‬‭follow-up‬‭at‬‭least‬‭30‬‭days‬‭after‬‭the‬‭intake‬‭of‬‭the‬‭last‬‭dose‬‭of‬‭study‬‭treatment‬‭.‬
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‭This information should be included in the first survival follow-up visit if any.‬
‭●‬
‭Survival‬‭follow-up‬‭period:‬‭All‬‭patients‬‭will‬‭be‬‭followed-up‬‭for‬‭survival‬‭purposes,‬‭up‬
‭to‬ ‭patient’s‬ ‭death‬ ‭140±8‬ ‭weeks‬ ‭+‬ ‭30‬ ‭days,‬‭or‬‭study‬‭end‬‭(this‬‭is,‬‭last‬‭visit‬‭of‬‭last‬‭patient‬
‭included), whatever comes first.‬
‭When‬‭treatment‬‭follow‬‭up‬‭period‬‭of‬ ‭14‬‭months‬‭(60‬‭weeks)‬‭is‬‭completed‬‭for‬‭the‬‭last‬‭patient‬
‭included‬‭there‬‭will‬‭be‬‭enough‬‭data‬‭to‬‭analyze‬‭the‬‭primary‬‭study‬‭variable,‬‭so‬‭the‬‭statistical‬
‭analysis and publication of the first data will take place.‬
‭7.2‬
‭STUDY ASSESSMENTS‬
‭7.2.1‬‭Physical examination and vital signs‬
‭Physical‬ ‭examination‬ ‭will‬ ‭include‬ ‭examination‬ ‭of‬ ‭the‬ ‭whole‬ ‭body‬ ‭(general‬ ‭appearance,‬
‭skin,‬ ‭neck,‬ ‭thyroids,‬ ‭eyes,‬ ‭ears,‬‭nose,‬‭throat,‬‭lungs,‬‭heart,‬‭abdomen,‬‭back,‬‭lymph‬‭nodes,‬
‭extremities and basic nervous system).‬
‭The‬‭following‬‭vital‬‭signs‬‭should‬‭be‬‭measured:‬‭pulse,‬‭respiratory‬‭rate,‬‭blood‬‭pressure‬‭and‬
‭height only at the screening visit.‬
‭Other‬ ‭relevant‬ ‭vital‬ ‭signs‬ ‭should‬ ‭be‬ ‭measured‬ ‭at‬ ‭the‬ ‭investigator’s‬ ‭discretion‬ ‭when‬ ‭an‬
‭adverse event occurs.‬
‭7.2.2‬‭ECOG Performance status‬
‭Initially‬ ‭at‬ ‭screening,‬ ‭and‬ ‭then‬ ‭repeatedly‬ ‭at‬ ‭every‬ ‭cycle‬ ‭before‬ ‭intake‬ ‭of‬ ‭first‬ ‭dose,‬
‭performance status will be recorded according to ECOG scale (Annex I to the protocol).‬
‭7.2.3‬‭Chest X-ray and pulmonary function tests‬
‭A‬‭chest‬‭X-ray‬‭(and/or‬‭if‬‭the‬‭disease‬‭is‬‭present‬‭in‬‭the‬‭chest,‬‭a‬‭chest‬‭CT)‬‭will‬‭be‬‭performed‬
‭in‬‭all‬‭patients.‬‭During‬‭treatment‬‭period,‬‭chest‬‭X-ray‬‭will‬‭be‬‭performed‬‭every‬‭12‬‭weeks;‬‭if‬
‭any‬ ‭lesion‬ ‭occurs,‬ ‭then‬ ‭a‬ ‭chest‬ ‭CT‬ ‭scan‬ ‭will‬ ‭be‬ ‭performed‬ ‭for‬ ‭tumour‬ ‭assessment‬ ‭(a‬
‭radiography will be no longer necessary).‬
‭If‬ ‭non-infectious‬ ‭pneumonitis‬ ‭is‬ ‭suspected,‬ ‭chest‬ ‭X-ray‬ ‭will‬ ‭be‬ ‭repeated‬ ‭as‬ ‭considered‬
‭appropriate by the investigator.‬
‭Pulmonary‬‭function‬‭tests‬‭(spirometry,‬‭DLCO‬‭and‬‭oxygen‬‭saturation‬‭at‬‭rest‬‭in‬‭a‬‭ventilated‬
‭room‬‭(room‬‭air‬‭O‬‭2‬ ‭saturation‬‭at‬‭rest)‬‭will‬‭be‬‭performed‬‭if‬‭clinically‬‭necessary‬‭in‬‭case‬‭of‬
‭evidence of non-infectious pneumonitis.‬
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‭If‬ ‭non-infectious‬ ‭pneumonitis‬ ‭is‬ ‭diagnosed,‬ ‭pneumologist‬ ‭consultation‬ ‭should‬ ‭be‬
‭considered.‬ ‭When‬ ‭necessary‬ ‭to‬ ‭ensure‬ ‭patient‬ ‭care,‬ ‭a‬ ‭bronchoscopy‬ ‭with‬ ‭biopsy‬ ‭and/or‬
‭bronchoalveolar lavage (BAL) will be performed.‬
‭Information‬‭on‬‭Pulmonary‬‭function‬‭tests‬‭should‬‭be‬‭collected‬‭if‬‭clinically‬‭indicated‬‭when‬‭an‬
‭AE or SAE occurs.‬
‭7.2.4‬‭Electrocardiogram (ECG)‬
‭During‬‭the‬‭screening‬‭period,‬‭a‬‭12-lead‬‭ECG‬‭will‬‭be‬‭performed.‬‭Records‬‭should‬‭be‬‭dated‬
‭and signed by the investigator (or designee) and kept with the source documents of patient.‬
‭An‬ ‭ECG‬ ‭can‬ ‭be‬ ‭repeated‬ ‭at‬ ‭the‬ ‭investigator’s‬ ‭discretion‬ ‭at‬ ‭any‬ ‭time‬ ‭of‬ ‭the‬ ‭study,‬ ‭as‬
‭clinically‬ ‭indicated;‬ ‭clinically‬ ‭significant‬ ‭findings‬ ‭will‬ ‭be‬ ‭noted‬ ‭in‬ ‭the‬ ‭Adverse‬ ‭Event‬
‭section of the CRF.‬
‭7.2.5‬‭Radiological tumor assessment‬
‭Tumour‬ ‭lesions‬‭should‬‭be‬‭measured‬‭following‬‭RECIST‬‭criteria‬‭version‬‭1.0‬‭at‬‭each‬‭site.‬
‭Main study endpoint will be based on local assessment (section 7.2.5.1).‬
‭ENETS‬ ‭Score‬ ‭will‬ ‭be‬ ‭assessed‬ ‭retrospectively‬ ‭by‬ ‭an‬ ‭ENETS‬ ‭Central‬ ‭Radiological‬
‭Commission‬ ‭in‬ ‭Paris‬ ‭(section‬ ‭7.2.5.2).‬ ‭A‬ ‭copy‬ ‭of‬ ‭the‬ ‭radiological‬ ‭assessments‬ ‭must‬‭be‬
‭sent/provided‬ ‭by‬ ‭the‬ ‭site‬ ‭to‬ ‭the‬ ‭ENETS‬ ‭Central‬ ‭Radiological‬ ‭Commission‬ ‭for‬ ‭a‬
‭retrospective‬ ‭centralized‬ ‭assessment‬ ‭(see‬ ‭7.2.5.2)‬ ‭every‬ ‭3‬ ‭months‬ ‭or‬‭as‬‭soon‬‭as‬‭the‬‭last‬
‭patient‬ ‭at‬ ‭site‬ ‭has‬ ‭been‬ ‭discontinued‬ ‭or‬ ‭completed‬ ‭the‬ ‭study.‬ ‭Assessments‬ ‭will‬ ‭be‬ ‭sent‬
‭electronically.‬
‭7.2.5.1 Local assessment following RECIST criteria version 1.0‬
‭Tumour‬‭lesions‬‭should‬‭be‬‭measured‬‭following‬‭RECIST‬‭criteria‬‭version‬‭1.0‬‭before‬‭the‬‭start‬
‭of each treatment‬‭and every 12 weeks, procedures‬
‭All‬‭assessments‬‭performed‬‭during‬‭the‬‭study‬‭(at‬‭baseline‬‭and‬‭every‬‭12‬‭weeks‬‭)‬‭should‬‭be‬
‭done using the‬‭same method and the same technique‬‭.‬
‭Assessments‬‭and‬‭measurements‬‭should‬‭be‬‭performed‬‭by‬‭the‬‭same‬‭radiologist‬‭or‬‭physician‬
‭throughout‬ ‭the‬ ‭study.‬ ‭Therefore,‬ ‭each‬ ‭site‬ ‭must‬‭designate‬‭a‬‭radiologist‬‭or‬‭other‬‭medical‬
‭staff‬ ‭responsible‬ ‭for‬ ‭the‬ ‭interpretation‬ ‭of‬ ‭the‬ ‭radiographs‬ ‭and‬ ‭triphasic‬ ‭CT‬ ‭scans‬ ‭or‬
‭multiple-phase MRI.‬
‭All‬ ‭patients‬ ‭discontinuing‬ ‭the‬ ‭treatment‬ ‭due‬ ‭to‬ ‭disease‬ ‭progression,‬ ‭should‬ ‭have‬ ‭a‬
‭documented diagnosis. Date of progression must be recorded on the CRF.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭7.2.5.2 Retrospective centralised assessment of ENETS Score‬
‭An‬‭ENETS‬‭Central‬‭Radiological‬‭Commission‬‭will‬‭be‬‭set‬‭up‬‭for‬‭a‬‭centralized‬‭evaluation‬
‭of‬ ‭CTs.‬ ‭The‬ ‭radiological‬ ‭commission‬ ‭will‬ ‭assess‬ ‭second‬ ‭progression‬ ‭free‬ ‭survival‬
‭according‬‭to‬‭the‬‭four‬‭radiology‬‭criteria‬‭for‬‭response‬‭evaluation‬‭(RECIST‬‭versions‬‭1.0‬‭and‬
‭1.1, and Composite Scores according to RECIST 1.0 and to RECIST 1.1) here described:‬
‭1.      RECIST version 1.0.‬
‭See protocol Annex III.‬
‭2.‬
‭RECIST version 1.1.‬
‭See protocol Annex III.‬
‭3&4. ENETS Score‬
‭Tumour‬ ‭response‬ ‭following‬ ‭Composite‬ ‭ENETS‬ ‭Score‬ ‭will‬ ‭be‬ ‭assessed‬ ‭following‬ ‭the‬
‭modified criteria of ENETS (based on Haesun Choi criteria), as defined on the next table:‬
‭Response‬
‭Definition‬
‭CR*‬
‭- Disappearance of all lesions‬
‭- No new lesions‬
‭PR*‬
‭- A decrease in‬‭size of 30 %‬
‭or a decrease in tumour‬‭density (HU) **‬‭on CT‬
‭- No new lesions‬
‭- No obvious progression of non-measurable disease‬
‭SD*‬
‭- Does not meet the criteria for CR, PR, or PD‬
‭PD‬
‭- An increase in tumour‬‭size of 20%‬‭and does not meet‬
‭criteria of PR by tumour density (HU) on CT‬
‭- New lesions‬
‭*‬ ‭Without‬ ‭symptomatic‬ ‭deterioration‬ ‭of‬ ‭general‬ ‭condition‬ ‭according‬ ‭to‬ ‭WHO‬ ‭scale‬ ‭or‬
‭ECOG (modified ENETS criteria).‬
‭**‬‭A‬‭percentage‬‭of‬‭density‬‭decrease‬‭will‬‭be‬‭defined‬‭for‬‭the‬‭analysis,‬‭based‬‭on‬‭the‬‭results‬‭of‬
‭the‬‭on-going‬‭validation‬‭studies‬‭for‬‭the‬‭ENETS‬‭Score.‬‭The‬‭results‬‭of‬‭validation‬‭studies‬‭will‬
‭be‬ ‭available‬ ‭for‬ ‭the‬ ‭Statistical‬ ‭Analysis‬ ‭Plan‬ ‭of‬‭SEQTOR‬‭study‬‭and‬‭for‬‭the‬‭central‬‭and‬
‭retrospective analysis of images.‬
‭Abbreviations:‬‭CR, complete response; PR, partial‬‭response; HU, Hounsfield‬
‭Unit;‬‭CT,‬‭computed‬‭tomography;‬‭SD,‬‭stable‬‭disease;‬‭PD,‬‭progression‬‭of‬‭disease;‬‭RECIST,‬
‭Response Evaluation Criteria in Solid Tumours.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭3.1 ENETS Score following RECIST criteria version 1.0‬
‭Definitions‬
‭Baseline‬ ‭lesions‬‭:‬ ‭All‬ ‭patients‬ ‭must‬ ‭have‬‭at‬‭least‬‭one‬‭measurable‬‭lesion‬‭by‬‭triphasic‬‭CT‬
‭scan‬‭performed‬‭at‬‭three‬‭specific‬‭time‬‭points:‬‭before‬‭the‬‭contrast,‬‭during‬‭the‬‭arterial‬‭phase‬
‭and‬ ‭in‬ ‭the‬ ‭venous‬ ‭phase.‬ ‭If‬ ‭contrast‬ ‭is‬ ‭contraindicated‬ ‭in‬ ‭the‬ ‭patient,‬ ‭it‬ ‭is‬ ‭accepted‬ ‭a‬
‭multiple-phase MRI instead.‬
‭Measurable‬ ‭lesions‬ ‭can‬ ‭be‬ ‭accurately‬ ‭measured‬‭in‬‭at‬‭least‬‭the‬‭dimension‬‭containing‬‭the‬
‭longest‬ ‭diameter;‬ ‭if‬ ‭the‬ ‭diameter‬ ‭is‬ ‭≥‬‭20‬‭mm‬‭the‬‭measurement‬‭should‬‭be‬‭performed‬‭by‬
‭conventional‬ ‭techniques‬ ‭and‬ ‭in‬ ‭case‬ ‭the‬ ‭diameter‬ ‭is‬ ‭≥‬ ‭10‬ ‭mm‬ ‭assessment‬ ‭should‬ ‭be‬
‭performed‬‭by‬‭a‬‭triphasic‬‭CT‬‭scan‬‭(with‬‭a‬‭minimum‬‭lesion‬‭size,‬‭not‬‭below‬‭two‬‭times‬‭the‬
‭layer thickness).‬
‭Selection of target lesions‬‭:‬
‭Target‬‭lesions‬‭should‬‭be‬‭selected‬‭based‬‭on‬‭their‬‭size‬‭(lesions‬‭with‬‭the‬‭longest‬‭diameter)‬‭and‬
‭the‬ ‭possibility‬ ‭that‬ ‭precise‬ ‭repeated‬ ‭measurements‬ ‭can‬ ‭be‬ ‭performed.‬ ‭All‬ ‭measurable‬
‭lesions‬‭will‬‭be‬‭identified‬‭as‬‭target‬‭lesions‬‭up‬‭to‬‭5‬‭lesions‬‭per‬‭organ‬‭and‬‭10‬‭lesions‬‭in‬‭total,‬
‭representative‬‭of‬‭all‬‭organs‬‭involved.‬‭A‬‭baseline‬‭measurement‬‭of‬‭all‬‭target‬‭lesions‬‭will‬‭be‬
‭available.‬
‭The‬‭sum‬‭of‬‭the‬‭longest‬‭diameter‬‭of‬‭all‬‭lesions‬‭will‬‭be‬‭calculated‬‭at‬‭baseline.‬‭The‬‭sum‬‭of‬‭the‬
‭longest diameter at baseline will be used as reference to define objective tumour response.‬
‭Response evaluation‬‭:‬
‭Criteria‬ ‭defined‬ ‭in‬ ‭the‬ ‭schema‬ ‭included‬ ‭in‬ ‭section‬ ‭3‬ ‭and‬ ‭describing‬ ‭assessment‬ ‭of‬
‭Composite Score.‬
‭The sum of longest diameters of target lesions measured as defined in‬‭RECIST 1.0‬‭.‬
‭3.2. ENETS Score following RECIST criteria version 1.1‬
‭Definitions‬‭:‬
‭Baseline‬‭: the closer time point before the beginning‬‭of the treatment‬
‭Nadir‬‭:‬‭the‬‭time‬‭point‬‭of‬‭the‬‭lowest‬‭size‬‭of‬‭the‬‭lesion‬‭since‬‭treatment‬‭started,‬‭progression‬‭is‬
‭compared to this size.‬
‭Selection of target lesions‬‭:‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Five‬‭target‬‭lesions‬‭(2‬‭per‬‭organ)‬‭(if‬‭present)‬‭should‬‭be‬‭selected‬‭on‬‭the‬‭basis‬‭of‬‭their‬‭size‬
‭(those with the longest diameter) and their suitability for accurate repeated measurements.‬
‭It‬‭may‬‭be‬‭the‬‭case‬‭that,‬‭on‬‭occasion,‬‭the‬‭largest‬‭lesion‬‭does‬‭not‬‭lend‬‭itself‬‭to‬‭reproducible‬
‭measurement‬ ‭in‬ ‭which‬ ‭circumstance‬ ‭the‬ ‭next‬ ‭largest‬ ‭lesion‬ ‭which‬ ‭can‬ ‭be‬ ‭measured‬
‭reproducibly‬‭should‬‭be‬‭selected.‬‭Measurement‬‭is‬‭performed‬‭at‬‭the‬‭portal‬‭phase‬‭of‬‭injection,‬
‭the‬‭more‬‭clearly‬‭delineated‬‭and‬‭easy‬‭to‬‭locate‬‭in‬‭the‬‭liver,‬‭on‬‭the‬‭slice‬‭where‬‭the‬‭lesion‬‭is‬
‭the biggest.‬
‭Non target lesions‬‭:‬
‭All‬‭other‬‭lesions‬‭(or‬‭sites‬‭of‬‭disease)‬‭should‬‭be‬‭identified‬‭as‬‭non-target‬‭lesions‬‭and‬‭should‬
‭also‬ ‭be‬ ‭recorded‬ ‭at‬ ‭baseline.‬ ‭Measurements‬ ‭of‬ ‭these‬ ‭lesions‬ ‭are‬ ‭not‬ ‭required,‬ ‭but‬ ‭the‬
‭presence‬ ‭or‬ ‭absence‬ ‭of‬ ‭each‬ ‭should‬‭be‬‭noted‬‭throughout‬‭the‬‭follow-up.‬‭It‬‭is‬‭possible‬‭to‬
‭record‬‭multiple‬‭non‬‭target‬‭lesions‬‭involving‬‭the‬‭same‬‭organ‬‭as‬‭a‬‭single‬‭item‬‭on‬‭the‬‭case‬
‭record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).‬
‭Response evaluation‬‭:‬
‭Criteria‬ ‭defined‬ ‭in‬ ‭the‬ ‭schema‬ ‭included‬ ‭in‬ ‭section‬ ‭3‬ ‭and‬ ‭describing‬ ‭assessment‬ ‭of‬
‭Composite‬‭Score.‬‭The‬‭sum‬‭of‬‭longest‬‭diameters‬‭of‬‭target‬‭lesions‬‭measured‬‭as‬‭defined‬‭on‬
‭RECIST 1.1‬‭.‬
‭7.2.6‬‭Laboratory‬
‭7.2.6.1 During everolimus treatment‬
‭Throughout‬‭treatment‬‭period‬‭with‬‭everolimus,‬‭several‬‭laboratory‬‭measurements‬‭should‬‭be‬
‭carried‬ ‭out‬ ‭for‬ ‭the‬ ‭evaluation‬ ‭of‬ ‭patient‬ ‭safety‬ ‭as‬ ‭per‬ ‭clinical‬ ‭protocol‬ ‭at‬ ‭site;‬
‭recomendations are detailed below.‬
‭All‬ ‭blood‬ ‭samples‬ ‭will‬ ‭be‬ ‭obtained‬ ‭before‬ ‭the‬ ‭start‬ ‭of‬ ‭the‬ ‭next‬ ‭cycle‬ ‭treatment‬ ‭and‬ ‭in‬
‭fasting conditions.‬
‭Haematology‬
‭Haematology‬‭measurements‬‭should‬‭be‬‭performed‬‭and‬‭results‬‭available‬‭at‬‭each‬‭visit‬‭before‬
‭start of next cycle study treatment. The haematological analysis should include:‬
‭●‬
‭Haemoglobin‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭●‬
‭Haematocrit‬
‭●‬
‭Platelets‬
‭●‬
‭Red Blood Cell Count‬
‭●‬
‭Total,‬ ‭absolute‬ ‭and‬ ‭differential‬ ‭white‬ ‭blood‬ ‭cell‬ ‭count,‬ ‭including‬ ‭neutrophils,‬
‭lymphocytes,‬‭monocytes,‬‭eosinophils,‬‭and‬‭basophils.‬‭The‬‭laboratory‬‭should‬‭calculate‬‭the‬
‭absolute neutrophil count (ANC).‬
‭Coagulation‬
‭The‬ ‭following‬ ‭parameter‬ ‭should‬ ‭be‬ ‭measured‬ ‭and‬ ‭its‬ ‭results‬ ‭should‬ ‭be‬ ‭available‬ ‭at‬ ‭the‬
‭screening‬ ‭period‬ ‭or‬ ‭before‬ ‭second‬ ‭treatment‬ ‭as‬ ‭applicable;‬ ‭during‬ ‭the‬ ‭study‬ ‭it‬ ‭is‬
‭recommended to have it determined‬‭every 12 weeks‬‭:‬
‭Prothrombin‬‭time‬‭(it‬‭should‬‭be‬‭noted‬‭as‬‭international‬‭normalised‬‭ratio‬‭of‬‭prothrombin‬‭or‬
‭INR).‬
‭Biochemistry and hormones‬
‭At‬‭the‬‭day‬‭1‬‭of‬‭every‬‭cycle‬‭,‬‭the‬‭following‬‭parameters‬‭should‬‭be‬‭measured‬‭and‬‭the‬‭results‬
‭available:‬
‭●‬
‭Sodium, potassium, ion chloride, bicarbonate‬
‭●‬
‭Creatinine, albumin, total protein‬
‭●‬
‭AST (GOT) and ALT (GPT) in serum, total bilirubin, alkaline phosphatase‬
‭●‬
‭Uric acid, BUN‬
‭●‬
‭Calcium, magnesium, phosphate‬
‭●‬
‭Fasting glucose‬
‭●‬
‭Total LDH‬
‭Cases‬‭of‬‭hyperglycaemia‬‭have‬‭been‬‭reported.‬‭It‬‭is‬‭recommended‬‭to‬‭measure‬‭fasting‬‭glucose‬
‭serum levels before starting treatment with everolimus and then monitor them regularly.‬
‭At‬‭screening‬‭period‬‭and‬‭every‬‭12‬‭weeks‬‭all‬‭along‬‭treatment‬‭period,‬‭the‬‭following‬‭should‬
‭be measured and results available:‬
‭●‬
‭Total Cholesterol‬
‭●‬
‭Triglycerides‬
‭●‬
‭LDL and HDL‬
‭At‬ ‭screening‬ ‭period,‬ ‭every‬ ‭24‬ ‭weeks‬ ‭all‬ ‭along‬ ‭treatment‬ ‭period,‬ ‭and‬ ‭whenever‬ ‭the‬
‭investigator considers appropriate, the following should be measured:‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭●‬
‭Vitamin B12.‬
‭Urinalysis‬
‭A‬ ‭standard‬ ‭urinalysis‬ ‭(pH,‬ ‭proteins,‬ ‭glucose,‬ ‭blood,‬ ‭ketones‬ ‭and‬ ‭WBC)‬ ‭should‬ ‭be‬
‭performed‬ ‭during‬ ‭the‬ ‭screening‬ ‭period.‬ ‭During‬ ‭routine‬ ‭clinical‬ ‭procedures,‬ ‭Dipstick‬ ‭is‬
‭used; then if abnormal, quantitative analysis should be performed.‬
‭A measurement with dipstick should be performed routinely on Day 1 of every cycle.‬
‭The pregnancy test can be performed in urine (see next section).‬
‭Viremia‬
‭Those‬ ‭patients‬ ‭considered,‬ ‭at‬‭investigator’s‬‭discretion,‬‭as‬‭pertaining‬‭to‬‭the‬‭risk‬‭group‬‭of‬
‭hepatitis‬‭B‬‭and/or‬‭C‬‭(Section‬‭6.2.1.3:‬‭tables‬‭III‬‭y‬‭IV;‬‭section‬‭6.2.1.4:‬‭table‬‭V),‬‭an‬‭analysis‬
‭of‬‭viremia‬‭and‬‭serological‬‭markers‬‭should‬‭be‬‭performed‬‭at‬‭screening‬‭and‬‭throughout‬‭the‬
‭study, following the criteria set out in Sections‬‭6.2.1.3 and 6.2.1.4.‬
‭Biomarkers‬
‭Circulating‬‭Cromogranin‬‭A‬‭(CgA)‬‭levels‬‭will‬‭be‬‭determined‬‭at‬‭baseline‬‭(time‬‭0)‬‭and‬‭also‬
‭at‬ ‭4‬ ‭weeks‬‭.‬ ‭Blood‬ ‭samples‬ ‭should‬ ‭be‬ ‭sent‬ ‭to‬‭the‬‭Institut‬‭Gustave-Roussy,‬‭Rue‬‭Camille‬
‭Desmoulins 39, 94805 Villejuif, France to be centrally analyzed.‬
‭Participation‬‭on‬‭Ancillary‬‭trials‬‭(included‬‭in‬‭protocol‬‭amendment‬‭2)‬‭is‬‭optional‬‭for‬‭sites‬
‭and patients.‬
‭7.2.6.2 During STZ-5FU treatment‬
‭Throughout‬‭treatment‬‭period,‬‭several‬‭laboratory‬‭measurements‬‭should‬‭be‬‭carried‬‭out‬‭for‬‭the‬
‭evaluation‬ ‭of‬ ‭patient‬ ‭safety,‬ ‭as‬ ‭detailed‬ ‭below.‬‭All‬‭blood‬‭samples‬‭should‬‭be‬‭obtained‬‭in‬
‭fasting‬‭conditions.‬‭Hematology‬‭and‬‭Biochemistry‬‭standard‬‭analysis‬‭as‬‭per‬‭clinical‬‭protocol‬
‭at site should be followed.‬
‭At‬‭baseline‬‭,‬‭all‬‭patients‬‭will‬‭have‬‭an‬‭Haematology‬‭and‬‭Biochemistry‬‭standard‬‭analysis‬
‭as per clinical protocol at site.‬
‭At‬‭every cycle‬‭during STZ-5FU treatment‬‭, all patients‬‭should have at least:‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Haematology‬
‭At‬‭every‬‭cycle‬‭a‬‭routine‬‭haematology‬‭should‬‭be‬‭performed‬‭and‬‭results‬‭available‬‭(before‬‭the‬
‭start of next cycle):‬
‭●‬
‭Haemoglobin‬
‭●‬
‭Haematocrit‬
‭●‬
‭Platelets‬
‭●‬
‭Red Blood Cell Count‬
‭●‬
‭Total,‬ ‭absolute‬ ‭and‬ ‭differential‬ ‭red‬ ‭blood‬ ‭cell‬ ‭count,‬ ‭including‬ ‭neutrophils,‬
‭lymphocytes,‬ ‭monocytes,‬ ‭eosinophils,‬ ‭and‬ ‭basophils.‬ ‭The‬ ‭laboratory‬ ‭will‬ ‭calculate‬ ‭the‬
‭absolute neutrophil count (ANC).‬
‭Biochemistry and hormones‬
‭At‬ ‭the‬ ‭day‬ ‭1‬ ‭of‬ ‭every‬ ‭cycle,‬ ‭the‬‭following‬‭standard‬‭determinations‬‭should‬‭be‬‭done‬‭and‬
‭results available:‬
‭•‬‭Sodium, potassium, ion chloride, bicarbonate‬
‭•‬‭Creatinine, clearance of albumin, total protein‬
‭•‬‭AST (GOT) and ALT (GPT) in serum, total bilirubin, alkaline phosphatase‬
‭•‬‭Uuric acid, BUN‬
‭•‬‭Calcium, magnesium, phosphate‬
‭•‬‭Fasting glucose‬
‭Urinalysis‬
‭A‬ ‭standard‬ ‭urinalysis‬ ‭(pH,‬ ‭proteins,‬ ‭glucose,‬ ‭blood,‬ ‭ketones‬ ‭and‬ ‭WBC)‬ ‭should‬ ‭be‬
‭performed‬ ‭during‬ ‭the‬ ‭screening‬ ‭period.‬ ‭During‬ ‭routine‬ ‭clinical‬ ‭procedures,‬ ‭Dipstick‬ ‭is‬
‭used; then if abnormal, quantitative analysis should be performed.‬
‭At least dipstick measurement should be performed routinely on Day 1 of every cycle.‬
‭The pregnancy test can be performed in urine (see next section).‬
‭Biomarkers‬
‭Circulating‬‭Cromogranin‬‭A‬‭(CgA)‬‭levels‬‭should‬‭be‬‭determined‬‭at‬‭baseline‬‭(time‬‭0)‬‭and‬
‭also at‬‭4 weeks.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Blood‬‭samples‬‭should‬‭be‬‭sent‬‭to‬‭the‬‭Institut‬‭Gustave-Roussy,‬‭Rue‬‭Camille‬‭Desmoulins‬‭39,‬
‭94805 Villejuif, France to be analyzed.‬
‭7.2.7‬‭Pregnancy test. Male contraception.‬
‭Pregnancy‬ ‭test‬ ‭will‬ ‭be‬ ‭performed‬ ‭at‬ ‭screening‬ ‭period.‬ ‭In‬ ‭case‬ ‭of‬ ‭an‬ ‭undesired‬ ‭and‬
‭unexpected pregnancy, it will be notified immediately as a Serious Adverse Event.‬
‭All‬ ‭women‬ ‭with‬ ‭child-bearing‬ ‭potential‬ ‭must‬ ‭have‬ ‭a‬ ‭negative‬ ‭pregnancy‬ ‭test‬‭within‬‭14‬
‭days‬‭prior‬‭to‬‭the‬‭first‬‭dose‬‭of‬‭everolimus/chemotherapy‬‭and/or‬‭a‬‭negative‬‭urine‬‭test‬‭48‬
‭hours‬ ‭before‬ ‭the‬ ‭first‬ ‭dose‬ ‭of‬ ‭treatment.‬ ‭A‬ ‭pregnancy‬ ‭test‬ ‭in‬ ‭urine‬‭will‬‭be‬‭performed‬
‭monthly (if necessary) and at the end of treatment visit (mandatory).‬
‭It‬ ‭is‬‭recommended‬‭that‬‭postmenopausal‬‭status‬‭is‬‭considered‬‭after‬‭at‬‭least‬‭12‬‭months‬‭of‬
‭amenorrhoea‬‭or‬‭FSH‬‭levels‬‭>40‬‭mIU/ml‬‭in‬‭order‬‭to‬‭consider‬‭women‬‭as‬‭“non-procreators”;‬
‭it‬ ‭is‬ ‭recommended‬ ‭a‬ ‭6‬ ‭weeks‬ ‭elapse‬ ‭since‬ ‭a‬ ‭surgical‬ ‭bilateral‬ ‭oophorectomy,‬ ‭with‬ ‭or‬
‭without hysterectomy.‬
‭Contraception‬ ‭will‬ ‭be‬ ‭acceptable‬ ‭for‬ ‭the‬ ‭study‬ ‭when‬ ‭in‬ ‭the‬ ‭following‬ ‭cases:‬ ‭surgical‬
‭sterilisation‬ ‭(for‬ ‭instance,‬ ‭bilateral‬ ‭tubal‬ ‭ligation,‬ ‭vasectomy),‬ ‭hormonal‬ ‭contraception‬
‭(implantable,‬ ‭patch,‬ ‭oral)‬ ‭and‬ ‭double‬ ‭barrier‬ ‭methods‬ ‭(any‬ ‭combination‬ ‭of:‬ ‭intrauterine‬
‭device‬‭(IUD),‬‭intrauterine‬‭system‬‭(IUS),‬‭male‬‭condom‬‭or‬‭female‬‭condom‬‭with‬‭spermicide‬
‭gel,‬ ‭diaphragm,‬ ‭contraceptive‬ ‭sponge,‬ ‭cervical‬ ‭capsule).‬ ‭Acceptable‬ ‭and‬ ‭efficient‬
‭contraception‬ ‭must‬ ‭be‬ ‭used‬ ‭throughout‬ ‭the‬ ‭study‬ ‭and‬ ‭up‬ ‭to‬ ‭eight‬ ‭weeks‬ ‭(as‬ ‭per‬
‭clinical‬‭sheet)‬ ‭following‬‭the‬‭last‬‭dose‬‭of‬‭everolimus,‬‭and‬‭up‬‭to‬‭6‬‭months‬‭(at‬‭least‬‭in‬
‭France as per clinical protocol) after the last dose of chemotherapy.‬
‭Male fertility and‬‭Male contraception‬
‭During‬ ‭the‬ ‭course‬ ‭of‬ ‭a‬ ‭clinical‬ ‭trial,‬ ‭sexually‬ ‭active‬ ‭males‬ ‭must‬ ‭use‬ ‭a‬ ‭condom‬ ‭during‬
‭intercourse while taking the drug and should not father a child in this period and for up to 8‬
‭weeks‬‭after‬‭stopping‬‭treatment.‬‭A‬‭condom‬‭is‬‭required‬‭to‬‭be‬‭used‬‭also‬‭by‬‭vasectomised‬‭men‬
‭in order to prevent delivery of the drug via seminal fluid.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Female‬ ‭partners‬ ‭of‬ ‭male‬ ‭patients‬ ‭must‬ ‭also‬ ‭be‬ ‭advised‬ ‭to‬ ‭use‬ ‭one‬ ‭of‬ ‭the‬ ‭following‬
‭contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of‬
‭contraception,‬ ‭or‬ ‭(2)‬ ‭intrauterine‬‭device‬‭(IUD)‬‭or‬‭intrauterine‬‭system‬‭(IUS),‬‭or‬‭(3)‬‭prior‬
‭male/female sterilization.‬
‭In‬‭order‬‭to‬‭preserve‬‭patient’s‬‭safety,‬‭any‬‭pregnancy‬‭of‬‭a‬‭patient‬‭receiving‬‭study‬‭drug‬‭must‬
‭be‬‭notified‬‭to‬‭the‬‭Pharmacovigilance‬‭Unit‬‭within‬‭24‬‭hours‬‭after‬‭it‬‭is‬‭known.‬‭Any‬‭pregnancy‬
‭must‬‭be‬‭monitored‬‭to‬‭record‬‭the‬‭outcome,‬‭including‬‭abortion‬‭or‬‭miscarriage,‬‭details‬‭of‬‭birth‬
‭and‬ ‭presence‬ ‭or‬ ‭absence‬ ‭of‬ ‭birth‬ ‭defects,‬ ‭congenital‬ ‭anomalies‬ ‭or‬‭maternal‬‭or‬‭newborn‬
‭complications.‬ ‭Pregnancies‬ ‭must‬ ‭be‬ ‭recorded‬ ‭on‬ ‭the‬ ‭pregnancy‬ ‭form‬ ‭and‬ ‭the‬ ‭site‬
‭investigator‬ ‭must‬ ‭notify‬ ‭it‬ ‭to‬ ‭the‬ ‭clinical‬ ‭safety‬ ‭and‬ ‭epidemiology‬ ‭department.‬ ‭The‬
‭follow-up‬‭of‬‭pregnancy‬‭must‬‭be‬‭recorded‬‭in‬‭the‬‭same‬‭form‬‭and‬‭must‬‭include‬‭the‬‭possible‬
‭causal‬ ‭relationship‬ ‭of‬ ‭any‬ ‭outcome‬ ‭with‬ ‭the‬ ‭study‬ ‭drug.‬ ‭Any‬ ‭SAE‬ ‭occurring‬ ‭during‬
‭pregnancy must be reported in the SAE form.‬
‭Furthermore,‬ ‭any‬‭pregnancy‬‭of‬‭a‬‭partner‬‭from‬‭a‬‭patient‬‭taking‬‭the‬‭study‬‭drug‬‭should‬‭be‬
‭communicated‬ ‭to‬ ‭the‬ ‭investigator/Pharmacology‬ ‭Unit‬ ‭and‬ ‭its‬ ‭outcome‬ ‭collected.‬ ‭In‬‭this‬
‭situation,‬ ‭the‬ ‭mother‬ ‭should‬ ‭give‬ ‭her‬ ‭consent‬ ‭for‬ ‭the‬ ‭record‬ ‭of‬ ‭information‬ ‭about‬ ‭the‬
‭pregnancy outcome.‬
‭7.2.8‬‭Quality of Life assessments‬
‭The‬‭EORTC‬‭QLQ-C30‬‭is‬‭a‬‭questionnaire‬‭developed‬‭to‬‭assess‬‭the‬‭quality‬‭of‬‭life‬‭of‬‭cancer‬
‭patients.‬‭Presently‬‭QLQ-C30‬‭Version‬‭3.0‬‭is‬‭the‬‭most‬‭recent‬‭version‬‭and‬‭it‬‭is‬‭supplemented‬
‭by‬ ‭disease‬ ‭specific‬ ‭modules‬ ‭for‬ ‭NET,‬ ‭the‬ ‭EORTC‬ ‭QLQ‬ ‭GINET21‬‭20,‬ ‭21,22‬‭.‬‭Both‬‭the‬‭core‬
‭questionnaire‬‭and‬‭its‬‭specific‬‭module‬‭will‬‭be‬‭used‬‭for‬‭the‬‭assessments‬‭of‬‭quality‬‭of‬‭life‬‭of‬
‭patients under both treatments.‬
‭EORTC‬‭QLQ-C30‬‭and‬‭the‬‭specific‬‭module‬‭for‬‭NET‬‭EORTC‬‭QLQ‬‭GINET21‬‭Quality‬‭of‬
‭Life‬ ‭Questionnaire‬ ‭will‬ ‭be‬ ‭administrated‬‭before‬‭the‬‭start‬‭of‬‭each‬‭treatment‬‭period,‬‭upon‬
‭progression‬ ‭or‬ ‭unacceptable‬ ‭toxicity,‬ ‭or‬ ‭at‬‭the‬‭end‬‭of‬‭second‬‭treatment‬‭period‬‭if‬‭second‬
‭period event (progression) is not reached.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭7.2.9‬‭Assessment of health resources used during study treatment‬
‭The‬‭following‬‭resources‬‭used‬‭for‬‭the‬‭care‬‭of‬‭all‬‭patients‬‭on‬‭each‬‭treatment‬‭will‬‭be‬‭recorded‬
‭on the CRF at every visit:‬
‭- treatments: drugs, total dose and presentation.‬
‭-‬‭outpatient‬‭visits:‬‭number‬‭of‬‭visits‬‭including‬‭but‬‭not‬‭limited‬‭to‬‭the‬‭specialist,‬‭generalist,‬
‭and emergency.‬
‭- hospitalizations: number of days‬
‭- AE related, diagnostic tests and treatment procedures performed.‬
‭To‬ ‭assess‬ ‭resource‬ ‭utilization‬ ‭and‬ ‭cost‬ ‭effectiveness‬ ‭of‬ ‭treatments‬ ‭during‬ ‭the‬ ‭study,‬
‭information‬ ‭will‬ ‭be‬ ‭used‬ ‭from‬ ‭the‬ ‭clinical‬ ‭parts‬ ‭of‬ ‭the‬ ‭CRF‬ ‭(study‬ ‭treatments,‬
‭concomitant‬‭medication,‬‭SAE‬‭treatment),‬‭as‬‭well‬‭as‬‭from‬‭the‬‭specific‬‭resource‬‭utilization‬
‭pages.‬
‭7.2.10‬ ‭Translational research‬
‭Translational‬ ‭research‬ ‭will‬ ‭be‬ ‭done‬ ‭in‬ ‭the‬ ‭next‬ ‭future‬ ‭as‬ ‭a‬ ‭sub-study‬ ‭of‬ ‭this.‬ ‭This‬
‭translational‬‭research‬‭will‬‭include‬‭the‬‭detection‬‭of‬‭a‬‭panel‬‭of‬‭predictive‬‭markers.‬‭Predictive‬
‭markers‬ ‭will‬ ‭be‬ ‭detected‬ ‭on‬ ‭paraffin‬ ‭embedded‬ ‭tumour‬ ‭blocks.‬ ‭The‬ ‭following‬ ‭panel‬‭of‬
‭analysis has been planned:‬
‭(i)‬‭a‬‭selected‬‭set‬‭of‬‭mutational‬‭analysis‬‭using‬‭an‬‭amplicon‬‭next-generation-approach,‬‭based‬
‭on the data published.‬
‭(ii) a genome expression profiling.‬
‭For‬ ‭these‬ ‭purposes,‬ ‭both‬ ‭paraffin‬‭embedded‬‭tumour‬‭block‬‭and‬‭blood‬‭samples‬‭should‬‭be‬
‭available for each patient.‬
‭Blood/serum samples may be stored for future analysis not defined here.‬
‭The‬ ‭Patient‬ ‭must‬ ‭have‬ ‭accepted‬ ‭to‬ ‭donate‬ ‭samples‬ ‭for‬ ‭translational‬ ‭analysis‬ ‭at‬ ‭his/her‬
‭enrolment;‬‭the‬‭Pathologist‬‭at‬‭each‬‭site‬‭should‬‭agree‬‭to‬‭deliver‬‭paraffin‬‭embedded‬‭tumour‬
‭block‬ ‭from‬ ‭included‬ ‭patients‬ ‭including‬ ‭an‬ ‭anonymous‬ ‭copy‬ ‭of‬ ‭pathology‬ ‭report.‬ ‭All‬
‭samples should be return back to hospital at the end of the analysis if so required.‬
‭For‬‭the‬‭validation‬‭of‬‭predictive‬‭markers‬‭by‬‭Immunochemistry‬‭23,‬ ‭24‬‭,‬‭tumour‬‭blocks‬‭will‬‭be‬
‭sent to Verona, Italy, to the following address:‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭Professor Aldo Scarpa‬
‭Centre for Applied Research on Cancer ‬
‭University of Verona - Policlinico G.B. Rossi‬
‭c/o Piastra Odontoiatrica - secondo piano‬
‭Piazzale L.A. Scuro, 10, 37134 Verona, Italy‬
‭Telephone (+39) 045 812 7431‬
‭Blood/serum samples will be sent to London, to the following address:‬
‭Dr Tim Meyer‬
‭UCL Cancer Institute and Royal Free Hospital‬
‭Neuroendocrine Tumour Unit‬
‭Royal Free Hospital‬
‭Pond Street, London‬
‭NW3 2QG‬
‭Telephone:‬‭(‬‭+44)‬‭0‬‭20 7794 0500‬
‭Shipment‬ ‭material‬ ‭will‬ ‭be‬ ‭provided‬ ‭to‬ ‭the‬ ‭sites.‬ ‭The‬ ‭collection‬ ‭of‬ ‭samples‬ ‭will‬ ‭be‬
‭coordinated by Kantar Health.‬
‭The‬‭protocol‬‭for‬‭both‬‭analyses‬‭will‬‭be‬‭developed‬‭as‬‭a‬‭sub-study‬‭of‬‭this‬‭clinical-trial‬‭and‬
‭added as an Annex to the protocol.‬
‭7.3‬
‭ASSESSMENTS’ SCHEDULE‬
‭The study is scheduled as follows:‬
‭●‬
‭Baseline‬‭visit‬‭(screening):‬‭It‬‭will‬‭be‬‭better‬‭performed‬‭on‬‭day‬‭-28‬‭to‬‭-0‬‭before‬‭the‬
‭start‬‭of‬‭first‬‭study‬‭treatment.‬‭Some‬‭procedures‬‭(laboratory‬‭tests)‬‭will‬‭be‬‭performed‬‭within‬
‭14 days before intake of first treatment dose.‬
‭Baseline visit includes:‬
‭-‬
‭Tumour block will be separated for Translational research in Italy.‬
‭-‬
‭Blood samples will be taken for future research, as described above in this protocol.‬
‭-‬
‭CgA levels will be measured at baseline‬
‭-‬
‭The‬‭CT‬‭scans‬‭will‬‭be‬‭used‬‭for‬‭the‬‭local‬‭assessment‬‭of‬‭tumour‬‭response‬‭and‬‭kept‬‭at‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭site;‬ ‭a‬ ‭copy‬ ‭will‬ ‭be‬ ‭sent‬ ‭electronically/on‬ ‭CD‬ ‭to‬ ‭the‬ ‭Radiology‬ ‭Service‬ ‭of‬
‭Neuroendocrine‬ ‭Tumor‬ ‭(NET)‬ ‭Center,‬ ‭Hôpital‬ ‭Beaujon,‬ ‭Clichy,‬ ‭France,‬ ‭for‬ ‭the‬
‭centralised retrospective assessment of ENETS Score.‬
‭●‬
‭Treatment‬‭visits:‬‭A‬‭visit‬‭will‬‭be‬‭performed‬‭on‬‭the‬‭first‬‭day‬‭of‬‭every‬‭cycle‬‭until‬
‭disease progression.‬
‭-‬
‭-‬
‭CgA levels will be measured at 4 weeks of tretment.‬
‭-‬
‭Tumour‬ ‭evaluation‬ ‭following‬ ‭RECIST‬ ‭criteria‬ ‭1.0‬ ‭will‬ ‭be‬ ‭done‬ ‭every‬‭12‬‭weeks‬
‭during‬‭both‬‭treatments.‬‭Radiological‬‭assessment‬‭can‬‭be‬‭done‬‭before‬‭the‬‭scheduled‬
‭12‬ ‭weeks‬ ‭if‬ ‭disease‬‭progression‬‭is‬‭suspected.‬‭On‬‭those‬‭cases,‬‭the‬‭next‬‭CT‬‭scans‬
‭should be done at 12 weeks of last assessment.‬
‭●‬
‭30‬‭days‬‭Follow-up‬‭visit:‬‭A‬‭follow-up‬‭visit‬‭will‬‭be‬‭performed‬‭(30‬‭days‬‭after‬‭the‬‭last‬
‭dose of last patient). This follow-up can be performed by phone or during a visit.‬
‭●‬
‭Survival‬‭follow-up‬‭after‬‭the‬‭end‬‭of‬‭treatment:‬‭As‬‭per‬‭site‬‭clinical‬‭protocol,‬‭every‬
‭3‬ ‭months‬‭until‬‭the‬‭patient‬‭dies‬‭or‬‭up‬‭to‬‭the‬‭end‬‭of‬‭the‬‭study‬‭(last‬‭patient‬‭out),‬‭whatever‬
‭takes‬‭place‬‭first;‬‭survival‬‭information‬‭will‬‭be‬‭collected.‬‭This‬‭follow-up‬‭can‬‭be‬‭performed‬
‭by phone or during a visit.‬
‭All‬‭potential‬‭patients‬‭screened‬‭for‬‭its‬‭enrolment‬‭in‬‭the‬‭study‬‭will‬‭be‬‭recorded‬‭in‬‭the‬‭CRF,‬
‭including‬ ‭screening‬ ‭failures‬ ‭specifying‬ ‭the‬ ‭reason‬ ‭for‬ ‭its‬ ‭exclusion‬ ‭from‬ ‭the‬ ‭study.‬
‭Screening‬‭failures‬‭are‬‭considered‬‭to‬‭be‬‭patients‬‭completing‬‭the‬‭information‬‭and‬‭informed‬
‭consent‬‭procedures‬‭and‬‭finally‬‭not‬‭receiving‬‭everolimus‬‭after‬‭performing‬‭the‬‭tests‬‭for‬‭the‬
‭evaluation‬‭of‬‭their‬‭eligibility‬‭because‬‭they‬‭do‬‭not‬‭meet‬‭some‬‭of‬‭the‬‭study‬‭screening‬‭criteria.‬
‭This will be noted in the relevant CRF section.‬
‭7.3.1‬‭Screening‬ ‭period/baseline‬ ‭visit:‬ ‭Baseline‬ ‭information‬ ‭and‬
‭assessments‬
‭☞‬‭The following information will be collected at baseline:‬
‭●‬ ‭EORTC‬‭QLQ-C30‬‭and‬‭the‬‭specific‬‭module‬‭for‬‭NET‬‭EORTC‬‭QLQ‬‭GINET21‬‭should‬‭be‬
‭administrated‬‭at randomization.‬
‭●‬ ‭A‬‭blood‬‭sample‬‭should‬‭be‬‭taken‬‭prior‬‭to‬‭commencing‬‭long‬‭therapy‬‭with‬‭everolimus‬‭or‬
‭chemotherapy,‬ ‭for‬ ‭future‬‭research‬‭and‬‭measurement‬‭of‬‭CgA‬‭levels‬‭at‬‭local‬‭or‬‭central‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭laboratory (Gustave Roussy, Villejuif, France) depending on funds available.‬
‭●‬ ‭Tumour block‬‭will be collected and stored properly‬‭for the study.‬
‭●‬ ‭Demographic‬‭data‬‭of‬‭the‬‭patient‬‭(age,‬‭sex,‬‭race,‬‭height‬‭and‬‭weight‬‭as‬‭allowed‬‭per‬‭local‬
‭laws).‬
‭●‬ ‭Baseline‬ ‭characteristics‬ ‭and‬ ‭relevant‬ ‭clinical‬ ‭history‬ ‭of‬ ‭the‬ ‭study‬‭disease‬‭(history‬‭of‬
‭cancer,‬‭diagnosis‬‭and‬‭extension‬‭of‬‭cancer,‬‭and‬‭anticancer‬‭therapies‬‭received‬‭before‬‭the‬
‭patient enters the study).‬
‭●‬ ‭ECOG Performance status.‬
‭●‬ ‭Complete‬ ‭physical‬ ‭examination‬ ‭including‬ ‭an‬ ‭exam‬ ‭of‬ ‭the‬ ‭whole‬ ‭body‬ ‭(general‬
‭appearance,‬‭skin,‬‭neck,‬‭thyroids,‬‭eyes,‬‭ears,‬‭nose,‬‭throat,‬‭lungs,‬‭heart,‬‭abdomen,‬‭back,‬
‭lymph nodes, extremities and basic nervous system).‬
‭●‬ ‭Weight and height. Height will only be recorded at baseline.‬
‭●‬ ‭Vital‬ ‭signs:‬ ‭Pulse,‬ ‭respiratory‬ ‭rate‬ ‭and‬ ‭blood‬ ‭pressure,‬ ‭temperature.‬ ‭Blood‬‭pressure,‬
‭pulse‬ ‭and‬ ‭respiratory‬ ‭rate‬ ‭will‬ ‭be‬ ‭measured‬ ‭for‬ ‭at‬ ‭least‬ ‭3‬ ‭minutes‬ ‭with‬ ‭the‬ ‭patient‬
‭seated.‬‭These‬‭measurements‬‭will‬‭only‬‭be‬‭performed‬‭at‬‭the‬‭screening‬‭visit,‬‭unless‬‭the‬
‭clinical condition of the patient requires so (for instance, in case of an adverse event).‬
‭☞‬‭The following criteria will be verified during the‬‭screening period:‬
‭●‬ ‭Disease‬ ‭evaluation‬ ‭(progression)‬ ‭should‬ ‭be‬‭performed‬‭at‬‭any‬‭time‬‭within‬‭12‬‭months‬
‭prior to the visit by the RECIST criteria, version 1.0.‬
‭●‬ ‭Detection of hepatitis B:‬
‭An‬ ‭analysis‬ ‭of‬ ‭viremia‬ ‭and‬ ‭serological‬‭markers‬‭for‬‭hepatitis‬‭B‬‭(HBV-DNA,‬‭HbsAg,‬
‭anti-HbsAb‬ ‭and‬ ‭anti-HbcAb)‬ ‭will‬ ‭be‬ ‭performed‬ ‭in‬ ‭all‬ ‭patients‬ ‭meeting‬ ‭any‬ ‭of‬ ‭the‬
‭following risk factors:‬
‭-‬
‭confirmed or suspected infection by hepatitis B virus in the past;‬
‭-‬
‭blood transfusion receptors before 1990;‬
‭-‬
‭users of intravenous abuse drugs currently or in the past;‬
‭-‬
‭subject to dialysis currently or in the past;‬
‭-‬
‭regularly in contact with somebody infected by hepatitis B virus;‬
‭-‬
‭with high risk due to sexual activity currently or in the past;‬
‭-‬
‭with piercings or tattoos;‬
‭-‬
‭mother with presence of hepatitis B.‬
‭-‬
‭all‬‭patients‬‭with‬‭a‬‭history‬‭that‬‭indicates‬‭infection‬‭by‬‭hepatitis‬‭B‬‭virus,‬‭such‬‭as‬‭dark‬
‭urine, jaundice or pain in the right hypochondrium‬‭.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭See‬‭Tables‬‭III‬‭and‬‭IV‬‭(section‬‭5.1.3)‬‭for‬‭the‬‭administration‬‭of‬‭prophylactic‬‭treatment‬
‭between 1 and 2 weeks before the start of the study treatment.‬
‭●‬ ‭Detection of hepatitis C‬‭(under investigator’s judgement)‬
‭Patients‬ ‭with‬ ‭a‬ ‭known‬ ‭history‬ ‭of‬ ‭infection‬ ‭by‬ ‭HCV‬ ‭and‬ ‭those‬ ‭with‬ ‭detectable‬
‭HCV-RNA will not be eligible for the study (section 5.1.4, Table V).‬
‭It‬‭is‬‭recommended‬‭an‬‭RNA‬‭analysis‬‭by‬‭quantitative‬‭PCR‬‭in‬‭patients‬‭meeting‬‭any‬‭of‬‭the‬
‭following risk factors:‬
‭-‬
‭confirmed‬‭or‬‭suspected‬‭infection‬‭by‬‭hepatitis‬‭C‬‭virus‬‭in‬‭the‬‭past‬‭(including‬‭patients‬
‭treated with “intent-to-cure” interferon).‬
‭-‬
‭blood transfusion receptors before 1990.‬
‭-‬
‭users of intravenous abuse drugs currently or in the past.‬
‭-‬
‭subject to dialysis currently or in the past.‬
‭-‬
‭regularly in contact with somebody infected by the hepatitis C virus.‬
‭-‬
‭with high risk sexual activity currently or in the past.‬
‭-‬
‭with piercings or tattoos.‬
‭☞‬‭In the 28 days prior to the start with study drugs‬‭the following tests will be performed:‬
‭●‬ ‭Chest X-ray and/or chest CT in case of chest disease.‬
‭●‬ ‭ECG‬
‭●‬
‭Haematology‬ ‭and‬‭biochemistry‬‭tests;‬‭patients‬‭on‬‭everolimus‬‭will‬‭include‬‭hormonal,‬
‭coagulation and lipid profile tests before treatment start (see Section 7.2.6).‬
‭●‬
‭It‬‭is‬‭recommended‬‭to‬‭monitor‬‭fasting‬‭glucose‬‭serum‬‭levels‬‭before‬‭starting‬‭treatment‬
‭with‬ ‭everolimus‬‭as‬‭well‬‭as‬‭regular‬‭monitoring.‬‭Optimum‬‭control‬‭of‬‭blood‬‭sugar‬‭levels‬
‭should be obtained before starting administration with everolimus.‬
‭●‬ ‭Standard urinalysis (pH, proteins, glucose, blood, ketones, and WBC).‬
‭●‬ ‭Concomitant‬‭medication‬‭(including‬‭non-drug‬‭therapies)‬‭taken‬‭within‬‭the‬‭last‬‭30‬‭days‬‭of‬
‭enrollment (see concomitant and allowed treatments sections in the protocol).‬
‭☞‬‭If‬‭no‬‭recent‬‭test‬‭and‬‭evaluation‬‭is‬‭available‬‭within‬‭28‬‭days‬‭before‬‭the‬‭start‬‭of‬‭treatment,‬
‭the following assessments‬‭will be done at baseline:‬
‭●‬ ‭Abdominal and pelvic three-phase CT scan or multiple-phase MRI.‬
‭●‬
‭Baseline‬ ‭evaluation‬ ‭of‬ ‭tumour‬ ‭and‬ ‭its‬ ‭metastasis‬‭,‬ ‭following‬ ‭RECIST‬ ‭criteria‬ ‭1.0‬
‭(Section‬‭7.2.5.1‬‭Radiological‬‭tests‬‭for‬‭the‬‭diagnosis‬‭of‬‭the‬‭disease).‬‭All‬‭patients‬‭should‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭have at least one measurable lesion by three-phase CT scan or multiple-phase MRI.‬
‭☞‬‭In the 14 days prior to the first dose of study‬‭drug women with child-bearing potential:‬
‭Should‬‭have‬‭a‬‭negative‬‭result‬‭in‬‭a‬‭pregnancy‬‭test‬‭or‬‭a‬‭pregnancy‬‭test‬‭in‬‭urine‬‭48‬‭hours‬
‭before‬‭the first dose of the study drug at first and‬‭second treatment.‬
‭☞‬ ‭Within‬ ‭7‬ ‭days‬ ‭after‬ ‭randomization‬‭date,‬‭the‬‭patient‬‭should‬‭start‬‭with‬‭study‬‭treatment‬
‭allocated by randomization.‬
‭7.3.2‬‭Treatment visits‬
‭☞‬‭The following procedures will be completed during‬‭treatment period:‬
‭●‬ ‭EORTC‬‭QLQ-C30‬‭and‬‭the‬‭specific‬‭module‬‭for‬‭NET‬‭EORTC‬‭QLQ‬‭GINET21‬‭Quality‬
‭of‬‭Life‬‭Questionnaire‬‭will‬‭be‬‭administered‬‭at‬‭randomization‬‭,‬‭at‬‭disease‬‭progression‬‭,‬
‭and‬‭at the end of treatment‬‭.‬
‭●‬ ‭A‬‭blood‬‭sample‬‭should‬‭be‬‭taken‬‭for‬ ‭the‬‭determination‬‭of‬‭CgA‬‭levels‬‭at‬‭4‬‭weeks‬‭after‬
‭the start‬‭of study treatment.‬
‭●‬ ‭A‬‭pregnancy‬‭test‬‭in‬‭urine‬‭will‬‭be‬‭performed‬‭monthly,‬‭when‬‭considered‬‭necessary‬‭under‬
‭investigator’s judgement and at the end of treatment (mandatory).‬
‭●‬ ‭In‬‭case‬‭of‬‭toxicity‬‭related‬‭to‬‭everolimus,‬‭the‬‭guidelines‬‭for‬‭dose‬‭adjustment‬‭specified‬‭in‬
‭Tables I and II (protocol, section 5) will be applied.‬
‭●‬ ‭In‬‭case‬‭of‬‭toxicity‬‭related‬‭to‬‭STZ-5FU,‬‭the‬‭recommendations‬‭specified‬‭in‬‭the‬‭Technical‬
‭Sheet of products will be applied.‬
‭☞‬ ‭The‬ ‭following‬ ‭procedures‬ ‭will‬ ‭be‬ ‭completed‬‭at‬‭every‬‭cycle‬‭before‬‭the‬‭intake‬‭of‬‭first‬
‭dose:‬
‭●‬
‭Physical examination.‬
‭●‬
‭Measurement of vital signs.‬
‭●‬
‭Performance status according to ECOG scale.‬
‭●‬ ‭Haematology‬‭and‬‭biochemistry‬‭as‬‭per‬‭Section‬‭7.2.6‬‭Laboratory‬‭measurements.‬‭Results‬
‭of laboratory test done  before start of cycle x treatment, will be recorde in cycle x-1.‬
‭●‬
‭Urinalysis (Section 7.2.6).‬
‭●‬
‭Changes on concomitant medication (including non-drug therapies).‬
‭●‬ ‭Adverse events‬‭occurring during the screening period.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭●‬ ‭Health‬‭resources‬‭incurred‬‭on‬‭affecting‬‭direct‬‭costs,‬‭this‬‭is:‬‭treatments‬‭(drugs,‬‭doses‬‭and‬
‭presentation),‬ ‭visits‬ ‭outside‬ ‭the‬ ‭study‬ ‭(number‬ ‭of‬ ‭visits‬ ‭to‬ ‭the‬ ‭hospital:‬ ‭specialist,‬
‭generalist,‬ ‭and‬ ‭emergency),‬ ‭SAE‬ ‭treatment‬ ‭(drugs‬ ‭given‬ ‭and‬ ‭tests‬ ‭performed)‬ ‭and‬
‭hospitalizations (number of nihgts, number and kind of diagnostic tests performed).‬
‭In‬‭those‬‭patients‬‭with‬‭hepatitis‬‭B‬‭or‬‭C‬‭at‬‭baseline‬‭(screening),‬‭the‬‭results‬‭of‬‭HBV-DNA‬‭and‬
‭HCV-RNA‬‭by‬‭PCR‬‭should‬‭be‬‭available‬‭and‬‭prophylactic‬‭treatment‬‭should‬‭have‬‭been‬‭given‬
‭for‬‭hepatitis‬‭B‬‭before‬‭the‬‭start‬‭of‬‭treatment‬‭with‬‭everolimus‬‭if‬‭applicable‬‭(section‬‭5.1.3‬‭and‬
‭5.1.4, Table III, IV, and V).‬
‭☞‬‭First visit at the start of second treatment‬‭will‬‭also include:‬
‭-‬ ‭Administration‬ ‭of‬ ‭EORTC‬ ‭QLQ-C30‬ ‭and‬ ‭the‬ ‭specific‬ ‭module‬ ‭for‬ ‭NET‬ ‭EORTC‬
‭QLQ-C30‬‭and‬‭QLQ‬‭GINET21‬‭Quality‬‭of‬‭Life‬‭Questionnaire‬‭(whenever‬‭possible,‬‭before‬
‭the visit; strongly recommended‬‭).‬
‭-‬‭Health resources‬‭incurred on as specified on section‬‭7.2.9.‬
‭-‬‭A blood sample‬‭for the determination of CgA levels.‬
‭☞‬‭The following tests will be performed during treatment‬‭with everolimus‬‭:‬
‭Every 12 weeks (3 cycles):‬
‭●‬
‭HCV‬‭reactivation‬‭should‬‭be‬‭monitored‬‭in‬‭patients‬‭with‬‭known‬‭history‬‭of‬‭infection‬
‭by‬ ‭HCV,‬ ‭despite‬ ‭having‬ ‭negative‬ ‭results‬ ‭in‬ ‭the‬ ‭viremia‬ ‭analysis‬ ‭at‬ ‭baseline‬ ‭(also‬ ‭in‬
‭patients receiving treatment and considered as "cured").‬
‭●‬
‭All‬‭the tests specified for day 1 of every cycle.‬
‭●‬
‭Haematology and biochemistry including:‬
‭-‬‭Serum lipid profile (cholesterol, triglycerides,‬‭and LDL and HDL)‬
‭- Coagulation tests (PT/INR).‬
‭-‬‭Monitoring of glucose levels is recommended‬
‭●‬
‭An‬ ‭analysis‬ ‭of‬ ‭HBV-DNA‬ ‭will‬ ‭be‬ ‭performed‬ ‭in‬ ‭patients‬ ‭receiving‬ ‭antiviral‬
‭prophylactic‬‭treatment‬‭or‬‭with‬‭antibodies‬‭against‬‭HBV,‬‭according‬‭to‬‭Table‬‭III‬‭in‬‭section‬
‭5.1.3.‬‭Patients‬‭with‬‭history‬‭of‬‭previous‬‭HCV‬‭infection,‬‭even‬‭if‬‭they‬‭received‬‭treatment‬‭or‬
‭considered‬ ‭as‬ ‭cured,‬ ‭should‬ ‭undergo‬ ‭the‬ ‭analysis‬ ‭of‬ ‭HCV-RNA‬ ‭by‬ ‭PCR‬‭according‬‭to‬
‭section 5.1.4.‬
‭Every 24 weeks (6 cycles):‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭●‬
‭Haematology and biochemistry should also include:‬
‭- Vitamin B‬‭12‬
‭☞‬‭The following tests should be performed during treatment‬‭with STZ-5FU‬
‭●‬
‭Standard Haematology‬
‭●‬
‭Recommended Biochemistry‬
‭☞‬‭The following will be performed for tumour evaluation‬‭(every 12 weeks):‬
‭●‬
‭Chest X-ray and, if applicable, pulmonary capacity test.‬
‭●‬
‭Triphasic CT scan or multiple-phase MRI.‬
‭●‬
‭Response assessment following RECIST criteria version 1.0.‬
‭7.3.3 Visit at the end of treatment‬
‭The‬ ‭information‬ ‭about‬ ‭the‬ ‭end‬ ‭of‬ ‭first‬ ‭treatment‬ ‭(chemotherapy‬ ‭or‬ ‭everolimus)‬ ‭can‬ ‭be‬
‭collected‬ ‭on‬ ‭the‬ ‭first‬ ‭visit‬ ‭of‬ ‭the‬ ‭second‬ ‭treatment‬ ‭(everolimus‬ ‭or‬ ‭chemotherapy),‬ ‭see‬
‭section 7.3.2.‬
‭☞‬‭Visit at the end of second treatment‬‭:‬
‭●‬ ‭Documented‬‭second‬‭disease‬‭progression‬‭by‬‭RECIST‬‭criteria‬‭1.0‬ ‭will‬‭be‬‭recorded‬‭at‬‭this‬
‭visit.‬
‭●‬ ‭Adverse Events since last visit.‬
‭●‬ ‭If‬‭the‬‭patient‬‭is‬‭receiving‬‭prophylactic‬‭treatment‬‭for‬‭HBV,‬‭this‬‭will‬‭be‬‭continued‬‭for‬‭at‬
‭least 4 weeks after the last dose of everolimus is taken.‬
‭●‬ ‭EORTC‬ ‭QLQ-C30‬ ‭and‬ ‭the‬ ‭specific‬ ‭module‬ ‭for‬ ‭NET‬ ‭EORTC‬ ‭QLQ-C30‬ ‭and‬ ‭QLQ‬
‭GINET21‬ ‭Quality‬ ‭of‬ ‭Life‬ ‭Questionnaire‬ ‭(whenever‬ ‭possible,‬ ‭(previously‬ ‭to‬ ‭the‬
‭assessment; it is strongly recommended).‬
‭●‬
‭Physical examination.‬
‭●‬
‭Measurement of vital signs.‬
‭●‬
‭Haematology and biochemistry (Section 7.2.6 Laboratory measurements).‬
‭●‬
‭Urinalysis (Section 7.2.6).‬
‭●‬ ‭Changes‬ ‭on‬ ‭concomitant‬ ‭medication‬ ‭(including‬ ‭non-drug‬ ‭therapies).‬ ‭Anticancer‬
‭treatment‬ ‭given‬ ‭after‬ ‭second‬ ‭disease‬ ‭progression‬‭will‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬‭in‬‭the‬
‭corresponding Concomitant Treatments section.‬
‭●‬
‭Pregnancy test.‬
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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭7.3.4‬‭Follow-up visits‬
‭30 days follow-up (visit at the end of treatment)‬
‭A‬‭follow-up‬‭should‬‭be‬‭performed‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭intake.‬‭This‬‭follow-up‬‭can‬‭be‬
‭performed by phone or face to face (this is, included in the first survival follow-up visit).‬
‭The following information will be collected in the CRF:‬
‭●‬ ‭Anticancer‬‭treatment‬‭given‬‭after‬‭second‬‭disease‬‭progression‬‭will‬‭be‬‭recorded‬‭in‬‭the‬‭CRF‬
‭in the corresponding Concomitant Treatments section.‬
‭●‬ ‭AE since last visit.‬
‭●‬ ‭Life status.‬
‭●‬ ‭Last available date‬
‭When‬ ‭applicable:‬‭main‬‭cause‬‭of‬‭death‬‭(disease‬‭progression,‬‭toxicity,‬‭chronic‬‭disease‬‭not‬
‭related to an AE or to progression, other cause not previously defined).‬
‭Survival follow-up after the end of treatment‬
‭Every‬‭3‬‭months‬‭,‬‭the‬‭patient‬‭will‬‭be‬‭treated‬‭as‬‭per‬‭usual‬‭clinical‬‭practice‬‭and‬‭the‬‭following‬
‭information will be collected in the CRF:‬
‭●‬‭Anticancer treatments received after discontinuation of study treatment.‬
‭●‬‭Life status.‬
‭●‬‭Last date available on their condition.‬
‭●‬‭When‬‭applicable:‬‭main‬‭cause‬‭of‬‭death‬‭(disease‬‭progression,‬‭toxicity,‬‭chronic‬‭disease‬‭not‬
‭related to an AE or to progression, other cause not previously defined).‬
‭This information can be collected at a visit or by phone.‬
‭Schema of study assessments‬
‭The‬ ‭table‬ ‭below‬ ‭shows‬ ‭a‬ ‭list‬ ‭with‬ ‭the‬ ‭assessments‬ ‭to‬ ‭be‬ ‭completed‬ ‭during‬ ‭the‬ ‭study,‬
‭specifying‬ ‭the‬ ‭visits‬ ‭to‬ ‭be‬ ‭completed‬ ‭(ticked‬ ‭with‬ ‭an‬ ‭X‬ ‭in‬ ‭the‬ ‭appropriate‬ ‭box).‬ ‭All‬
‭assessment’s‬‭should‬‭be‬‭part‬‭of‬‭the‬‭source‬‭documents‬‭of‬‭the‬‭study‬‭filed‬‭in‬‭medical‬‭records‬‭at‬
‭site.‬
‭Tests, procedures and visits should be completed as close as possible to study visits.‬
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‭SEQTOR Study‬
‭Protocol code GETNE1206‬
‭Assessment‬
‭Screening‬
‭FIRST TREATMENT‬
‭SECOND TREATMENT‬
‭FOLLOW-UP*‬
‭Cycle 1‬
‭Cycle‬
‭2‬
‭Cycle x‬
‭End of‬
‭Course 1‬
‭Cycle 1‬
‭Cycle 2‬
‭Cycle 3‬
‭End of‬
‭Course 2‬
‭30 days safety‬
‭follow-up‬
‭Every 3‬
‭months‬
‭Visit Number‬
‭1‬
‭2‬
‭3‬
‭4‬
‭n-1‬
‭n‬‭#‬
‭n+1‬
‭n+2‬
‭m‬
‭Time point (days)‬
‭-28 - 0‬‭a‬
‭1‬
‭1‬
‭1‬
‭n-1 plus‬
‭(approxi‬
‭mately‬
‭4weeks)‬
‭m+30d‬
‭Demography and Medical History‬
‭X‬
‭Anticancer‬
‭Treatment‬
‭received after‬
‭discontinuatio‬
‭n of study‬
‭treatment . AE‬
‭since last visit;‬
‭Life Status;‬
‭Last available‬
‭Date; if‬
‭applicable:‬
‭main cause of‬
‭death‬
‭Anticancer‬
‭Treatment‬
‭received‬
‭after‬
‭discontinua‬
‭tion of‬
‭study‬
‭treatment;‬
‭Life Status;‬
‭Last‬
‭available‬
‭date;  if‬
‭applicable:‬
‭main cause‬
‭of death‬
‭Vital signs (height only at baseline)‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭(X)‬
‭X‬
‭X‬
‭X‬
‭Physical examination‬‭b‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭(X)‬
‭X‬
‭X‬
‭X‬
‭ECOG Performance status‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭(X)‬
‭X‬
‭X‬
‭X‬
‭ECG‬‭c‬
‭X‬
‭X‬
‭Haematology‬‭d‬
‭X‬
‭X‬‭(if done‬
‭>14 days‬
‭ago)‬
‭X‬
‭X‬
‭X‬
‭(X)‬
‭X‬
‭X‬
‭X‬
‭Coagulation tests (PT/INR)‬
‭X‬
‭Every 12 weeks‬
‭X‬
‭(X)‬
‭Every 12 weeks‬
‭X‬
‭Serum biochemistry‬‭e‬
‭X‬
‭X***‬‭( (if‬
‭done >14‬
‭days ago)‬
‭X***‬
‭X***‬
‭X‬‭***‬
‭(X***)‬
‭X***‬
‭X***‬
‭X***‬
‭Serum lipid profile‬‭f‬
‭X‬
‭Every 12 weeks‬
‭when on everolimus‬
‭X‬
‭(X)‬
‭Every 12 weeks‬
‭when on everolimus‬
‭X‬
‭Vitamin B12 test‬
‭X‬
‭Every 24 weeks‬
‭when on everolimus‬
‭X‬
‭(X)‬
‭Every 24 weeks‬
‭when on everolimus‬
‭X‬
‭Biomarkers: CgA levels‬
‭X‬
‭At 4 weeks‬
‭X‬
‭(X)‬
‭At 4 weeks‬
‭Urinalysis‬‭g‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬‭f‬
‭(X‬‭f‬‭)‬
‭X‬
‭X‬
‭X‬
‭Serum or urine pregnancy test‬‭h‬
‭X‬
‭X‬
‭X‬
‭X‬
‭(X)‬
‭X‬
‭X‬
‭X‬
‭Concomitant Medication‬
‭X‬
‭Continuous‬
‭Adverse Events‬
‭X‬
‭Continuous‬
‭**Radiological tumour assessment‬‭o‬
‭X‬
‭Every 12 weeks‬
‭X‬
‭Every 12 weeks‬
‭ENETS Score CT copy‬
‭X‬
‭Every 12 weeks‬
‭(X)‬
‭Every 12 weeks‬
‭HE Resources‬
‭x‬
‭x‬
‭x‬
‭x‬
‭(X)‬
‭X‬
‭x‬
‭x‬
‭QoL questionnaire‬
‭X‬
‭(X)‬
‭X‬
‭Chest X-ray, pulmonary function test‬‭p‬
‭X‬
‭Every 12 weeks‬
‭Viremia: HBsAg, anti-HBsAb,‬
‭anti-HBcAb‬‭q‬
‭X‬
‭Viremia: HBV-DNA, HCV-RNA by PCR‬‭r‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Collection of serum sample‬‭s‬
‭X‬
‭Paraffin embedded tumour block‬‭s‬
‭X‬
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‭Protocol code GETNE1206‬
‭# Assessment between brackets should not be repeated whenever timeframe between visits‬‭n-1‬‭and‬‭n‬‭does‬‭not exceed the 4 weeks‬‭.‬
‭* Follow-up visits will include survival information (see section before in this protocol)** Tumour assessment by both, RR and ENETS Score is scheduled at 12‬
‭weeks unless progression is suspected.*** Biochemistry will be performed at baseline, and during study treatment.‬
‭EXPLANATORY NOTES ON THE ABOVE CHART‬
‭a‬‭The screening assessments include: administration‬‭of informed consent, demographics, inclusion/exclusion criteria, relevant clinical history/present medical‬
‭condition, confirmation of advanced NET, diagnosis and extension of cancer (disease metastasis sites), previous anticancer treatment, radiation therapy and/or‬
‭surgery, complete physical examination, and vital signs. QoL questionnaire and blood sample for future research and determination of CgA levels.‬
‭b‬‭Significant findings during the physical examination‬‭will  be recorded in the adverse event pages, as appropriate.‬
‭c‬‭The baseline ECG may be repeated at the investigator’s‬‭discretion if signs and symptoms of cardiotoxicity occur. Significant findings will be recorded in the‬
‭corresponding adverse event pages.‬
‭d‬‭Haematology should include: haemoglobin, haematocrit,‬‭platelets, WBC, total and differential WBC.‬
‭e‬‭Serum biochemistry measurement should include determination‬‭of: sodium, potassium, ion chloride, bicarbonate, creatinine, albumin, total protein, AST (SGOT),‬
‭ALT (SGPT), total bilirubin, alkaline phosphatase, uric acid, BUN, calcium, magnesium, phosphate, total LDH and fasting glucose when appropriate (see protocol‬
‭relevant section).‬
‭f‬ ‭Serum lipid profile will be repeated every 12 weeks‬‭when patient on everolimus treatment and will include total cholesterol, triglycerides, LDL, and HDL‬
‭determinations‬
‭g‬‭Standard urinalysis will include: pH, proteins,‬‭glucose, blood, ketones and WBC should be performed during the screening. In the next visits a dipstick should be‬
‭used for routine assessment. In the event of any relevant anomaly, a quantitative assessment will be performed..‬
‭h‬ ‭All women with child-bearing potential will have‬‭a negative serum pregnancy test in the 14 days prior to the first dose of study drug, and an urine test 48 hours‬
‭before the first administration of study treatment.  Whenever necessary throughout the study, pregnancy test may be performed in urine.‬
‭o‬ ‭The scanner (triphasic CT) will be performed using‬‭the same technique at baseline and at any assessment during the study.‬
‭P‬‭At screening and every 12 weeks, an X-ray (or chest‬‭CT) will be performed. A pulmonary function test and bronchoscopy with biopsy (and BAL) will be performed‬
‭if considered clinically necessary.‬
‭q‬ ‭Viremia: Presence of risk factors and history of‬‭hepatitis B or C will be determined in all patients. It is recommended a prophylactic treatment for those patients‬
‭with positive results in the HBV-DNA or HBsAg tests 1 to 2 weeks before starting with‬‭everolimus.‬‭Antiviral‬‭prophylactic treatment will continue to be administered‬
‭throughout the study and for at least 4 weeks after the last dose of‬‭everolimus‬‭. Patients with risk factors‬‭for infection by hepatitis C virus should undergo an analysis‬
‭of HCV-RNA by PCR.‬
‭r‬ ‭Viremia: An analysis of HBV-DNA will be performed‬‭in patientsreceiving antiviral prophylactic treatment or with antibodies against HBV, according to Table III in‬
‭section 5.1.3 Patients with history of previous HCV infection, even if they received treatment or considered as cured, should undergo the analysis of HCV-RNA by‬
‭PCR according to section 5.1.4.‬
‭s‬‭Paraffin blocks of tumour (primary or methastasis)‬‭will be sent to Centre for Applied Research on Cancer (arc-net) in Italy; blood samples will be sent to Free‬
‭Hospital in London. Those biological samples will be used for future translational sub-study purposes on prediction factors.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭7.4‬
‭SAFETY ASSESSMENTS‬
‭Safety assessments will include:‬
‭●‬
‭adverse events recording and monitoring (serious as well as non-serious adverse events).‬
‭●‬
‭regular monitoring of laboratory determinations‬
‭●‬
‭regular monitoring of vital signs and physical exam‬
‭Any‬‭degree‬‭of‬‭clinical‬‭adverse‬‭event‬‭will‬‭be‬‭evaluated‬‭as‬‭compared‬‭to‬‭normal‬‭reference‬‭values‬‭and‬
‭according to‬‭CTCAE version 4.0.‬
‭Dose‬ ‭reduction‬ ‭will‬ ‭be‬ ‭performed‬ ‭according‬‭to‬‭recommendations‬‭followed‬‭in‬‭former‬‭studies‬‭of‬
‭everolimus in pNET/recommended on the Investigator’s Brochure.‬
‭7.4.1‬‭Adverse events‬
‭Those‬ ‭patients‬ ‭included‬ ‭in‬ ‭the‬ ‭study‬ ‭who‬ ‭experience‬ ‭disease‬ ‭progression‬ ‭will‬ ‭be‬ ‭treated‬
‭following the standard clinical protocols at site.‬
‭Bi-annual‬‭cumulative‬‭listings‬‭of‬‭all‬‭serious‬‭and‬‭non-serious‬‭events‬‭will‬‭be‬‭generated‬‭throughout‬
‭the study.‬
‭Definitions‬
‭An‬‭adverse‬‭event‬‭(AE)‬‭is‬‭defined‬‭as‬‭any‬‭untoward‬‭medical‬‭occurrence‬‭in‬‭a‬‭patient‬‭or‬‭clinical‬
‭investigation‬ ‭subject‬ ‭administered‬ ‭a‬ ‭pharmaceutical‬ ‭product‬ ‭and‬ ‭which‬ ‭does‬ ‭not‬ ‭necessarily‬
‭have‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭with‬ ‭this‬ ‭treatment.‬ ‭An‬ ‭adverse‬ ‭event‬ ‭(AE)‬ ‭can‬ ‭therefore‬ ‭be‬ ‭any‬
‭unfavourable‬‭and‬‭unintended‬‭sign‬‭(e.g.‬‭an‬‭abnormal‬‭laboratory‬‭finding),‬‭symptom,‬‭or‬‭disease‬
‭temporally‬ ‭associated‬ ‭with‬ ‭the‬ ‭use‬ ‭of‬ ‭a‬ ‭medicinal‬ ‭(investigational)‬ ‭product,‬ ‭whether‬ ‭or‬ ‭not‬
‭related to the investigational medicinal product.‬
‭An‬‭adverse reaction (AR)‬
‭A response to a medicinal product which is noxious and unintended.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Response‬‭in‬‭this‬‭context‬‭means‬‭that‬‭a‬‭causal‬‭relationship‬‭between‬‭a‬‭medicinal‬‭product‬‭and‬‭an‬
‭adverse event is at least a reasonable possibility.‬
‭Adverse‬‭reactions‬‭may‬‭arise‬‭from‬‭use‬‭of‬‭the‬‭product‬‭within‬‭or‬‭outside‬‭the‬‭terms‬‭of‬‭the‬‭marketing‬
‭authorisation‬ ‭or‬ ‭from‬ ‭occupational‬ ‭exposure.‬ ‭Conditions‬ ‭of‬ ‭use‬ ‭outside‬ ‭the‬ ‭marketing‬
‭authorisation include off-label use, overdose, misuse, abuse and medication errors.‬
‭An‬‭unexpected‬‭adverse‬‭reaction‬‭is‬‭any‬‭adverse‬‭reaction,‬‭the‬‭nature‬‭or‬‭severity‬‭of‬‭which‬‭is‬‭not‬
‭consistent‬‭with‬‭the‬‭applicable‬‭product‬‭information‬‭(for‬‭instance,‬‭investigator’s‬‭brochure‬‭for‬‭an‬
‭unauthorised investigational product or summary of product characteristics when authorised).‬
‭A‬‭Serious‬‭Adverse‬‭Event‬‭(SAE)‬‭is‬‭defined‬‭as‬‭any‬‭undesirable‬‭experience‬‭occurring‬‭to‬‭a‬‭patient‬
‭whether‬‭or‬‭not‬‭considered‬‭related‬‭to‬‭the‬‭protocol‬‭treatment.‬‭A‬‭SAE‬‭considered‬‭to‬‭be‬‭related‬‭to‬
‭the protocol treatment, is defined as a Serious Adverse Reaction.‬
‭Any‬ ‭AE‬ ‭or‬ ‭AR‬ ‭ocurred‬ ‭at‬ ‭any‬ ‭dose‬ ‭should‬ ‭be‬ ‭classified‬‭as‬‭an‬‭SAE‬‭if‬‭any‬‭of‬‭the‬‭following‬
‭occurs:‬
‭●‬ ‭results in death (this is an outcome, not an event),‬
‭●‬ ‭is‬‭life-threatening‬‭(i.e.,‬‭an‬‭event‬‭where‬‭the‬‭subject‬‭was‬‭at‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭of‬‭the‬
‭event;‬ ‭it‬ ‭does‬ ‭not‬ ‭refer‬ ‭to‬‭an‬‭event‬‭which‬‭might‬‭have‬‭caused‬‭death‬‭had‬‭it‬‭were‬‭more‬
‭severe).‬
‭●‬ ‭requires hospitalization or extension of existing inpatients hospitalization,‬
‭●‬ ‭results in persistent or significant disability or incapacity,‬
‭●‬ ‭is a congenital abnormality or birth defect,‬
‭●‬ ‭results‬‭in‬‭any‬‭other‬‭medically‬‭important‬‭condition‬‭(i.e.,‬‭important‬‭adverse‬‭reactions‬‭that‬
‭are‬‭not‬‭immediately‬‭life-threatening‬‭or‬‭do‬‭not‬‭result‬‭in‬‭death‬‭or‬‭hospitalisation,‬‭but‬‭may‬
‭jeopardize‬ ‭the‬ ‭patient‬ ‭or‬‭require‬‭an‬‭intervention‬‭to‬‭prevent‬‭any‬‭of‬‭the‬‭other‬‭outcomes‬
‭listed above).‬
‭7.4.2‬‭Adverse event reporting‬
‭Monitoring‬‭and‬‭safety‬‭of‬‭the‬‭investigational‬‭treatment‬‭will‬‭be‬‭performed‬‭in‬‭accordance‬
‭with‬‭the‬‭Detailed‬‭Guidance‬‭2011/C‬‭172/01‬‭based‬‭on‬‭Article‬‭18‬‭of‬‭Directive‬‭2001/20/EC‬‭of‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭the‬‭European‬‭Parliament‬‭and‬‭of‬‭the‬‭Council‬‭of‬‭4‬‭April‬‭2001‬‭on‬‭the‬‭approximation‬‭of‬‭the‬‭laws,‬
‭regulations‬‭and‬‭administrative‬‭provisions‬‭of‬‭the‬‭Member‬‭States‬‭relating‬‭to‬‭the‬‭implementation‬
‭of‬‭good‬‭clinical‬‭practice‬‭in‬‭the‬‭conduct‬‭of‬‭clinical‬‭trials‬‭on‬‭medicinal‬‭products‬‭for‬‭human‬‭use‬
‭(http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm;‬ ‭"Detailed‬ ‭guidance‬ ‭on‬
‭the‬ ‭collection,‬ ‭verification‬ ‭and‬ ‭presentation‬ ‭of‬ ‭adverse‬ ‭event/reaction‬ ‭reports‬ ‭arising‬ ‭from‬
‭clinical trials on medicinal products for human use”).‬
‭Reporting criteria‬
‭Any‬‭SAE‬‭occurring‬‭from‬‭the‬‭time‬‭the‬‭patient‬‭signs‬‭Informed‬‭Consent‬‭for‬‭the‬‭study‬‭until‬‭30‬
‭days‬‭after‬‭the‬ ‭intake‬‭of‬‭the‬‭last‬‭dose‬‭of‬‭treatment‬‭must‬‭be‬‭reported‬‭to‬‭the‬‭Pharmacovigilance‬
‭Unit within 24 hours.‬
‭Death for any cause different from disease progression must be reported within 24 hours.‬
‭Any‬‭death‬‭considered‬‭to‬‭be‬‭related‬‭to‬‭study‬‭drugs,‬‭regardless‬‭of‬‭the‬‭time‬‭since‬‭treatment‬‭was‬
‭interrupted/finished must be reported immediately.‬
‭An‬ ‭experience‬ ‭will‬ ‭not‬ ‭be‬ ‭considered‬ ‭as‬ ‭an‬ ‭SAEs‬ ‭for‬ ‭reporting‬ ‭purposes‬ ‭if‬ ‭any‬ ‭of‬ ‭the‬
‭following occurs:‬
‭●‬ ‭signs‬‭and‬‭symptoms‬‭of‬‭study‬‭disease,‬‭unless‬‭they‬‭are‬‭more‬‭severe‬‭than‬‭expected‬‭for‬‭the‬
‭patient’s condition.‬
‭●‬ ‭disease progression, unless more severe than expected for patient’s condition.‬
‭●‬ ‭hospitalisation‬‭planned‬‭before‬‭patient‬‭gives‬‭consent‬‭to‬‭participate‬‭in‬‭the‬‭study‬‭not‬‭lasting‬
‭more than expected.‬
‭SAE reporting procedures‬
‭SAEs‬ ‭will‬ ‭be‬ ‭reported‬ ‭to‬ ‭the‬ ‭Pharmacovigilance‬ ‭(PV)‬ ‭Unit‬ ‭of‬ ‭Kanthar-Health,‬ ‭for‬ ‭the‬
‭follow-up, documentation and reporting of the event:‬
‭Pharmacovigilance Department‬
‭Kantar Health‬
‭Fax: + 49 89 919290841‬
‭Email: safety-munich@kantarhealth.com‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Initial report‬
‭The‬‭SAE‬‭form‬‭will‬‭be‬‭sent‬‭automatically‬‭via‬‭the‬‭EDC‬‭system‬‭(eCRF)‬‭or‬‭by‬‭fax‬‭within‬‭24‬‭hours‬
‭after the event is first known.‬
‭The‬‭investigator‬‭will‬‭document‬‭any‬‭SAE‬‭in‬‭the‬‭EDC‬‭system‬‭within‬‭24‬‭hours‬‭after‬‭the‬‭event‬‭is‬
‭first‬‭known.‬‭After‬‭completion‬‭of‬‭the‬‭SAE‬‭form,‬‭the‬‭investigator‬‭will‬‭send‬‭a‬‭pdf‬‭of‬‭the‬‭report‬‭via‬
‭the‬ ‭EDC‬ ‭system‬ ‭(eCRF)‬ ‭to‬ ‭Kantar‬ ‭Health.‬ ‭In‬ ‭case‬ ‭of‬ ‭technical‬ ‭issues,‬ ‭the‬ ‭SAE‬ ‭can‬ ‭be‬
‭documented‬ ‭on‬ ‭the‬ ‭paper‬ ‭SAE‬ ‭form‬ ‭included‬ ‭in‬ ‭the‬ ‭investigator’s‬ ‭file‬ ‭and‬ ‭faxed‬ ‭to‬‭Kantar‬
‭Health.‬
‭This first report should contain at least‬‭the following‬‭information:‬
‭●‬ ‭Name of the SAE‬
‭●‬ ‭No. of patient in the study‬
‭●‬ ‭Date of event onset‬
‭●‬ ‭Severity‬
‭●‬ ‭Resolution/Outcome‬
‭Severity‬‭of‬‭the‬‭event‬‭:‬‭The‬‭greatest‬‭severity‬‭shown‬‭by‬‭the‬‭patient‬‭throughout‬‭the‬‭event‬‭will‬‭be‬
‭reported.‬ ‭The‬ ‭severity‬ ‭of‬ ‭the‬ ‭AE‬ ‭will‬ ‭be‬ ‭assessed‬ ‭according‬ ‭to‬ ‭version‬ ‭4.0‬ ‭of‬ ‭the‬ ‭CTCAE‬
‭(Common Terminology Criteria for Adverse Events):‬‭http://ctep.cancer.gov/reporting/ctc.html‬‭.‬
‭AEs for which the CTCAE does not define a severity rating scale will be assessed as follows:‬
‭Grade‬‭1=‬‭mild,‬‭Grade‬‭2=‬‭moderate,‬‭Grade‬‭3=‬‭severe,‬‭Grade‬‭4=‬‭life-threatening,‬‭and‬‭Grade‬‭5‬‭=‬
‭death.‬
‭Causal‬‭relationship‬‭:‬‭The‬‭investigator‬‭must‬‭evaluate‬‭the‬‭relationship‬‭between‬‭each‬‭investigational‬
‭product‬ ‭and‬‭the‬‭onset‬‭of‬‭each‬‭SAE.‬‭The‬‭investigator‬‭will‬‭use‬‭clinical‬‭criteria‬‭to‬‭establish‬‭the‬
‭relationship;‬ ‭this‬ ‭information‬ ‭will‬ ‭be‬ ‭recorded‬ ‭on‬ ‭the‬ ‭relevant‬ ‭CRF‬ ‭section.‬ ‭The‬ ‭principal‬
‭investigator‬ ‭and‬ ‭the‬ ‭co-investigator‬ ‭will‬ ‭eventually‬ ‭decide‬ ‭whether‬ ‭or‬ ‭not‬ ‭these‬ ‭events‬ ‭are‬
‭related‬ ‭to‬ ‭the‬ ‭study‬ ‭treatment‬ ‭(i.e.,‬ ‭unrelated,‬ ‭probably‬ ‭related‬ ‭and‬ ‭non-evaluable)‬ ‭and‬ ‭the‬
‭decision will be recorded in the serious adverse event form.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭The following definitions will be used for the assessment of causal relationship:‬
‭Relationship with study drug‬
‭Description‬
‭UNRELATED‬
‭There‬ ‭is‬ ‭no‬ ‭evidence‬ ‭of‬ ‭a‬ ‭causal‬ ‭relationship‬ ‭with‬ ‭study‬
‭treatment.‬
‭PROBABLY RELATED‬
‭There‬‭is‬‭(some)‬‭evidence‬‭suggesting‬‭a‬‭causal‬‭relationship‬
‭with‬ ‭study‬ ‭treatment‬ ‭and‬ ‭the‬ ‭influence‬ ‭of‬ ‭other‬‭factors‬‭is‬
‭improbable or nonexistent.‬
‭NON-EVALUABLE‬
‭There‬ ‭is‬ ‭insufficient‬‭or‬‭incomplete‬‭evidence‬‭to‬‭establish‬‭a‬
‭clinical‬ ‭criterion‬ ‭of‬ ‭the‬ ‭causal‬ ‭relationship‬ ‭with‬ ‭study‬
‭treatment.‬
‭The‬
‭The‬‭reference‬‭document‬‭for‬‭streptozotocin-5FU‬‭chemotherapy‬‭and‬‭everolimus‬‭is‬‭the‬‭Summary‬
‭of‬ ‭product‬ ‭characteristics‬ ‭(‬‭http://www.emea.eu.int/htms/human/epar/epar.htm#‬‭)‬ ‭or‬ ‭Technical‬
‭Sheet.‬
‭Reporting to Health Authorities‬
‭The‬‭Pharmacovigilance‬‭Unit‬‭delegated‬‭on‬‭by‬‭GETNE‬‭(Kanthar‬‭Health),‬‭will‬‭notify‬‭to‬‭the‬‭local‬
‭Health‬‭Authorities,‬‭including‬‭the‬‭European‬‭Medicine‬‭Agency‬‭(EMA)‬‭via‬‭Eudravigilance,‬‭of‬‭all‬
‭suspected‬‭unexpected‬‭serious‬‭adverse‬‭reaction‬‭(SUSARs),‬‭occurring‬‭during‬‭the‬‭study‬‭(expedite‬
‭reporting);‬‭Kantar‬‭Health‬‭unit‬‭will‬‭also‬‭be‬‭responsible‬‭for‬‭the‬‭generation‬‭of‬‭the‬‭annual‬‭safety‬
‭report of the study.‬
‭Follow-up reporting‬
‭Follow-up‬‭reports‬‭of‬‭on‬‭going‬‭SAEs‬‭should‬‭be‬‭made‬‭every‬‭15‬‭days‬‭by‬‭the‬‭reporting‬‭site,‬‭until‬
‭its‬‭resolution‬‭or‬‭stabilisation‬‭or‬‭when‬‭there‬‭is‬‭an‬‭alternative‬‭explanation‬‭for‬‭the‬‭event,‬‭using‬‭the‬
‭adverse event form of the eCRF or study forms available in the Investigator’s File.‬
‭7.4.3‬‭Pregnancies‬
‭Each‬ ‭pregnancy‬ ‭occurring‬ ‭in‬ ‭a‬ ‭patient‬ ‭taking‬ ‭study‬ ‭drug‬ ‭should‬ ‭be‬ ‭notified‬ ‭to‬ ‭the‬
‭Pharmacovigilance‬‭Unit‬‭within‬‭24‬‭hours‬‭since‬‭it‬‭is‬‭first‬‭known.‬‭Pregnancy‬‭should‬‭be‬‭followed‬
‭up‬‭to‬‭determine‬‭outcome,‬‭including‬‭spontaneous‬‭or‬‭voluntary‬‭termination,‬‭details‬‭of‬‭birth,‬‭and‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭the‬‭presence‬‭or‬‭absence‬‭of‬‭any‬‭birth‬‭defect,‬‭congenital‬‭abnormalities‬‭or‬‭maternal‬‭and‬‭newborn‬
‭complications.‬ ‭The‬ ‭follow-up‬ ‭of‬ ‭pregnancies‬ ‭should‬ ‭include‬ ‭an‬ ‭assessment‬ ‭of‬ ‭possible‬
‭relationship‬ ‭of‬ ‭study‬ ‭drugs‬ ‭with‬ ‭any‬ ‭pregnancy‬ ‭outcome.‬ ‭Any‬ ‭SAE‬ ‭experienced‬ ‭during‬
‭pregnancy should be recorded in the SAE form.‬
‭8.‬
‭STATISTICS‬
‭8.1 PRIMARY ENDPOINT‬
‭PFS‬‭is‬‭used‬‭as‬‭the‬‭primary‬‭endpoint‬‭for‬‭the‬‭evaluation‬‭of‬‭metastatic‬‭disease‬‭treatment‬‭for‬‭the‬
‭control‬ ‭of‬ ‭the‬ ‭disease‬ ‭(not‬ ‭curative‬ ‭intention),‬ ‭where‬ ‭patients‬ ‭follow‬ ‭diferent‬ ‭treatments‬ ‭at‬
‭relapse.‬‭PFS‬‭is‬‭particularly‬‭useful‬‭to‬‭evaluate‬‭slow-growing‬‭diseases‬‭difficult‬‭to‬‭cure,‬‭such‬‭as‬
‭low-grade‬‭lymphoma,‬‭renal‬‭carcinoma,‬‭CHC‬‭or‬‭NET.‬‭PFS‬‭rates‬‭represents‬‭an‬‭early‬‭marker‬‭of‬
‭treatment efficacy over time.‬
‭Proportion‬‭of‬‭patients‬‭who‬‭are‬‭alive‬‭without‬‭progression‬‭to‬‭Course‬‭1‬‭therapy‬‭at‬‭12‬‭months‬‭from‬
‭the date of randomization in STZ based CT vs Everolimus arms.‬
‭Main analysis definition of an Event:‬
‭Patient will be considered as an Event in the following cases:‬
‭●‬ ‭If first progression occurs before or in 48th week radiological evaluation.‬
‭●‬ ‭If‬ ‭first‬ ‭progression‬ ‭occurs‬ ‭in‬ ‭60th‬ ‭week‬ ‭radiological‬ ‭evaluation‬ ‭and‬ ‭patient‬ ‭did‬ ‭not‬
‭received trial treatment from week 52.‬
‭●‬ ‭If death occurs before week 52.‬
‭●‬ ‭If‬ ‭death‬ ‭occurs‬ ‭between‬ ‭week‬ ‭52‬ ‭and‬ ‭theoretical‬ ‭date‬ ‭for‬ ‭60th‬ ‭week‬‭for‬‭radiological‬
‭evaluation, and death cause is disease under study or toxicity due to trial treatment‬
‭Patient will be considered as Event free in the following cases:‬
‭●‬ ‭If patient is alive and free of progression on 60th week radiological evaluation.‬
‭●‬ ‭If‬ ‭patient‬ ‭was‬ ‭free‬ ‭of‬ ‭progression‬ ‭on‬ ‭48‬ ‭the‬ ‭week‬ ‭radiological‬ ‭evaluation,‬ ‭suffers‬
‭progression‬‭on‬‭60th‬‭week‬‭radiological‬‭evaluation‬‭but‬‭receives‬‭at‬‭minimum‬‭one‬‭cycle‬‭of‬
‭treatment posterior to 52th week.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭●‬ ‭If‬‭death‬‭occurs‬‭between‬‭52th‬‭week‬‭plus‬‭one‬‭day‬‭and‬‭the‬‭theoretical‬‭date‬‭for‬‭60th‬‭week‬
‭for‬‭radiological‬‭evaluation,‬‭and‬‭cause‬‭of‬‭death‬‭was‬‭not‬‭related‬‭to‬‭nor‬‭disease‬‭under‬‭study‬
‭neither toxicity due to trial treatments‬
‭8.1.2‬
‭Sensitivity‬ ‭analysis‬ ‭and‬ ‭optimistic‬ ‭and‬ ‭conservative‬ ‭event‬
‭definitions‬
‭Since‬‭12‬‭months‬‭has‬‭been‬‭chosen‬‭as‬‭the‬‭time‬‭point‬‭(52‬‭weeks)‬‭for‬‭the‬‭main‬‭analysis‬‭and‬‭radiological‬
‭evaluations‬‭were‬‭planned‬‭for‬‭48‬‭and‬‭60‬‭weeks,‬‭it‬‭is‬‭necessary‬‭to‬‭establish‬‭a‬‭well‬‭defined‬‭criteria‬‭for‬
‭considering‬ ‭patients‬‭as‬‭event‬‭or‬‭event‬‭free,‬‭especially‬‭when‬‭the‬‭event‬ ‭happens‬‭between‬‭these‬‭two‬
‭radiological evaluations.‬
‭In‬‭order‬‭to‬‭measure‬‭the‬‭robustness‬‭of‬‭the‬‭result,‬‭a‬‭sensitivity‬‭analysis‬‭will‬‭be‬‭performed‬‭adding‬‭two‬
‭scenarios.‬‭Therefore‬‭they‬‭will‬‭be‬‭three‬‭scenarios:‬‭Main‬‭analysis‬‭(already‬‭defined),‬‭conservative‬‭and‬
‭optimistic.‬
‭Conservative event scenario:‬
‭Event:‬
‭●‬ ‭If first progression occurs before or in 48th week radiological evaluation.‬
‭●‬ ‭If‬‭first‬‭progression‬‭occurs‬‭in‬‭60th‬‭week‬‭radiological‬‭evaluation‬‭regardless‬‭patient‬‭had‬‭received‬
‭study treatment between week 48 and 60.‬
‭●‬ ‭If death occurs before week 52.‬
‭●‬ ‭If‬ ‭death‬ ‭occurs‬ ‭between‬ ‭week‬ ‭52‬ ‭and‬ ‭theoretical‬ ‭date‬ ‭for‬ ‭60th‬ ‭week‬ ‭for‬ ‭radiological‬
‭evaluation, whichever had been the cause of death.‬
‭Event free:‬
‭●‬ ‭If patient is alive and free of progression on 60th week radiological evaluation.‬
‭Optimistic event scenario:‬
‭Event:‬
‭●‬ ‭If first progression occurs before or in 48th week radiological evaluation.‬
‭●‬ ‭If death occurs before week 52.‬
‭Event free:‬
‭●‬ ‭If patient is alive and free of progression on 60th week radiological evaluation.‬
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‭●‬ ‭If‬‭patient‬‭was‬‭free‬‭of‬‭progression‬‭on‬‭48‬‭th‬‭week‬‭radiological‬‭evaluation,‬‭suffers‬‭progression‬‭on‬
‭60th week radiological evaluation regardless patient had received or not study treatment‬
‭●‬ ‭If‬‭death‬‭occurs‬‭between‬‭52th‬‭week‬‭plus‬‭one‬‭day‬‭and‬‭the‬‭theoretical‬‭date‬‭for‬‭60th‬‭week‬‭for‬
‭radiological evaluation, whichever had been the cause of death‬
‭8.2‬
‭S‬‭ECONDARY‬‭ENDPOINTS‬
‭The following definitions will be used for the secondary endpoints:‬
‭Second‬‭progression‬‭free‬‭survival‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭randomization‬‭to‬‭the‬
‭date of second disease progression.‬
‭Progression‬‭free‬‭survival‬‭Course‬‭1‬‭(PFS1)‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭start‬‭of‬‭the‬‭first‬
‭treatment to the first disease progression or death for any cause, whichever comes first.‬
‭Progression‬‭free‬‭survival‬‭Course‬‭2‬‭(PFS2)‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭start‬‭of‬‭the‬
‭second‬ ‭treatment‬ ‭to‬ ‭the‬‭second‬‭disease‬‭progression‬‭or‬‭death‬‭for‬‭any‬‭cause,‬‭whichever‬‭comes‬
‭first.‬
‭Overall‬‭survival‬‭(OS)‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭patient‬‭randomization‬‭to‬‭the‬‭date‬‭of‬
‭death‬ ‭for‬ ‭any‬ ‭cause.‬ ‭OS‬ ‭will‬ ‭be‬ ‭evaluated‬ ‭at‬ ‭the‬ ‭end‬ ‭of‬ ‭study.‬ ‭It‬‭is‬‭estimated‬‭that‬‭all‬‭study‬
‭patients will be on disease progression at this point.‬
‭The‬ ‭interest‬ ‭of‬ ‭performing‬ ‭an‬‭OS‬‭assessment‬‭with‬‭mature‬‭data‬‭(i.e.,‬‭when‬‭death‬‭of‬‭all‬‭study‬
‭patients has occurred), will be evaluated before study clossure.‬
‭Time‬‭to‬‭first‬‭progression‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭randomization‬‭to‬‭the‬‭date‬‭of‬‭first‬
‭disease progression (this happens during the first treatment administrated in sequence).‬
‭Time‬‭to‬‭second‬‭progression‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭from‬‭the‬‭date‬‭of‬‭randomization‬‭to‬‭the‬‭date‬‭of‬
‭second‬ ‭disease‬ ‭progression‬ ‭(this‬ ‭happens‬ ‭during‬ ‭the‬ ‭second‬ ‭treatment‬ ‭administrated‬ ‭in‬
‭sequence).‬
‭Time‬‭from‬‭first‬‭progression‬‭to‬‭second‬‭progression‬‭is‬‭defined‬‭as‬‭the‬‭time‬‭between‬‭the‬‭date‬‭of‬‭first‬
‭disease progression to the date of second disease progression.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Response‬‭Rate‬‭is‬‭defined‬‭as‬‭the‬‭rate‬‭of‬‭objective‬‭response‬‭(CR+PR+SD)‬‭measured‬‭by‬‭RECIST‬
‭criteria version 1.0.‬
‭Biochemical reasponse: reduction on CgA levels at four weeks of the start with study  treatment.‬
‭Cost‬ ‭per‬ ‭progression‬ ‭free‬ ‭survival‬ ‭gain‬ ‭will‬ ‭be‬ ‭estimated‬ ‭using‬ ‭the‬ ‭Incremental‬
‭Cost-effectiveness‬ ‭ratio‬ ‭(ICER)‬ ‭defined‬ ‭as‬ ‭the‬ ‭ratio‬ ‭between‬ ‭the‬ ‭difference‬ ‭of‬ ‭costs‬
‭incurred‬‭on‬‭by‬‭each‬‭treatment‬‭arm‬‭and‬‭the‬‭difference‬‭of‬‭first‬‭and/or‬‭second‬‭progression‬‭free‬
‭survival‬‭at‬‭each‬‭arm.‬‭D‬‭irects‬‭costs‬‭include‬‭the‬‭use‬‭of‬‭the‬‭following‬‭health‬‭resources:‬‭treatments,‬
‭visits and hospitalizations.‬
‭8.3‬
‭A‬‭NALYSIS‬‭POPULATIONS‬
‭The main analysis of efficacy will be based on ITT population.‬
‭Intention‬ ‭to‬ ‭treat‬ ‭(ITT)‬ ‭population‬ ‭will‬ ‭comprise‬ ‭all‬ ‭randomized‬ ‭patients‬‭.‬ ‭Those‬ ‭patients‬ ‭died‬
‭during‬‭the‬‭first‬‭study‬‭treatment‬‭will‬‭be‬‭also‬‭considered‬‭for‬‭the‬‭ITT‬‭analysis‬‭as‬‭a‬‭“failure”.‬‭Patients‬
‭who‬ ‭will‬ ‭not‬ ‭receive‬ ‭second‬ ‭treatment‬ ‭due‬ ‭to‬ ‭different‬ ‭reasons‬ ‭(toxicity,‬ ‭patients’‬ ‭will‬ ‭of‬ ‭not‬
‭receive more treatment,…etc)  will be classified for intention to treat population as “failure”..‬
‭Per‬‭protocol‬‭(PP)‬‭population‬‭will‬‭comprise‬‭all‬‭patients‬‭of‬‭the‬‭ITT‬‭population‬‭meeting‬‭all‬‭screening‬
‭criteria‬‭(no‬‭major‬‭protocol‬‭violation)‬‭and‬‭population‬‭completing‬‭study‬‭treatment‬‭according‬‭to‬‭the‬
‭protocol‬‭or‬‭been‬‭withdrawn‬‭from‬‭treatment‬‭due‬‭to‬‭an‬‭early‬‭disease‬‭progression‬‭(i.e.,‬‭within‬‭the‬
‭first 12 weeks of each treatment).‬
‭Efficacy population (per protocol)‬
‭Patients must be dosed with the first therapy (everolimus or chemotherapy),‬
‭Patients‬ ‭being‬ ‭dead‬ ‭before‬ ‭first‬ ‭progression‬ ‭will‬ ‭not‬ ‭be‬ ‭included‬ ‭into‬ ‭the‬ ‭group‬ ‭from‬ ‭first‬ ‭to‬
‭second progression free survival analysis‬‭.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Patients‬‭with‬‭no‬‭documented‬‭first‬‭progression‬‭won’t‬‭be‬‭included‬‭into‬‭the‬‭analysis‬‭from‬‭first‬‭to‬
‭second progression analysis‬‭.‬
‭Patients‬‭dead‬‭because‬‭of‬‭disease‬‭progression‬‭will‬‭be‬‭censored‬‭at‬‭date‬‭of‬‭death‬‭for‬‭time‬‭to‬‭first‬
‭progression analysis‬‭.‬
‭At‬‭the‬‭end‬‭of‬‭the‬‭study‬‭as‬‭scheduled‬‭before‬‭in‬‭this‬‭protocol,‬‭and‬‭before‬‭locking‬‭the‬‭data‬‭base,‬‭the‬
‭relevance‬‭of‬‭performing‬‭an‬‭assessment‬‭of‬‭overall‬‭survival‬‭with‬‭mature‬‭data‬‭will‬‭be‬‭evaluated,‬‭i.e.,‬
‭continuing the follow-up of all patients to death‬‭.‬
‭Safety population‬
‭Safety‬‭population‬‭will‬‭comprise‬‭all‬‭patients‬‭included‬‭in‬‭the‬‭study,‬‭having‬‭taken‬‭at‬‭least‬‭one‬‭dose‬
‭of‬ ‭either‬ ‭of‬ ‭the‬ ‭two‬‭study‬‭drugs‬‭and‬‭undergoing‬‭at‬‭least‬‭one‬‭safety‬‭analysis‬‭after‬‭the‬‭baseline‬
‭assessment.‬‭Patients‬‭receiving‬‭at‬‭least‬‭one‬‭dose‬‭of‬‭the‬‭study‬‭drug,‬‭but‬‭with‬‭no‬‭safety‬‭data‬‭of‬‭any‬
‭type after the start of treatment will be excluded from the safety population.‬
‭8.4‬
‭S‬‭TATISTICAL‬‭M‬‭ETHODS‬
‭All‬ ‭calculations‬ ‭will‬ ‭be‬ ‭made‬ ‭with‬ ‭the‬ ‭statistical‬ ‭package‬ ‭SAS‬ ‭version‬ ‭9‬ ‭or‬ ‭SPSS‬ ‭version‬‭16,‬
‭respectively,‬‭or‬‭a‬‭subsequent‬‭version.‬‭The‬‭use‬‭of‬‭bilateral‬‭tests‬‭will‬‭be‬‭applied,‬‭with‬‭a‬‭significance‬
‭level of 0.05.‬
‭8.4.1‬‭Randomization procedure‬
‭Arms‬ ‭assignment‬ ‭will‬ ‭be‬ ‭performed‬ ‭by‬ ‭randomization‬ ‭blocks.‬ ‭The‬ ‭stratifying‬ ‭factor‬ ‭to‬ ‭be‬
‭considered‬‭for‬‭randomization‬‭is‬‭Performance‬‭Status‬‭(PS):‬‭0‬‭vs‬‭1‬‭or‬‭2.‬‭The‬‭length‬‭of‬‭blocks‬‭will‬‭be‬
‭defined in the Statistical Analysis Plan.‬
‭8.4.2‬‭Main Analysis‬
‭The main analysis of efficacy is going to be performed using Contrast Hypothesis testing.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭The‬‭null‬‭hypothesis‬‭assumes‬‭that‬‭everolimus‬‭achieves‬‭a‬‭first‬‭progression‬‭free‬‭survival‬‭of‬‭50‬‭%‬‭at‬
‭52‬‭weeks‬‭(arm‬‭A:‬‭everolimus‬‭followed‬‭by‬‭STZ-5-FU‬‭upon‬‭progression)‬‭and‬‭arm‬‭B,‬‭the‬‭reverse‬
‭sequence,‬ ‭achieves‬ ‭a‬ ‭first‬ ‭progression‬ ‭free‬ ‭survival‬ ‭of‬ ‭75‬ ‭%‬ ‭at‬ ‭52‬ ‭weeks.‬ ‭(data‬ ‭based‬ ‭on‬
‭RADIANT-3 results of 11 months or 48 weeks; Yao et al, NEJM 2011‬‭13‬‭,).‬
‭Therefore H‬‭0‬‭: P‬‭B‬‭-P‬‭A‬‭=0, having P‬‭A‬‭=P‬‭B‬‭=0.5 at  52 weeks‬‭(12 months).‬
‭The‬‭alternative‬‭hypothesis‬‭assumes‬‭that‬‭the‬‭best‬‭treatment‬‭will‬‭achieve‬‭a‬‭first‬‭progression‬‭free‬
‭survival of 75 %.‬
‭8.4.3‬‭Main analysis of efficacy‬
‭The‬ ‭main‬ ‭hypothesis‬ ‭test‬ ‭to‬ ‭fix‬ ‭the‬ ‭trial‬ ‭result‬ ‭is‬ ‭a‬ ‭two-proportion‬ ‭binomial‬‭test‬‭with‬‭normal‬
‭asymptotical‬ ‭approximation.‬ ‭If‬ ‭Z‬ ‭statistic‬ ‭(see‬ ‭appendix)‬ ‭is‬ ‭over‬ ‭the‬ ‭value‬ ‭1.96‬ ‭then‬‭the‬‭best‬
‭treatment‬ ‭will‬ ‭be‬ ‭considered‬ ‭as‬ ‭superior‬ ‭significantly.‬ ‭This‬ ‭test‬ ‭has‬‭to‬‭be‬‭performed‬‭when‬‭all‬
‭patients‬‭had‬‭been‬‭followed-up‬‭during‬‭52‬‭weeks‬‭(12‬‭months)‬‭or‬‭when‬‭event‬‭had‬‭been‬‭observed‬
‭(first progression).‬
‭This‬ ‭main‬ ‭hypothesis‬‭test‬‭will‬‭be‬‭performed‬‭using‬‭the‬‭main‬‭analysis‬‭definition‬‭of‬‭an‬‭event.‬‭A‬
‭sensitivity‬‭analysis‬‭will‬‭be‬‭performed‬‭using‬‭the‬‭same‬‭test‬‭but‬‭considering‬‭the‬‭two‬‭definitions‬‭of‬
‭event /event free (optimistic and conservative).‬
‭8.4.4‬‭Other analysis‬
‭All‬‭time‬‭based‬‭endpoints‬‭(PFSI,‬‭PFS2,‬‭time‬‭to‬‭first‬‭progression,‬‭time‬‭to‬‭second‬‭progression,‬‭time‬
‭from‬ ‭first‬ ‭to‬ ‭second‬ ‭progression)‬ ‭will‬ ‭be‬ ‭analyzed‬ ‭as‬ ‭follows:‬ ‭a‬ ‭Kaplan-Meier‬ ‭estimation‬
‭(Kaplan-Meier‬ ‭1958)‬ ‭will‬ ‭be‬ ‭performed,‬ ‭and‬ ‭also‬ ‭a‬ ‭log-rank‬ ‭test‬ ‭(Mantel‬ ‭N.1966)‬ ‭to‬ ‭detect‬
‭possible‬ ‭differences‬ ‭between‬ ‭arms.‬ ‭Although‬ ‭sample‬ ‭size‬ ‭has‬ ‭not‬ ‭been‬ ‭calculated‬ ‭for‬ ‭these‬
‭comparisons,‬ ‭it‬ ‭is‬ ‭planned‬ ‭to‬ ‭perform‬ ‭a‬ ‭Cox‬ ‭regression‬ ‭(Cox‬ ‭1972)‬ ‭for‬ ‭detecting‬ ‭possible‬
‭influencing factors.‬
‭A‬‭recurrent‬‭event‬‭analysis‬‭will‬‭be‬‭performed‬‭in‬‭order‬‭to‬‭estimate‬‭the‬‭confidence‬‭interval‬‭of‬‭the‬
‭effect‬‭of‬‭the‬‭treatment‬‭in‬‭first‬‭progression‬‭and‬‭second‬‭progression‬‭(Juan‬‭R.‬‭Gonzalez‬‭&‬‭Edsel‬‭A.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Peña‬ ‭2004).‬ ‭Recurrent‬ ‭event‬ ‭analysis‬ ‭will‬ ‭follow‬ ‭a‬ ‭cross-over‬ ‭design;‬ ‭the‬ ‭other‬ ‭secondary‬
‭endpoints will be analyzed following a parallel design.‬
‭Response‬‭Rate‬‭is‬‭defined‬‭as‬‭the‬‭rate‬‭of‬‭objective‬‭response‬‭(CR+PR+SD)‬‭measured‬‭by‬‭RECIST‬
‭criteria‬‭version‬‭1.0.‬‭A‬‭confidence‬‭interval‬‭at‬‭level‬‭95‬‭%‬‭will‬‭be‬‭estimated‬‭and‬‭with‬‭an‬‭exploratory‬
‭aim a logistic regression will be performed in order to detect factors that influence this rate.‬
‭CgA‬ ‭levels‬ ‭will‬ ‭be‬ ‭analysed‬ ‭using‬ ‭a‬ ‭paired‬‭Wilcoxon‬‭test‬‭comparing‬‭baseline‬‭and‬‭four‬‭weeks‬
‭values.‬
‭Correlation‬ ‭and‬ ‭Kendall’s‬ ‭tau‬ ‭values‬ ‭will‬ ‭be‬ ‭calculated‬ ‭between‬ ‭overall‬ ‭survival‬ ‭and‬ ‭the‬ ‭four‬
‭proposed‬ ‭surrogate‬ ‭endpoints:‬ ‭progression‬ ‭free‬ ‭survival‬ ‭(RECIST‬ ‭1.0,‬‭RECIST‬‭1.1,‬‭composite‬
‭RECIST‬‭1.0‬‭and‬‭composite‬‭RECIST‬‭1.1).‬‭The‬‭endpoint‬‭in‬‭terms‬‭of‬‭correlation‬‭and‬‭Kendall‬‭tau‬
‭values could be suggested for future studies.‬
‭Recurrent‬‭event‬‭analysis‬‭will‬‭follow‬‭a‬‭cross-over‬‭design;‬‭the‬‭other‬‭secondary‬‭endpoints‬‭will‬‭be‬
‭analyzed following a parallel design.‬
‭Estimation‬‭of‬‭cost-efficiency‬‭and‬‭descriptive‬‭analysis‬‭of‬‭safety‬‭is‬‭described‬‭in‬‭sections‬‭8.4.5‬‭and‬
‭8.4.6.‬
‭Minimal level of patient compliance regarding intake of Afinitor‬
‭Adherence‬‭to‬‭“Afinitor”‬‭has‬‭been‬‭for‬‭large‬‭studied‬‭in‬‭previous‬‭trials;‬‭no‬‭patient‬‭will‬‭be‬‭excluded‬
‭from‬‭efficacy‬‭analysis‬‭because‬‭of‬‭treatment‬‭adherence.‬‭This‬‭is‬‭a‬‭phase‬‭III‬‭trial‬‭with‬‭the‬‭purpose‬‭of‬
‭having a scenario as close as possible to clinical practice.‬
‭Estimation‬‭of‬‭Cost-effectiveness‬‭and‬‭descriptive‬‭analysis‬‭of‬‭safety‬‭is‬‭described‬‭in‬‭sections‬‭8.4.5‬
‭and 8.4.6.‬
‭8.4.5‬‭Pharmacoeconomic analysis‬
‭The‬‭Cost-effectiveness‬‭analysis‬‭will‬‭be‬‭estimated‬‭using‬‭the‬‭incremental‬‭Cost-effectiveness‬‭ratio‬
‭ratio (ICER) of the differential of costs incurred on by each treatment arm (A and B):‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ICER=‬
‭(Arm A costs‬‭– Arm B costs)‬
‭)‬
‭Arm A 1‬‭st‬‭/2‬‭nd‬‭progression free survival – Arm B 1‬‭st‬‭/2‬‭nd‬‭progression free survival‬
‭The‬ ‭perspective‬ ‭of‬ ‭the‬ ‭cost‬ ‭analysis‬ ‭will‬ ‭be‬ ‭direct‬ ‭medical‬ ‭costs‬ ‭from‬ ‭an‬ ‭overall‬ ‭health‬ ‭care‬
‭provider.‬ ‭It‬ ‭is‬ ‭planned‬ ‭to‬ ‭perform‬ ‭a‬ ‭cost‬ ‭analysis‬ ‭per‬ ‭country.‬ ‭Cost‬ ‭–efficiency‬ ‭results‬ ‭will‬ ‭be‬
‭expressed as cost per progression free survival gained (PFS1 and/or PFS2).‬
‭Quality‬‭of‬‭Life‬‭score‬‭will‬‭be‬‭presented‬‭descriptively‬‭at‬‭each‬‭study‬‭time‬‭(at‬‭baseline‬‭and‬‭at‬‭the‬‭end‬
‭of each treatment).‬
‭8.4.6‬‭Safety analysis‬
‭A‬ ‭table‬ ‭of‬ ‭AE‬ ‭and‬ ‭dose‬ ‭reductions‬ ‭specifying‬ ‭both,‬ ‭absolute‬ ‭and‬‭relative‬‭frequencies,‬‭will‬‭be‬
‭generated.‬‭This‬‭table‬‭will‬‭contain‬‭information‬‭for‬‭different‬‭arms,‬‭including‬‭treatment‬‭relationship.‬
‭A cross-over analysis will be done.‬
‭All‬ ‭grade‬ ‭3‬ ‭and‬ ‭4‬ ‭toxicities,‬ ‭the‬ ‭number‬ ‭and/or‬ ‭frequency‬ ‭of‬ ‭dose‬ ‭reduction‬ ‭and‬ ‭treatment‬
‭discontinuations‬ ‭will‬ ‭be‬‭also‬‭assessed‬‭separately,‬‭and‬‭grade‬‭2‬‭toxicities‬‭of‬‭abnormal‬‭laboratory‬
‭values‬ ‭for‬ ‭lymphocytes‬ ‭and‬ ‭neutrophils,‬ ‭haemoglobin‬ ‭and‬ ‭platelets,‬ ‭high‬ ‭levels‬ ‭of‬ ‭glucose,‬
‭phosphate, cholesterol and triglycerides, creatinine and liver enzymes, will be also collected.‬
‭8.5.‬ ‭PLANNED INTERIM ANALYSES‬
‭No interim analyses have been planned.‬
‭8.6‬
‭SAMPLE SIZE AND NUMBER OF SUBJECTS PLANNED‬
‭This‬‭study‬‭has‬‭been‬‭designed‬‭assuming‬‭that‬‭Chemotherapy‬‭administered‬‭as‬‭first‬‭line‬‭achieves‬‭a‬
‭higher progression free survival rate at 52 weeks (12 months) than everolimus.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Sample‬ ‭size‬ ‭is‬‭based‬‭on‬‭the‬‭ability‬‭to‬‭detect‬‭a‬‭clinically‬‭meaningful‬‭improvement‬‭on‬‭the‬‭main‬
‭endpoint.‬‭The‬‭hypothesis‬‭considered‬‭under‬‭this‬‭study‬‭assumes‬‭the‬‭treatment‬‭everolimus‬‭followed‬
‭by‬‭STZ-5-FU‬‭upon‬‭progression‬‭(arm‬‭A)‬‭achieves‬‭a‬‭first‬‭progression‬‭free‬‭survival‬‭of‬‭50‬‭%‬‭at‬‭52‬
‭weeks‬‭(12‬‭months)‬‭(data‬‭based‬‭on‬‭RADIANT-3‬‭results;‬‭Yao‬‭et‬‭al,‬‭NEJM‬‭2011).‬‭To‬‭demonstrate‬
‭that‬ ‭STZ-5-FU‬ ‭followed‬ ‭by‬ ‭everolimus‬ ‭10mg/day‬ ‭(arm‬ ‭B)‬ ‭achieves‬ ‭a‬ ‭first‬ ‭progression‬ ‭free‬
‭survival‬‭of‬‭75‬‭%‬‭(alternative‬‭hypothesis,‬‭H1)‬‭a‬‭two-sided‬‭binomial‬‭test‬‭of‬‭proportion‬‭differences‬
‭has‬‭been‬‭run.‬‭In‬‭order‬‭to‬‭ensure‬‭that‬‭type‬‭I‬‭error‬‭(alpha)‬‭is‬‭0.05‬‭and‬‭with‬‭a‬‭type‬‭II‬‭error‬‭(beta)‬‭of‬
‭0.20,‬‭a‬‭minimum‬‭sample‬‭size‬‭of‬‭132‬‭patients‬‭is‬‭required‬‭(Fleiss‬‭1980).‬‭Assuming‬‭that‬‭a‬‭5%‬‭of‬
‭patients‬‭could‬‭be‬‭lost‬‭by‬‭several‬‭reasons,‬‭the‬‭proposed‬‭sample‬‭size‬‭is‬‭140‬‭patients‬‭(70‬‭patients‬‭per‬
‭study arm).‬
‭8.7‬
‭PROCEDURE‬ ‭FOR‬ ‭REPORTING‬ ‭ANY‬ ‭DEVIATION‬ ‭FROM‬ ‭THE‬
‭ORIGINAL STATISTICAL PLAN‬
‭A‬ ‭statistical‬ ‭analysis‬ ‭plan‬ ‭will‬ ‭be‬ ‭prepared‬ ‭in‬ ‭detail‬ ‭prior‬ ‭to‬ ‭the‬ ‭closure‬ ‭of‬ ‭clinical‬ ‭database‬
‭detailing‬ ‭all‬ ‭the‬ ‭analyses‬ ‭to‬ ‭be‬ ‭performed,‬ ‭procedures‬ ‭and‬ ‭techniques‬ ‭to‬ ‭be‬ ‭used‬‭for‬‭the‬‭final‬
‭drafting‬‭of‬‭final‬‭clinical‬‭study‬‭report.‬‭Any‬‭change‬‭and/or‬‭modification‬‭in‬‭the‬‭originally‬‭planned‬
‭analyses will be recorded in the SAP.‬
‭In‬‭the‬‭case‬‭that‬‭changes‬‭should‬‭be‬‭made‬‭in‬‭the‬‭analyses‬‭planned‬‭in‬‭the‬‭SAP‬‭in‬‭order‬‭to‬‭draft‬‭the‬
‭report, this will be recorded in the final report.‬
‭9.‬
‭STUDY RECORDS AND DATA HANDLING‬
‭9.1‬
‭STUDY RECORDS‬
‭A‬‭log‬‭of‬‭all‬‭patients‬‭evaluated‬‭for‬‭this‬‭protocol‬‭must‬‭be‬‭maintained‬‭at‬‭each‬‭site;‬‭the‬‭screening‬‭log‬
‭will‬ ‭be‬ ‭completed‬ ‭with‬ ‭a‬ ‭clear‬ ‭explanation‬ ‭of‬ ‭the‬ ‭reasons‬ ‭why‬ ‭potential‬ ‭patients‬ ‭have‬ ‭been‬
‭excluded from its participation in the study.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭The‬‭trial‬‭master‬‭file‬‭will‬‭contain‬‭the‬‭essential‬‭documents‬‭which‬‭enable‬‭both‬‭the‬‭conduct‬‭of‬‭the‬
‭study‬ ‭and‬ ‭the‬ ‭quality‬ ‭of‬ ‭the‬ ‭data‬ ‭produced‬ ‭to‬ ‭be‬ ‭evaluated‬ ‭as‬ ‭recommended‬ ‭by‬ ‭International‬
‭Harmonized‬‭Conference‬‭(ICH)‬‭guidelines.‬‭The‬‭media‬‭used‬‭to‬‭store‬‭essential‬‭documents‬‭will‬‭be‬
‭such‬‭that‬‭those‬‭documents‬‭remain‬‭complete‬‭and‬‭legible‬‭throughout‬‭the‬‭required‬‭period‬‭of‬‭retention‬
‭and can be made available to the competent authorities upon request.‬
‭The‬‭investigator‬‭should‬‭retain‬‭the‬‭essential‬‭documents‬‭relating‬‭to‬‭a‬‭clinical‬‭trial‬‭for‬‭at‬‭least‬‭five‬
‭years‬‭after‬‭its‬‭completion.‬‭They‬‭shall‬‭retain‬‭the‬‭documents‬‭for‬‭a‬‭longer‬‭period,‬‭where‬‭so‬‭required‬
‭by‬‭other‬‭applicable‬‭requirements.‬‭Essential‬‭documents‬‭will‬‭be‬‭archived‬‭in‬‭a‬‭way‬‭that‬‭ensures‬‭that‬
‭they are readily available, upon request, to the competent authorities.‬
‭Medical‬ ‭records‬ ‭of‬ ‭patients‬ ‭included‬ ‭in‬ ‭the‬ ‭study‬ ‭will‬‭be‬‭retained‬‭in‬‭accordance‬‭with‬‭national‬
‭legislation‬ ‭and‬ ‭in‬ ‭accordance‬ ‭with‬ ‭the‬ ‭maximum‬ ‭period‬ ‭of‬ ‭time‬ ‭permitted‬ ‭by‬ ‭the‬ ‭hospital,‬
‭institution or private practice.‬
‭If‬ ‭the‬ ‭investigator‬ ‭withdraws‬ ‭from‬ ‭the‬ ‭study‬ ‭for‬ ‭whatever‬ ‭reason,‬ ‭study‬ ‭records‬ ‭should‬ ‭be‬
‭transferred‬ ‭to‬ ‭a‬ ‭designee‬ ‭before‬ ‭leaving.‬ ‭Any‬ ‭transfer‬ ‭of‬ ‭responsibilities‬ ‭over‬ ‭the‬ ‭data‬ ‭or‬
‭documents‬‭will‬‭be‬‭documented‬‭in‬‭study‬‭files.‬‭The‬‭new‬‭investigator‬‭shall‬‭assume‬‭responsibility‬‭for‬
‭data retention and archiving in accordance with procedures detailed above.‬
‭The‬ ‭investigator's/institution's‬ ‭will‬ ‭retain‬ ‭the‬ ‭trial‬‭related‬‭essential‬‭documents‬‭until‬‭the‬‭sponsor‬
‭informs the investigator/institution these documents are no longer needed.‬
‭9.2‬
‭CASE‬‭REPORT‬‭FORM‬
‭All‬‭data‬‭from‬‭each‬‭patient‬‭will‬‭be‬‭recorded‬‭in‬‭a‬‭Case‬‭Report‬‭Form‬‭(CRF)‬‭provided‬‭by‬‭the‬‭sponsor‬
‭or‬‭its‬‭designee.‬‭The‬‭CRF‬‭will‬‭be‬‭completed‬‭on‬‭a‬‭continuous‬‭basis‬‭at‬‭the‬‭site‬‭by‬‭the‬‭investigator‬‭or‬
‭his/her designee.‬
‭The‬ ‭investigator‬ ‭or‬ ‭his/her‬ ‭designee‬ ‭is‬ ‭responsible‬ ‭for‬ ‭recording‬ ‭all‬ ‭data‬ ‭as‬ ‭specified‬ ‭in‬ ‭this‬
‭protocol.‬ ‭Study‬ ‭CRF‬ ‭must‬ ‭be‬ ‭legibly,‬ ‭completed‬ ‭from‬ ‭the‬ ‭information‬ ‭gathered‬ ‭in‬ ‭the‬ ‭source‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭documents‬‭filed‬‭at‬‭the‬‭site.‬‭The‬‭study‬‭investigator‬‭at‬‭each‬‭site‬‭will‬‭confirm‬‭that‬‭the‬‭data‬‭recorded‬
‭in the CRF are accurate and correct.‬
‭Traceability‬‭of‬‭any‬‭change‬‭on‬‭the‬‭CRF‬‭will‬‭be‬‭assured.‬‭Specific‬‭guidelines‬‭for‬‭data‬‭management‬
‭will be generated for a correct data management at sites and for data entry purposes.‬
‭9.3‬
‭PUBLICATION POLICY‬
‭Trial‬‭results‬‭will‬‭be‬‭written‬‭on‬‭basis‬‭of‬‭the‬‭analysis‬‭performed‬‭with‬‭mature‬‭data‬‭at‬‭52‬ ‭weeks‬‭of‬
‭treatment‬ ‭and/or‬ ‭at‬ ‭the‬ ‭end‬ ‭of‬ ‭survival‬ ‭follow-up.‬ ‭The‬ ‭manuscript‬ ‭should‬ ‭be‬ ‭approved‬ ‭by‬ ‭all‬
‭co-authors prior to its submission to the appropriate journal.‬
‭Any‬‭formal‬‭presentation‬‭or‬‭publication‬‭of‬‭data‬‭gathered‬‭as‬‭a‬‭direct‬‭or‬‭indirect‬‭result‬‭of‬‭this‬‭study‬
‭will‬‭be‬‭considered‬‭as‬‭a‬‭joint‬‭publication‬‭by‬‭the‬‭investigator(s)‬‭and‬‭GETNE.‬‭Study‬‭results‬‭will‬‭be‬
‭published‬‭once‬‭the‬‭main‬‭analysis‬‭and/or‬‭the‬‭study‬‭has‬‭been‬‭completed‬‭and‬‭statistical‬‭analysis‬‭has‬
‭been‬‭performed.‬‭Papers‬‭will‬‭be‬‭written‬‭considering‬‭the‬‭revised‬‭CONSORT‬‭statement‬‭for‬‭reporting‬
‭randomized trials (the CONSORT group- 2001).‬
‭For‬‭the‬‭purpose‬‭of‬‭enabling‬‭Novartis,‬‭the‬‭Authorized‬‭Marketing‬‭Holder‬‭of‬‭everolimus,‬‭to‬‭provide‬
‭peer‬‭input‬‭regarding‬‭the‬‭scientific‬‭content‬‭and‬‭conclusions‬‭of‬‭such‬‭publications‬‭and‬‭presentations,‬
‭to‬‭provide‬‭the‬‭Study‬‭Principal‬‭Investigator‬‭with‬‭information‬‭which‬‭may‬‭not‬‭have‬‭been‬‭previously‬
‭provided,‬‭a‬‭copy‬‭of‬‭each‬‭proposed‬‭publication‬‭and‬‭presentation‬‭will‬‭be‬‭submitted‬‭to‬‭Novartis‬‭for‬
‭review‬‭at‬‭least‬‭forty-five‬‭business‬‭days‬‭(or‬‭fifteen‬‭business‬‭days‬‭in‬‭the‬‭case‬‭of‬‭abstracts‬‭and‬‭full‬
‭papers,‬ ‭posters‬ ‭presentations‬ ‭and‬ ‭oral‬ ‭presentations‬ ‭not‬ ‭exceeding‬‭two‬‭double‬‭spaced‬‭pages‬‭in‬
‭length) prior to such submission.‬
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‭10.‬ ‭ETHICS‬
‭10.1‬ ‭STUDY IMPLEMENTATION‬
‭This‬‭study‬‭will‬‭be‬‭performed‬‭in‬‭compliance‬‭with‬‭the‬‭Protocol‬‭and‬‭with‬‭all‬‭applicable‬‭laws‬‭and‬
‭guidelines,‬‭including‬‭without‬‭limitation‬‭any‬‭European‬‭Union‬‭and‬‭appropriate‬‭national‬‭regulations,‬
‭the‬ ‭ICH‬ ‭Guideline‬ ‭for‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭or‬ ‭appropriate‬ ‭national‬ ‭good‬ ‭clinical‬ ‭practice‬
‭(“GCP”)‬ ‭guidelines‬ ‭which‬ ‭are‬ ‭consistent‬ ‭with‬ ‭the‬ ‭principles‬ ‭of‬ ‭the‬ ‭ICH‬ ‭Guideline‬ ‭for‬ ‭Good‬
‭Clinical‬‭Practice‬‭and‬‭applicable‬‭laws,‬‭as‬‭well‬‭as,‬‭where‬‭applicable,‬‭generally‬‭accepted‬‭conventions‬
‭such‬ ‭as‬ ‭the‬ ‭World‬ ‭Medical‬ ‭Association‬ ‭Declaration‬ ‭of‬ ‭Helsinki‬‭Ethical‬‭Principles‬‭for‬‭Medical‬
‭Research‬‭Involving‬‭Human‬‭Subjects.‬‭The‬‭ICH‬‭Guidelines‬‭(Harmonized‬‭Tripartite‬‭Guideline)‬‭on‬
‭Good‬
‭Clinical‬
‭Practice‬
‭can‬
‭be‬
‭found‬
‭on‬
‭the‬
‭web‬
‭page‬
‭address:‬
‭http://www.ich.org/products/guidelines.html‬
‭All‬‭necessary‬‭approvals‬‭of‬‭the‬‭appropriate‬‭ethics‬‭committee‬‭and‬‭competent‬‭health‬‭authorities‬‭must‬
‭be‬‭obtained‬‭prior‬‭to‬‭commencement‬‭of‬‭the‬‭Study.‬‭All‬‭necessary‬‭approvals‬‭of‬‭the‬‭appropriate‬‭ethics‬
‭committee‬‭and‬‭competent‬‭health‬‭authorities‬‭must‬‭be‬‭sent‬‭to‬‭the‬‭sponsor‬‭prior‬‭to‬‭commencement‬‭of‬
‭the‬ ‭Study.‬ ‭The‬ ‭Sponsor‬ ‭will‬ ‭give‬ ‭his‬ ‭approval‬‭before‬‭the‬‭initiation‬‭of‬‭any‬‭site‬‭involved‬‭in‬‭the‬
‭study.‬
‭10.2‬ ‭PROTOCOL MODIFICATIONS‬
‭Any‬‭changes‬‭to‬‭this‬‭protocol‬‭will‬‭be‬‭documented‬‭in‬‭a‬‭memorandum‬‭and‬‭filed‬‭on‬‭the‬‭study‬‭master‬
‭file.‬ ‭Any‬ ‭relevant‬ ‭changes‬ ‭(this‬ ‭is,‬ ‭affecting‬ ‭study‬ ‭objectives,‬ ‭study‬ ‭design,‬ ‭study‬‭procedures,‬
‭patient‬ ‭population‬ ‭or‬ ‭any‬ ‭significant‬ ‭administrative‬ ‭procedures)‬ ‭will‬ ‭be‬ ‭registered‬ ‭as‬ ‭a‬‭formal‬
‭Amendment to the protocol.‬
‭Any‬‭Amendment‬‭must‬‭be‬‭presented‬‭to‬‭the‬‭applicable‬‭institutional‬‭review‬‭boards‬‭(IRB)‬‭and‬‭should‬
‭be‬‭approved‬‭by‬‭them‬‭and‬‭any‬‭applicable‬‭Health‬‭Authorities‬‭before‬‭its‬‭implementation‬‭following‬
‭local laws.‬
‭The‬ ‭investigator‬ ‭will‬ ‭not‬ ‭implement‬ ‭any‬ ‭deviation‬ ‭from,‬ ‭or‬ ‭changes‬ ‭of‬ ‭the‬ ‭protocol‬ ‭without‬
‭agreement‬‭by‬‭the‬‭sponsor‬‭and‬‭prior‬‭review‬‭and‬‭documented‬‭approval/favourable‬‭opinion‬‭from‬‭the‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭IRB/IEC‬‭of‬‭an‬‭amendment,‬‭except‬‭where‬‭necessary‬‭to‬‭eliminate‬‭an‬‭immediate‬‭hazard(s)‬‭to‬‭trial‬
‭subjects,‬‭or‬‭when‬‭the‬‭change(s)‬‭involves‬‭only‬‭logistical‬‭or‬‭administrative‬‭aspects‬‭of‬‭the‬‭trial‬‭(e.g.,‬
‭change in monitor(s), change of telephone number(s)).‬
‭The‬ ‭investigator,‬ ‭or‬ ‭person‬ ‭designated‬ ‭by‬ ‭the‬ ‭investigator,‬ ‭should‬ ‭document‬ ‭and‬ ‭explain‬ ‭any‬
‭deviation‬‭from‬‭the‬‭approved‬‭protocol.‬‭As‬‭soon‬‭as‬‭possible,‬‭the‬‭implemented‬‭deviation‬‭or‬‭change,‬
‭the‬‭reasons‬‭for‬‭it,‬‭should‬‭be‬‭submitted‬‭to‬‭the‬‭sponsor‬‭for‬‭agreement‬‭and,‬‭if‬‭required,‬‭to‬‭be‬‭sent‬‭to‬
‭the regulatory authority (ies).‬
‭10.3‬ ‭PATIENT‬‭INFORM‬‭ED CONSENT‬
‭The‬ ‭Informed‬ ‭Consent‬ ‭must‬ ‭meet‬ ‭the‬ ‭requirements‬ ‭of‬ ‭the‬ ‭latest‬ ‭version‬ ‭of‬‭the‬‭Declaration‬‭of‬
‭Helsinki‬‭when‬‭applicable‬‭and‬‭any‬‭other‬‭applicable‬‭and‬‭current‬‭local‬‭regulations‬‭and‬‭guidelines‬‭at‬
‭the‬‭time‬‭of‬‭study‬‭development.‬‭It‬‭will‬‭be‬‭approved‬‭by‬‭the‬‭corresponding‬‭IRB,‬‭together‬‭with‬‭the‬
‭protocol.‬‭Any‬‭changes‬‭on‬‭the‬‭Patient‬‭Informed‬‭Consent‬‭will‬‭be‬‭also‬‭approved‬‭by‬‭the‬‭IRB‬‭before‬
‭its implementation.‬
‭Prior‬ ‭to‬ ‭entry‬ ‭into‬ ‭the‬ ‭trial‬ ‭and‬ ‭before‬ ‭any‬ ‭procedure‬ ‭specific‬ ‭for‬ ‭this‬ ‭study‬ ‭are‬ ‭performed,‬
‭investigators‬ ‭must‬ ‭explain‬ ‭the‬ ‭nature‬ ‭of‬ ‭the‬ ‭study,‬ ‭its‬ ‭objectives,‬ ‭and‬ ‭the‬ ‭implications‬ ‭of‬
‭participation‬‭to‬‭any‬‭potential‬‭patient.‬‭They‬‭will‬‭also‬‭inform‬‭that‬‭patients’‬‭participation‬‭is‬‭voluntary‬
‭and‬‭they‬‭may‬‭withdraw‬‭consent‬‭at‬‭any‬‭time.‬‭Potential‬‭patients‬‭will‬‭be‬‭given‬‭the‬‭opportunity‬‭to‬‭ask‬
‭questions‬‭about‬‭the‬‭protocol.‬‭They‬‭will‬‭be‬‭also‬‭informed‬‭of‬‭local‬‭procedures‬‭followed‬‭to‬‭preserve‬
‭confidentiality of patients’ records as well as any personal information recorded for the study.‬
‭The‬ ‭entire‬ ‭trial‬‭can‬‭be‬‭finished‬‭for‬‭administrative‬‭reasons‬‭(section‬‭4.2).‬‭Patient’s‬‭rights‬‭will‬‭be‬
‭fully‬ ‭respected:‬ ‭This‬ ‭is‬ ‭a‬ ‭comparative‬ ‭study‬ ‭of‬ ‭the‬ ‭effect‬ ‭of‬ ‭sequential‬ ‭order‬ ‭of‬‭two‬‭accepted‬
‭therapies‬‭used‬‭in‬‭clinical‬‭practice;‬‭study‬‭discontinuation‬‭will‬‭not‬‭affect‬‭patient’s‬‭treatment‬‭which‬
‭is prescribed in accordance with medical guidelines and licensed indication (section 5).‬
‭Patient‬‭informed‬‭consent‬‭will‬‭be‬‭obtained‬‭in‬‭written.‬‭Consent‬‭will‬‭be‬‭signed‬‭and‬‭dated‬‭by‬‭each‬
‭patient before any procedure specific for the study and before patient randomization into the study.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭10.4‬ ‭CONFIDENTIALITY‬
‭Patients‬ ‭will‬ ‭receive‬ ‭a‬ ‭unique‬ ‭number‬ ‭assigned‬ ‭at‬ ‭entry.‬ ‭Patients‬ ‭will‬ ‭be‬ ‭registered‬ ‭with‬ ‭this‬
‭number in the study database.‬
‭The‬ ‭privacy‬ ‭of‬ ‭the‬ ‭patients‬ ‭will‬ ‭be‬ ‭protected‬ ‭at‬ ‭all‬ ‭times.‬ ‭The‬ ‭investigator‬ ‭at‬ ‭each‬ ‭site‬ ‭is‬
‭responsible‬ ‭for‬ ‭assuring‬ ‭that‬ ‭all‬ ‭information‬ ‭collected‬ ‭from‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭handled‬ ‭for‬ ‭the‬
‭protection of personal data according to local laws.‬
‭The‬‭staff‬‭at‬‭site‬‭as‬‭well‬‭as‬‭any‬‭other‬‭representative‬‭of‬‭the‬‭sponsor‬‭will‬‭keep‬‭strict‬‭confidentiality‬
‭about‬ ‭the‬ ‭information‬ ‭they‬ ‭may‬ ‭have‬ ‭access‬ ‭for‬ ‭the‬ ‭development‬ ‭of‬ ‭their‬ ‭tasks‬ ‭(source‬ ‭data‬
‭verification‬ ‭at‬ ‭site‬ ‭during‬ ‭field‬ ‭monitoring‬‭and/or‬‭quality‬‭assurance‬‭audits/visits).‬‭The‬‭site‬‭will‬
‭provide‬‭access‬‭to‬‭source‬‭documents‬‭to‬‭study‬‭monitors‬‭and‬‭other‬‭sponsor‬‭representatives‬‭to‬‭fulfill‬
‭their tasks. Regulatory authorities should have also access to this information in case of audits.‬
‭10.5  ADMINISTRATIVE RESPONSIBILITIES‬
‭10.5.1‬ ‭The‬
‭Coordinating‬
‭Investigator‬
‭and‬
‭the‬ ‭Coordinator‬ ‭of‬
‭Translational Studies‬
‭The‬‭coordinating‬‭investigator‬‭will‬‭be‬‭responsible‬‭for‬‭direction‬‭of‬‭the‬‭study‬‭(reviewing‬‭all‬‭clinical‬
‭data, discussing the contents of the report and for publishing the study results).‬
‭Principal investigator:‬
‭Dr Ramón Salazar‬
‭Catalan Institute of Oncology‬
‭Av. Gran Vía, 199-203‬
‭08907 L´Hospitalet-Barcelona‬
‭Telephone: +34 93 2607739‬
‭Fax: +34 93 2607741‬
‭E-mail: ramonsalazar@iconcologia.net‬
‭Coordinator of translational studies:‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭Dr Barbro Ericksson‬
‭Uppsala University Hospital‬
‭Uppsala SE-751 85‬
‭Sweden‬
‭Telephone: +46 18-51-01-33‬
‭Fax: +46-18-51-01-33‬
‭E-mail: barbro.eriksson@medsci.uu.se‬
‭10.5.2‬ ‭The Sponsor‬
‭The‬‭sponsor‬‭transfers‬‭all‬‭of‬‭the‬‭sponsor's‬‭trial-related‬‭tasks‬‭and‬‭functions‬‭to‬‭a‬‭Contract‬‭Research‬
‭Organisation‬‭(CRO;‬‭Kantar‬‭Health).‬‭The‬‭CRO‬‭will‬‭be‬‭in‬‭charge‬‭of‬‭the‬‭study‬‭implementation‬‭and‬
‭development‬‭at‬‭closure‬‭in‬‭all‬‭countries,‬‭in‬‭full‬‭compliance‬‭with‬‭all‬‭the‬‭European‬‭and‬‭local‬‭laws‬‭in‬
‭force.‬
‭10.5.3 The site principal investigator‬
‭The‬ ‭site‬ ‭principal‬ ‭investigator‬ ‭is‬ ‭responsible‬ ‭of‬ ‭the‬ ‭study‬ ‭is‬ ‭been‬ ‭conducted‬‭at‬‭his/her‬‭site‬‭in‬
‭compliance‬‭with‬‭the‬‭Protocol.‬‭If‬‭a‬‭trial‬‭is‬‭conducted‬‭by‬‭a‬‭team‬‭of‬‭individuals‬‭at‬‭the‬‭trial‬‭site,‬‭the‬
‭site principal investigator is the leader responsible for the team.‬
‭The‬‭site‬‭principal‬‭investigator‬‭is‬‭responsible‬‭to‬‭ensure‬‭that‬‭the‬‭local‬‭law‬‭and‬‭regulations‬‭currently‬
‭in‬‭force,‬‭including‬‭any‬‭European‬‭Union,‬‭appropriate‬‭national‬‭regulations,‬‭the‬‭ICH‬‭Guideline‬‭for‬
‭Good‬‭Clinical‬‭Practice‬‭or‬‭appropriate‬‭national‬‭good‬‭clinical‬‭practice‬‭(“GCP”),‬‭and‬‭is‬‭responsible‬
‭for adherence to local data protection laws.‬
‭All‬‭centres‬‭will‬‭have‬‭to‬‭declare‬‭to‬‭the‬‭sponsor‬‭of‬‭details‬‭of‬‭other‬‭satellite‬‭institutions‬‭which‬‭may‬
‭be‬ ‭responsible‬ ‭for‬ ‭providing‬ ‭protocol‬ ‭treatment‬ ‭to‬ ‭the‬ ‭patients.‬ ‭Details‬ ‭on‬ ‭these‬ ‭satellite‬
‭institutions‬ ‭including‬ ‭CV‬ ‭for‬ ‭the‬ ‭local‬ ‭investigator,‬ ‭laboratory‬ ‭normal‬ ‭ranges‬ ‭and‬ ‭the‬ ‭Ethical‬
‭approval,‬ ‭will‬ ‭have‬‭to‬‭be‬‭transmitted‬‭to‬‭the‬‭sponsor.‬‭Correspondence‬‭on‬‭study‬‭issues‬‭and‬‭data‬
‭collection‬ ‭will‬ ‭however‬ ‭only‬ ‭performed‬ ‭with‬ ‭the‬ ‭primary‬ ‭institution‬ ‭which‬ ‭will‬ ‭assume‬ ‭all‬
‭responsibilities and liabilities issues with the principal investigator.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭10.5.4‬ ‭The CRO‬
‭The‬‭CRO‬‭is‬‭responsible‬‭of‬‭overseeing‬‭the‬‭initiation,‬‭progress‬‭and‬‭the‬‭end‬‭of‬‭the‬‭clinical‬‭trial.‬‭The‬
‭CRO‬ ‭will‬ ‭ensure‬ ‭that‬ ‭the‬ ‭study‬ ‭is‬ ‭conducted,‬ ‭in‬ ‭compliance‬ ‭with‬ ‭the‬ ‭protocol,‬ ‭and‬ ‭with‬ ‭all‬
‭Applicable‬ ‭Laws‬ ‭and‬ ‭guidelines,‬ ‭including‬ ‭without‬ ‭limitation‬ ‭any‬ ‭European‬ ‭Union,‬ ‭the‬ ‭ICH‬
‭Guideline‬ ‭for‬ ‭Good‬ ‭Clinical‬ ‭Practice‬ ‭or‬ ‭appropriate‬ ‭national‬ ‭good‬ ‭clinical‬‭practice‬‭guidelines‬
‭which‬ ‭are‬ ‭consistent‬ ‭with‬ ‭the‬ ‭principles‬ ‭of‬ ‭the‬‭ICH‬‭Guideline‬‭for‬‭Good‬‭Clinical‬‭Practice‬‭and‬
‭applicable laws.‬
‭The‬ ‭CRO‬ ‭is‬ ‭responsible‬ ‭for‬ ‭adherence‬ ‭to‬ ‭all‬ ‭data‬ ‭protection‬ ‭laws‬ ‭applicable‬ ‭to‬ ‭the‬‭countries‬
‭involved‬‭in‬‭this‬‭study.‬ ‭The‬‭CRO‬‭shall‬‭in‬‭any‬‭case‬‭comply‬‭with‬‭the‬‭Organic‬‭Data‬‭Protection‬‭Law‬
‭15/1999, dated 13th December.‬
‭The‬‭CRO‬‭will‬‭maintain‬‭records‬‭of‬‭the‬‭receipt,‬‭storage,‬‭and‬‭administration‬‭or‬‭dispensing‬‭of‬‭Study‬
‭Drug,‬‭identifying‬‭(but‬‭not‬‭necessarily‬‭by‬‭name)‬‭each‬‭patient‬‭to‬‭whom‬‭the‬‭drug‬‭is‬‭administered‬‭or‬
‭dispensed‬‭at‬‭each‬‭site,‬‭and‬‭will‬‭make‬‭these‬‭records‬‭available‬‭to‬‭the‬‭sponsor‬‭at‬‭any‬‭time‬‭with‬‭the‬
‭patient‬ ‭details‬ ‭redacted‬ ‭so‬‭as‬‭to‬‭preserve‬‭the‬‭patients’‬‭anonymity‬‭and‬‭Organic‬‭Data‬‭Protection‬
‭Law 15/1999, dated 13th December.‬
‭The‬ ‭CRO‬ ‭shall‬ ‭submit‬ ‭all‬ ‭necessary‬ ‭reports‬ ‭for‬ ‭the‬ ‭Study/ies‬ ‭(e.g.,‬ ‭EU‬ ‭Annual‬ ‭Safety‬
‭Report/Development‬‭Safety‬‭Update‬‭Report‬‭(DSUR))‬‭to‬‭applicable‬‭health‬‭authorities‬‭according‬‭to‬
‭local national and international regulations.‬
‭10.5.5  T‬‭RIAL‬‭F‬‭INANCING‬
‭Novartis‬ ‭Pharma‬ ‭AG‬ ‭located‬ ‭at‬ ‭Lichtstrasse‬ ‭35,‬ ‭CH-4056‬ ‭Basel,‬ ‭Switzerland,‬ ‭will‬ ‭provide‬
‭financial support for the Study.‬
‭European‬
‭Neuroendocrine‬
‭Tumour‬
‭Society‬
‭(ENETS)‬
‭located‬
‭at‬
‭Charite,‬
‭Campus‬
‭Virchow-Klinikum,‬‭Augustenburger‬‭Platz‬‭1,‬‭13353‬‭Berlin,‬‭Germany,‬‭may‬‭help‬‭the‬‭sponsor‬‭with‬
‭financial support for the prolongation of the Study.‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭11.  T‬‭RIAL‬‭INSURANCE‬
‭A‬‭clinical‬‭insurance‬‭has‬‭been‬‭taken‬‭according‬‭to‬‭the‬‭laws‬‭of‬‭the‬‭countries‬‭where‬‭the‬‭study‬‭will‬‭be‬
‭conducted.‬ ‭An‬ ‭insurance‬ ‭certificate‬ ‭will‬ ‭be‬‭made‬‭available‬‭to‬‭the‬‭participating‬‭sites‬‭at‬‭the‬‭time‬‭of‬
‭study initiation.‬
‭Clinical‬‭trial‬‭insurance‬‭is‬‭only‬‭valid‬‭if‬‭the‬‭treatment‬‭is‬‭given‬‭in‬‭a‬‭centre‬‭authorized‬‭by‬‭the‬‭sponsor‬‭and‬
‭which‬‭has‬‭obtained‬‭Ethical‬‭Committee‬‭approval‬‭(individually‬‭or‬‭centrally‬‭depending‬‭on‬‭the‬‭national‬
‭regulations applicable).‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭12.‬ ‭REFERENCES‬
‭1‬‭.-‬ ‭Moertel‬ ‭CG,‬ ‭Hanley‬ ‭JA,‬ ‭Johnson‬ ‭LA.‬ ‭Streptozocin‬ ‭alone‬ ‭compared‬ ‭with‬ ‭streptozocin‬ ‭plus‬
‭fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980; 303:1189-94.‬
‭2.-‬‭Eriksson‬‭B,‬‭Skogseid‬‭B,‬‭Lundqvist‬‭G,‬‭Wide‬‭L,‬‭Wilander‬‭E,‬‭Oberg‬‭K.‬‭Medical‬‭treatment‬‭and‬
‭long-term‬‭survival‬‭in‬‭a‬‭prospective‬‭study‬‭of‬‭84‬‭patients‬‭with‬‭endocrine‬‭pancreatic‬‭tumors.‬‭Cancer‬
‭1990; 65:1883-90.‬
‭3.-‬ ‭Moertel‬ ‭CG,‬ ‭Lefkopoulo‬ ‭M,‬ ‭Lipsitz‬ ‭S,‬ ‭Hahn‬ ‭RG,‬ ‭Klaassen‬ ‭D.‬ ‭Streptozocin-doxorubicin,‬
‭streptozocin-fluorouracil‬ ‭or‬ ‭chlorozotocin‬ ‭in‬ ‭the‬ ‭treatment‬ ‭of‬ ‭advanced‬ ‭islet-cell‬ ‭carcinoma.‬ ‭N‬
‭Engl J Med 1992; 326:519-23.‬
‭4.-‬‭Bukowski‬‭RM,‬‭Tangen‬‭C,‬‭Lee‬‭R,‬‭Macdonald‬‭JS,‬‭Einstein‬‭AB,‬‭Jr.,‬‭Peterson‬‭R,‬‭Fleming‬‭TR.‬
‭Phase‬ ‭II‬ ‭trial‬ ‭of‬ ‭chlorozotocin‬ ‭and‬ ‭fluorouracil‬ ‭in‬ ‭islet‬ ‭cell‬ ‭carcinoma:‬ ‭a‬ ‭Southwest‬ ‭Oncology‬
‭Group study. J Clin Oncol 1992; 10:1914-8.‬
‭5.-‬‭Eriksson‬‭B,‬‭Skogseid‬‭B,‬‭Lundqvist‬‭G,‬‭Wide‬‭L,‬‭Wilander‬‭E,‬‭Oberg‬‭K.‬‭Medical‬‭treatment‬‭and‬
‭long-term‬‭survival‬‭in‬‭a‬‭prospective‬‭study‬‭of‬‭84‬‭patients‬‭with‬‭endocrine‬‭pancreatic‬‭tumors.‬‭Cancer‬
‭1990; 65:1883-90.‬
‭6.-‬ ‭Kouvaraki‬ ‭MA,‬ ‭Ajani‬ ‭JA,‬ ‭Hoff‬ ‭P,‬ ‭Wolff‬ ‭R,‬ ‭Evans‬ ‭DB,‬ ‭Lozano‬ ‭R,‬ ‭Yao‬ ‭JC.‬ ‭Fluorouracil,‬
‭doxorubicin,‬ ‭and‬ ‭streptozocin‬ ‭in‬ ‭the‬ ‭treatment‬‭of‬‭patients‬‭with‬‭locally‬‭advanced‬‭and‬‭metastatic‬
‭pancreatic endocrine carcinomas. J Clin Oncol 2004; 22:4762-71.‬
‭7.-‬‭Cheng‬‭PN,‬‭Saltz‬‭LB.‬‭Failure‬‭to‬‭confirm‬‭major‬‭objective‬‭antitumor‬‭activity‬‭for‬‭streptozocin‬‭and‬
‭doxorubicin‬ ‭in‬ ‭the‬ ‭treatment‬ ‭of‬ ‭patients‬ ‭with‬ ‭advanced‬ ‭islet‬ ‭cell‬ ‭carcinoma.‬ ‭Cancer‬ ‭1999;‬
‭86:944-8.-‬ ‭McCollum‬ ‭AD,‬ ‭Kulke‬ ‭MH,‬ ‭Ryan‬ ‭DP,‬ ‭Clark‬‭JW,‬‭Shulman‬‭LN,‬‭Mayer‬‭RJ,‬‭Bartel‬‭S,‬
‭Fuchs‬‭CS.‬‭Lack‬‭of‬‭efficacy‬‭of‬‭streptozocin‬‭and‬‭doxorubicin‬‭in‬‭patients‬‭with‬‭advanced‬‭pancreatic‬
‭endocrine tumors. Am J Clin Oncol 2004; 27:485-488.‬
‭9.-‬‭Vilar‬‭E,‬‭Tabernero‬‭J,‬‭Casado‬‭E,‬‭Macarulla‬‭T,‬‭Ramos‬‭FJ,‬‭Martinelli‬‭E,‬‭Saura‬‭C.‬‭Lack‬‭of‬‭efficacy‬
‭of‬‭streptozocin‬‭and‬‭doxorubicin‬‭in‬‭patients‬‭with‬‭advanced‬‭pancreatic‬‭endocrine‬‭tumors.‬‭Am‬‭J‬‭Clin‬
‭Oncol 2005; 28:424.‬
‭10.-‬‭Isacoff‬‭WH,‬‭Moss‬‭RA,‬‭Pecora‬‭AL,‬‭Fine‬‭L.‬‭Temozolomide/capcitabine‬‭therapy‬‭for‬‭metastatic‬
‭neuroendocrine‬‭tumors‬‭of‬‭the‬‭pancreas.‬‭J‬‭Clin‬‭Oncol‬‭ASCO‬‭Annual‬‭Meeting‬‭Proceedings‬‭Part‬‭1‬
‭2006;24.‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭11.-‬‭Strosberg‬‭JR,‬‭Fine‬‭RL,‬‭Choi‬‭J,‬‭Nasir‬‭A,‬‭Coppola‬‭D,‬‭Chen‬‭DT,‬‭Helm‬‭J,‬‭Kvols‬‭L.‬‭First-line‬
‭chemotherapy‬ ‭with‬ ‭capecitabine‬ ‭and‬ ‭temozolomide‬ ‭in‬ ‭patients‬ ‭with‬ ‭metastatic‬ ‭pancreatic‬
‭endocrine carcinomas. Cancer 2011; 117(2):268-75‬
‭12.-‬‭Fjallskog‬‭ML,‬‭Janson‬‭ET,‬‭Falkmer‬‭UG,‬‭Vatn‬‭MH,‬‭Oberg‬‭KE,‬‭Eriksson‬‭BK.‬‭Treatment‬‭with‬
‭combined‬ ‭streptozotocin‬ ‭and‬ ‭liposomal‬ ‭doxorubicin‬ ‭in‬ ‭metastatic‬ ‭endocrine‬ ‭pancreatic‬ ‭tumors.‬
‭Neuroendocrinology 2008; 88:53-8.‬
‭13.-‬ ‭James‬ ‭C.‬ ‭Yao,‬ ‭M.D.,‬ ‭Manisha‬ ‭H.‬ ‭Shah‬ ‭et‬ ‭al.‬ ‭Everolimus‬ ‭for‬ ‭Advanced‬ ‭Pancreatic‬
‭Neuroendocrine Tumors. N Engl J Med 2011; 364:514-23.‬
‭14.-‬ ‭Salazar R., ‬‭Wiedenmann B.‬‭,‬ ‭Ruszniewski P.‬‭ ‬‭ENETS‬ ‭2011‬ ‭Consensus‬ ‭Guidelines‬ ‭for‬ ‭the‬
‭Management‬‭of‬‭Patients‬‭with‬‭Digestive‬‭Neuroendocrine‬‭Tumors:‬‭An‬‭Update‬‭Neuroendocrinology‬
‭2012, Vol. 95, No. 2‬‭.‬
‭15.-‬ ‭Loomba‬‭R,‬‭Rowley‬‭A,‬‭Wesley‬‭R,‬‭et‬‭al‬‭(2008).‬‭Systematic‬‭review:‬‭the‬‭effect‬‭of‬‭preventive‬
‭lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7): 519-28.‬
‭16.- Sorrell M, Belongia E, Costa J, et al (2009). National Institutes of Health Consensus.‬
‭17.-‬ ‭Robert‬ ‭S.‬ ‭Benjamin,‬ ‭Haesun‬ ‭Choi,‬ ‭Homer‬ ‭A.‬ ‭Macapinlac‬‭et‬‭al.‬‭We‬‭Should‬‭Dessist‬‭Using‬
‭RECIST, at Least in GIST. Clin Oncol, 2007; 25:1760-1764.‬
‭18.-‬‭Patrick‬‭Terrasse,‬‭Susan‬‭G.‬‭Arbuck,‬‭Elisabeth‬‭A‬‭Eisenhauer‬‭et‬‭al.‬‭New‬‭Guidelines‬‭to‬‭Evaluate‬
‭the Response to Treatment in Solid Tumours. J National Cancer Institute, 2000; 92(3): 205-216.‬
‭19.-‬ ‭E.A.‬ ‭Eisenhauer,‬ ‭P.‬ ‭Therasse,‬ ‭J.‬ ‭Bogaerts‬ ‭et‬ ‭al.‬ ‭New‬ ‭response‬ ‭evaluation‬ ‭criteria‬ ‭in‬ ‭solid‬
‭tumours: Revised RECIST guideline (version 1.1).‬‭European‬‭Journal of Cancer, 2009; 45:228-247.‬
‭20.-‬‭Bjordal‬‭K,‬‭Kaasa‬‭S.‬‭Psychometric‬‭validation‬‭of‬‭the‬‭EORTC‬‭core‬‭quality‬‭of‬‭life‬‭questionnaire‬‭,‬
‭30‬‭item‬‭version‬‭and‬‭a‬‭diagnosis‬‭specific‬‭module‬‭for‬‭head‬‭and‬‭neck‬‭cancer‬‭patients.‬‭Acta‬‭Oncol.‬‭31:‬
‭311-321, 1992.‬
‭21.-‬‭Aaronson‬‭NK,‬‭Ahmedzai‬‭S,‬‭Bergman‬‭B,‬‭et‬‭al.,‬‭for‬‭the‬‭European‬‭Organization‬‭for‬‭Research‬
‭and‬‭Treatment‬‭of‬‭Cancer‬‭QLQ-C30:‬‭A‬‭Quality-of-Life‬‭Instrument‬‭for‬‭Use‬‭in‬‭International‬‭Clinical‬
‭Trials in Oncology. JNCI 85: 365-376, 1993.‬
‭22.-‬ ‭Davies‬ ‭AHG,‬ ‭Larsson‬ ‭G,‬ ‭Ardill‬ ‭J‬ ‭et‬ ‭al.‬ ‭on‬ ‭behalf‬ ‭of‬ ‭the‬ ‭EORTC‬ ‭Quality‬‭of‬‭Life‬‭Group.‬
‭Development‬ ‭of‬ ‭a‬ ‭disease-specific‬ ‭quality‬ ‭of‬ ‭life‬ ‭questionnaire‬ ‭module‬ ‭for‬ ‭patients‬ ‭with‬
‭gastrointestinal neuroendocrine tumours. Eur J Cancer 42: 477-484, 2006.‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭92‬‭/ 87‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭23.-‬ ‭Edoardo‬ ‭Missiaglia,‬ ‭Irene‬ ‭Dalai,‬ ‭Stefano‬ ‭Barbi‬ ‭et‬ ‭al.‬ ‭Pancreatic‬ ‭Endocrine‬ ‭Tumors:‬
‭Expression Profiling Evidences a Role for AKT-mTOR Pathway. J Clin Oncol, 2009; 28:245-255.‬
‭24.-‬ ‭Yuchen‬ ‭Jiao,‬ ‭Chanjuan‬ ‭Shi,‬ ‭Barish‬ ‭and‬ ‭H.‬ ‭Edil,‬ ‭et‬ ‭al.‬ ‭DAXX/ATRX,‬ ‭MEN1,‬‭and‬‭mTOR‬
‭Pathway‬‭Genes‬‭Are‬‭Frequently‬‭Altered‬‭in‬‭Pancreatic‬‭Neuroendocrine‬‭Tumors.‬‭Supporting‬‭Online‬
‭Material ww.sciencemag.org/cgi/content/full/science.1200609/DC1.‬
‭25.-‬‭Marianne‬‭E.‬‭Pavel,‬‭Lisa-Marie‬‭Dilz,‬‭Timm‬‭Denecke,‬‭Ingo‬‭Steffen,‬‭Vikas‬‭Prasad,‬‭Ulrich-Frank‬
‭Pape,‬ ‭Andreas‬ ‭Pascher,‬ ‭Maximilian‬ ‭Heetfeld,‬ ‭Bertram‬ ‭Wiedenmann.‬ ‭Streptozocin-based‬
‭chemotherapy‬‭in‬‭patients‬‭with‬‭advanced‬‭pancreatic‬‭neuroendocrine‬‭tumors.‬‭J‬‭Clin‬‭Oncol‬‭32,‬‭2014‬
‭(suppl 3; abstr 295).‬
‭26.-‬‭Pavel‬‭M.a‬‭•‬‭O''Toole‬‭D.b‬‭•‬‭Costa‬‭F.c‬‭•‬‭Capdevila‬‭J.d‬‭•‬‭Gross‬‭D.e‬‭•‬‭Kianmanesh‬‭R.f‬‭•‬‭Krenning‬
‭E.g‬‭•‬‭Knigge‬‭U.h‬‭•‬‭Salazar‬‭R.i‬‭•‬‭Pape‬‭U.-F.a‬‭•‬‭Öberg‬‭K.j‬‭•‬‭all‬‭other‬‭Vienna‬‭Consensus‬‭Conference‬
‭participants.‬ ‭ENETS‬ ‭Consensus‬ ‭Guidelines‬ ‭Update‬ ‭for‬ ‭the‬ ‭Management‬ ‭of‬ ‭Distant‬ ‭Metastatic‬
‭Disease‬ ‭of‬ ‭Intestinal,‬ ‭Pancreatic,‬ ‭Bronchial‬ ‭Neuroendocrine‬ ‭Neoplasms‬ ‭(NEN)‬ ‭and‬ ‭NEN‬ ‭of‬
‭Unknown Primary Site. Neuroendocrinology; 103:172–185, 2016. DOI: 10.1159/000443167‬
‭Ver 4.0, 7‬‭th‬‭of August 2018‬
‭Page‬‭93‬‭/ 87‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX I: ECOG PERFORMANCE STATUS SCALE‬
‭The‬ ‭ECOG‬ ‭scale‬ ‭can‬ ‭be‬ ‭found‬ ‭on‬ ‭the‬ ‭Eastern‬ ‭Cooperative‬ ‭Oncology‬ ‭Group‬ ‭web‬ ‭site‬ ‭at‬ ‭the‬
‭following address:‬
‭http://www.ecog.org/general/perf_stat.html‬
‭Ver 4.0 7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX II: CTCAE VERSION 4.0‬
‭The‬ ‭Common‬‭Terminology‬‭Criteria‬‭for‬‭Adverse‬‭Events‬‭(CTCAE)‬‭will‬‭be‬‭used‬‭for‬‭recording‬‭of‬
‭AEs‬ ‭all‬ ‭along‬ ‭the‬ ‭study.‬ ‭The‬ ‭CTCAE‬ ‭criteria‬ ‭could‬ ‭be‬ ‭found‬ ‭at‬ ‭the‬ ‭following‬ ‭web‬ ‭address:‬
‭http://evs.nci.nih.gov/ftp1/CTCAE/About.html‬‭,‬
‭by‬
‭clicking‬
‭with‬
‭the‬
‭mouse‬
‭on‬
‭the‬
‭CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf‬‭document.‬
‭Ver 4.0 7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX III: RECIST CRITERIA VERSION 1.0 AND VERSION 1.1‬
‭The‬ ‭article‬ ‭of‬ ‭the‬ ‭published‬ ‭RECIST‬ ‭criteria‬ ‭version‬ ‭1.0‬ ‭can‬ ‭be‬ ‭found‬ ‭on‬ ‭the‬ ‭bottom‬ ‭of‬ ‭the‬
‭following web page address:‬
‭http://www.eortc.be/Services/Doc/Recist.pdf‬
‭The‬‭RECIST‬‭criteria‬‭version‬‭1.1‬‭for‬‭Composite‬‭Score‬‭measurement‬‭can‬‭be‬‭found‬‭in‬‭the‬‭following‬
‭website:‬
‭http://www.recist.com/‬
‭Ver 4.0 7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX IV:‬‭TUMOUR‬‭BLOCK‬‭ANALYSIS‬‭SUB-STUDY‬
‭Ver 4.0,7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX‬ ‭V:‬ ‭EVALUATION‬ ‭OF‬ ‭A‬ ‭BLOOD-BASED‬ ‭TRANSCRIPTIONAL‬
‭ASSAY‬ ‭–‬ ‭THE‬ ‭NETEST‬ ‭–‬ ‭AS‬ ‭A‬ ‭BIOMARKER‬ ‭OF‬ ‭NEUROENDOCRINE‬
‭TUMOUR RESPONSE‬
‭Ver 4.0,7‬‭th‬‭of August 2018‬

‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭ANNEX‬‭VI‬‭: P‬‭an‬‭NET‬‭ASSIGNER‬‭M‬‭OLECULAR‬‭S‬‭UBTYPES‬‭A‬‭SSAY‬
‭Ver 4.0,7‬‭th‬‭of August 2018‬

‭Kantar‬
‭Clinical & Real World Research, Germany‬
‭Health Division‬
‭S‬‭TATISTICAL‬‭A‬‭NALYSIS‬‭P‬‭LAN‬‭(SAP)‬
‭Study Title:‬
‭Randomized open label study to compare the efficacy and‬
‭safety of Everolimus followed by chemotherapy with‬
‭STZ-5FU upon progression or the reverse sequence,‬
‭chemotherapy with STZ-5FU followed by everolimus upon‬
‭progression, in advanced progressive pNETs (SEQTOR‬
‭study)‬
‭Sponsor’s Name:‬
‭Grupo Español de Tumores Neuroendocrinos (GETNE)‬
‭Protocol code:‬
‭GETNE1206‬
‭EudraCT number:‬
‭2013-000726-66‬
‭Study Drug:‬
‭Treatment sequence A: Everolimus + STZ-5FU‬
‭Treatment sequence B: STZ-5FU + Everolimus‬
‭Study Type:‬
‭Phase III‬
‭Coordinating investigator at‬
‭Sponsor:‬
‭Dr. Ramón Salazar, Grupo Español de Tumores‬
‭Neuroendocrinos (GETNE),‬‭Catalan Institute of Oncology‬
‭Study Statistician at Sponsor:‬
‭Valentí Navarro Pérez,‬‭Catalan Institute of Oncology‬
‭Trial Lead Coordinator at‬
‭Sponsor:‬
‭Cristina Vidal, MSc, PhD,‬‭Catalan Institute of Oncology‬
‭Project Manager at CRO‬
‭Kantar Health:‬
‭Jutta Brodesser, Kantar‬
‭Study Statistician at CRO‬
‭Kantar Health:‬
‭Klaus Laschke, Kantar‬
‭Confidential‬
‭The information provided in this document is strictly confidential. Unauthorized use,‬
‭disclosure and reproduction without the prior written consent of the sponsor are not permitted.‬
‭SEQTOR‬
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‭Document History‬
‭Status and‬
‭Version‬
‭Version‬
‭Date‬
‭Change‬
‭Reference‬
‭(page / chapter)‬
‭Reason for Change /‬
‭Description of Change‬
‭Draft 0.1‬
‭27 May‬
‭2019‬
‭-‬
‭-‬
‭Draft 0.2‬
‭25 Oct‬
‭2019‬
‭multiple changes‬
‭Split analyses in main and final analysis,‬
‭referring protocol version 3.0 and 4.0‬
‭Draft 0.3‬
‭29 Nov‬
‭2019‬
‭minor changes‬
‭Review of draft 0.2 with clarifications of‬
‭comments‬
‭Final 1.0‬
‭17 Dec‬
‭2019‬
‭no changes‬
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‭Abbreviations‬
‭5FU‬
‭5-fluorouracil‬
‭ADR‬
‭Adverse Drug Reaction‬
‭AE‬
‭Adverse Event‬
‭ALT (SGPT)‬
‭Alanine Transaminase (Serum Glutamate-Pyruvate Transaminase)‬
‭AST (SGOT)‬
‭Aspartate Transaminase (Serum Glutamic Oxaloacetic Transaminase)‬
‭BMI‬
‭Body Mass Index‬
‭BUN‬
‭Blood Urea Nitrogen‬
‭CI‬
‭Confidence Interval‬
‭CR‬
‭Complete Response‬
‭CRF‬
‭Case Report Form‬
‭CgA‬
‭Circulating Cromogranin A‬
‭CT‬
‭Computed Tomography‬
‭CTC‬
‭Common Toxicity Criteria‬
‭CTCAE‬
‭Common Terminology Criteria for Adverse Events‬
‭DMP‬
‭Data Management Plan‬
‭eCRF‬
‭Electronic Case Report Form‬
‭ECG‬
‭Electro-Cardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group‬
‭EDC‬
‭Electronic Data Capture‬
‭EMA‬
‭European Medicines Agency‬
‭ENETS‬
‭European Neuro Endocrine Tumor Society‬
‭EoT‬
‭End of Treatment‬
‭EU‬
‭European Union‬
‭FPFV‬
‭First Patient First Visit‬
‭FDA‬
‭Food and Drug Administration‬
‭HR‬
‭Hazard Ratio‬
‭ICF‬
‭Informed Consent Form‬
‭ITT‬
‭Intention to treat‬
‭LDH‬
‭Lactate Dehydrogenase‬
‭LLN‬
‭Lower Limit of Normal‬
‭Max‬
‭Maximum‬
‭MedDRA‬
‭Medical Dictionary for Regulatory Activities‬
‭Min‬
‭Minimum‬
‭mOS‬
‭Median Overall Survival‬
‭ORR‬
‭Overall Response Rate‬
‭OS‬
‭Overall Survival‬
‭PFS‬
‭Progression-free Survival‬
‭PFS1‬
‭First Progression-free Survival (equal to progression-free survival‬
‭course 1)‬
‭PFS2‬
‭Progression-free Survival course 2‬
‭PFS2nd‬
‭Second progression-free Survival‬
‭PFS1R12m‬
‭Progression-free Survival rate for course 1 at 12 months‬
‭PNET‬
‭Pancreatic Neuroendocrine Tumor‬
‭PP‬
‭Per-Protocol‬
‭PR‬
‭Partial Response‬
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‭PT‬
‭Preferred Term‬
‭PTT‬
‭Partial Thromboplastin Time‬
‭QoL‬
‭Quality of Life‬
‭QLQ‬
‭Quality of Life Questionnaire‬
‭RECIST‬
‭Response Evaluation Criteria in Solid Tumors‬
‭RR‬
‭Response Rate‬
‭SADR‬
‭Serious Adverse Drug Reaction‬
‭SAF‬
‭Safety Analysis Set‬
‭SAP‬
‭Statistical Analysis Plan‬
‭SD‬
‭Stable Disease‬
‭SI‬
‭International System of Units (Système international (d'unités))‬
‭SOC‬
‭System Organ Class‬
‭STD‬
‭Standard Deviation‬
‭STZ‬
‭Streptozotocin‬
‭TEAE‬
‭Treatment Emergent Adverse Events‬
‭TFL‬
‭Tables, Figures and Listings‬
‭TTP‬
‭Time to Progression‬
‭TTP1‬
‭Time to First Progression‬
‭TTP2nd‬
‭Time to Second Progression‬
‭ULN‬
‭Upper Limit of Normal‬
‭VRR‬
‭Validity Review Report‬
‭WHO DD‬
‭World Health Organization Drug Dictionary‬
‭SEQTOR‬
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‭Table of Contents‬
‭1‬ ‭Introduction‬
‭7‬
‭2‬ ‭Study Design‬
‭7‬
‭3‬ ‭Study Objectives and Endpoints‬
‭8‬
‭3.1‬
‭Primary study objective and endpoint‬
‭8‬
‭3.2‬
‭Secondary study objectives and endpoints‬
‭8‬
‭4‬ ‭Relevant Documents‬
‭9‬
‭5‬ ‭Study Evaluations‬
‭10‬
‭5.1‬
‭Population Characteristics‬
‭10‬
‭5.2‬
‭Study Medication‬
‭10‬
‭5.3‬
‭Efficacy‬
‭10‬
‭5.4‬
‭Safety‬
‭11‬
‭5.5‬
‭Other Variables‬
‭11‬
‭6‬ ‭Type of Analysis‬
‭12‬
‭7‬ ‭General Statistical Considerations‬
‭12‬
‭7.1‬
‭General Principles‬
‭12‬
‭7.2‬
‭Handling of Loss to Follow-up and Premature Discontinuation‬
‭13‬
‭7.3‬
‭Data Rules‬
‭13‬
‭7.3.1‬
‭General Definitions‬
‭13‬
‭7.3.2‬
‭Definition of Derived Variables‬
‭13‬
‭7.3.3‬
‭Handling of Data Inconsistencies‬
‭27‬
‭7.3.4‬
‭Handling of Missing Data‬
‭27‬
‭7.3.5‬
‭Decisions of the Data Review Meeting‬
‭27‬
‭7.4‬
‭Coding‬
‭27‬
‭8‬ ‭Patient Enrolment and Analysis Sets‬
‭27‬
‭9‬ ‭Statistical Analysis‬
‭28‬
‭9.1‬
‭Presentation of Analysis Results‬
‭28‬
‭9.2‬
‭Analysis variables‬
‭30‬
‭9.2.1‬
‭Population Characteristics‬
‭30‬
‭9.2.2‬
‭Study Medication‬
‭30‬
‭9.2.3‬
‭Efficacy‬
‭31‬
‭9.2.4‬
‭Safety‬
‭31‬
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‭9.2.5‬
‭Other Variables‬
‭32‬
‭9.3‬
‭Subgroup Analysis and Stratifications‬
‭33‬
‭10‬‭Changes to Planned Analyses‬
‭33‬
‭11‬‭References‬
‭33‬
‭12‬‭Appendix‬
‭34‬
‭12.1‬ ‭Tables, Figures and Listings (TFLs)‬
‭34‬
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‭1‬ ‭Introduction‬
‭Streptozotocin‬ ‭(STZ)‬ ‭based‬ ‭chemotherapy,‬ ‭i.e.‬‭Streptozotocin-5-fluorouracil‬‭(STZ-5FU),‬‭is‬
‭the‬‭current‬‭standard‬‭of‬‭care‬‭for‬‭advanced‬‭pancreatic‬‭neuroendocrine‬‭tumors‬‭(pNETs)‬‭in‬‭the‬
‭European‬ ‭Union‬ ‭(ENETS‬ ‭guidelines;‬ ‭Neuroendocrinology‬ ‭2012,‬ ‭Salazar‬ ‭et‬ ‭al.,‬ ‭2011).‬
‭Everolimus‬‭has‬‭been‬‭recently‬‭approved‬‭for‬‭its‬‭use‬‭in‬‭advanced‬‭pNETs‬‭by‬‭the‬‭FDA‬‭and‬‭in‬
‭Europe‬‭by‬‭the‬‭EMA.‬‭A‬‭randomized‬‭study‬‭is‬‭needed‬‭to‬‭have‬‭a‬‭clear‬‭knowledge‬‭about‬‭the‬
‭best‬ ‭sequence‬ ‭for‬ ‭its‬ ‭administration,‬ ‭i.e.‬ ‭before‬ ‭or‬ ‭after‬‭the‬‭palliative‬‭chemotherapy.‬‭The‬
‭information‬‭obtained‬‭from‬‭this‬‭study‬‭will‬‭help‬‭the‬‭physician‬‭to‬‭improve‬‭the‬‭treatment‬‭and‬‭the‬
‭management‬‭of‬‭patients‬‭with‬‭pNET.‬‭Variations‬‭of‬‭treatment‬‭choices‬‭are‬‭still‬‭dependent‬‭on‬
‭physician‬‭expertise,‬‭the‬‭complexity‬‭of‬‭the‬‭treatment‬‭center‬‭and‬‭access‬‭to‬‭novel‬‭treatments‬
‭(ENETS‬‭guidelines,‬‭Neuroendocrinology‬‭2016,‬‭Pavel‬‭et‬‭al.,‬‭2016).‬‭There‬‭are‬‭no‬‭randomized‬
‭trials‬ ‭comparing‬ ‭Progression‬ ‭Free‬ ‭Survival‬ ‭(PFS)‬ ‭of‬ ‭STZ‬ ‭based‬ ‭chemotherapy‬ ‭versus‬
‭Everolimus.‬
‭2‬ ‭Study Design‬
‭This‬ ‭is‬ ‭a‬ ‭randomized,‬ ‭phase‬ ‭III,‬ ‭open‬ ‭label‬ ‭study‬ ‭to‬ ‭compare‬ ‭the‬ ‭efficacy‬ ‭and‬‭safety‬‭of‬
‭Everolimus‬ ‭followed‬ ‭by‬ ‭chemotherapy‬ ‭with‬ ‭STZ-5FU‬ ‭upon‬ ‭progression,‬ ‭or‬ ‭the‬ ‭reverse‬
‭sequence,‬ ‭chemotherapy‬ ‭with‬ ‭STZ-5FU‬‭followed‬‭by‬‭Everolimus,‬‭in‬‭advanced‬‭progressive‬
‭pNETs.‬
‭Treatment and dosage plan:‬
‭Arm A: First Everolimus, followed by STZ-5FU‬
‭Arm B: First STZ-5FU, followed by Everolimus‬
‭Treatment STZ-5FU:‬
‭●‬ ‭Moertel: STZ 0.5 g/m² and 5-FU 400 mg/m² on days 1 to 5 every 6 weeks or‬
‭●‬ ‭Uppsala:‬ ‭STZ‬ ‭0.5‬ ‭g/m²‬ ‭on‬ ‭days‬ ‭1‬ ‭to‬ ‭5‬ ‭and‬ ‭5-FU‬‭400‬‭mg/m²‬‭on‬‭days‬‭1‬‭to‬‭3‬‭and‬
‭afterwards,‬ ‭every‬ ‭3‬ ‭weeks‬ ‭1-day‬ ‭treatment‬ ‭with‬ ‭STZ‬ ‭1‬ ‭g/m²‬ ‭and‬ ‭with‬ ‭5-FU‬ ‭400‬
‭mg/m²‬
‭Treatment Everolimus: 10 mg per day‬
‭Block‬‭randomization‬‭was‬‭performed,‬‭stratified‬‭according‬‭to‬‭ECOG‬‭Performance‬‭Status‬‭(PS):‬
‭0 versus 1 or 2. A block size of 4 patients per block was chosen.‬
‭It‬ ‭is‬ ‭planned‬ ‭to‬ ‭recruit‬ ‭140‬ ‭adult‬ ‭patients‬ ‭with‬ ‭a‬ ‭diagnosis‬ ‭of‬ ‭advanced‬ ‭pNET‬ ‭in‬
‭approximately‬‭8‬‭countries‬‭all‬‭around‬‭Europe.‬‭Assignment‬‭to‬‭treatment‬‭arm‬‭A‬‭and‬‭B‬‭is‬
‭done‬‭at‬‭random‬‭by‬‭an‬‭equal‬‭distribution‬‭algorithm‬‭automatically‬‭assigned‬‭by‬‭the‬‭EDC‬
‭system.‬ ‭Study‬ ‭groups‬ ‭are‬ ‭stratified‬ ‭according‬ ‭to‬ ‭ECOG‬ ‭Performance‬ ‭Status‬ ‭(PS):‬ ‭0‬
‭versus 1 or 2.‬
‭Study schedule:‬
‭Screening period / Baseline: day -28 to 0‬
‭Treatment period: estimated length 140 +/- 8 weeks‬
‭Safety follow-up: 30 days after last dose‬
‭Survival‬‭follow-up:‬‭up‬‭to‬‭patient’s‬‭death‬‭or‬‭study‬‭end‬‭(last‬‭visit‬‭of‬‭last‬‭patient),‬‭whatever‬
‭comes first‬
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‭3‬ ‭Study Objectives and Endpoints‬
‭The‬‭purpose‬‭of‬‭this‬‭study‬‭is‬‭to‬‭compare‬‭therapy‬‭STZ-5FU‬‭versus‬‭Everolimus‬‭as‬‭first‬‭line‬
‭treatment‬ ‭for‬ ‭advanced‬ ‭pNET‬ ‭and‬ ‭elucidate‬ ‭which‬ ‭sequence‬ ‭of‬ ‭STZ-5FU‬ ‭based‬
‭chemotherapy‬ ‭and‬ ‭the‬ ‭mTOR‬ ‭inhibitor,‬ ‭Everolimus,‬ ‭gives‬ ‭better‬ ‭results‬ ‭in‬ ‭terms‬ ‭of‬
‭progression‬‭free‬‭survival‬‭(PFS)‬‭in‬‭well‬‭differentiated‬‭and‬‭advanced‬‭pNETs‬‭assessed‬‭by‬
‭local investigator using RECIST criteria 1.0.‬
‭pNET‬ ‭lesions‬ ‭are‬ ‭usually‬ ‭multiple‬ ‭and‬ ‭difficult,‬ ‭therefore,‬ ‭a‬ ‭measurement‬ ‭of‬ ‭a‬ ‭lower‬
‭number‬‭of‬‭lesions,‬‭as‬‭suggested‬‭in‬‭version‬‭1.1‬‭of‬‭the‬‭RECIST‬‭criteria,‬‭not‬‭validated‬‭for‬
‭this disease, could be misleading.‬
‭Due‬‭to‬‭sponsor’s‬‭decision,‬‭data‬‭analysis‬‭will‬‭be‬‭split‬‭in‬‭two‬‭parts,‬‭the‬‭main‬‭analysis‬‭and‬
‭the‬ ‭final‬ ‭analysis.‬ ‭Main‬ ‭analysis‬ ‭will‬ ‭be‬ ‭scheduled‬ ‭at‬ ‭first‬ ‭quarter‬ ‭of‬ ‭2020‬ ‭and‬ ‭final‬
‭analysis at third quarter of 2020.‬
‭Main analysis will comprise:‬
‭●‬ ‭The analysis of screening data.‬
‭●‬ ‭The‬‭analysis‬‭of‬‭tumor‬‭evaluations‬‭as‬‭per‬‭local‬‭assessments‬‭up‬‭to‬‭60‬‭weeks‬‭for‬‭ITT‬
‭population.‬ ‭With‬ ‭it,‬ ‭the‬ ‭primary‬ ‭endpoint‬ ‭regarding‬‭Protocol‬‭version‬‭4.0‬‭will‬‭be‬
‭calculated.‬
‭Final analysis will comprise:‬
‭●‬ ‭The main analysis repeated for SAF and PP populations.‬
‭●‬ ‭All other analyses defined within this SAP but not yet performed in the main analysis.‬
‭3.1‬ ‭Primary study objective and endpoint‬
‭Based‬ ‭on‬ ‭study‬ ‭protocol,‬ ‭version‬ ‭4.0,‬ ‭the‬ ‭primary‬ ‭objective‬ ‭of‬ ‭this‬ ‭study‬ ‭is‬ ‭to‬ ‭compare‬
‭STZ-5FU versus Everolimus as first line treatment‬‭at 12 months.‬
‭Based‬ ‭on‬ ‭study‬ ‭protocol,‬ ‭version‬ ‭4.0,‬ ‭the‬ ‭primary‬ ‭endpoint‬ ‭is‬ ‭the‬ ‭f‬‭irst‬ ‭progression-free‬
‭survival‬ ‭rate‬ ‭at‬ ‭12‬ ‭months‬ ‭(PFS1R12m)‬ ‭of‬ ‭STZ-5FU‬ ‭versus‬ ‭Everolimus‬‭,‬ ‭based‬ ‭on‬
‭assessments by local investigator using RECIST criteria 1.0.‬
‭Based‬ ‭on‬ ‭study‬ ‭protocol,‬ ‭version‬ ‭3.0,‬ ‭the‬ ‭primary‬ ‭objective‬ ‭of‬ ‭this‬ ‭study‬ ‭is‬ ‭to‬ ‭compare‬
‭STZ-5FU‬ ‭followed‬ ‭by‬ ‭Everolimus‬ ‭(arm‬ ‭B)‬ ‭versus‬ ‭the‬ ‭reverse‬ ‭sequence‬ ‭(arm‬ ‭A)‬ ‭at‬
‭140±8weeks.‬
‭Based‬‭on‬‭study‬‭protocol,‬‭version‬‭3.0,‬‭the‬‭primary‬‭endpoint‬‭is‬‭the‬‭second‬‭progression-free‬
‭survival‬‭(PFS2nd)‬‭rate‬‭at‬‭140±8‬‭weeks‬‭of‬‭arm‬‭B‬‭versus‬‭arm‬‭A,‬‭based‬‭on‬‭assessments‬‭by‬
‭local investigator using RECIST criteria 1.0.‬
‭3.2‬ ‭Secondary study objectives and endpoints‬
‭The‬‭secondary objectives‬‭of the study are:‬
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‭●‬ ‭to‬ ‭compare‬ ‭the‬ ‭efficacy‬ ‭of‬ ‭the‬ ‭combination‬ ‭STZ-5FU‬ ‭chemotherapy‬ ‭followed‬ ‭by‬
‭Everolimus‬ ‭upon‬ ‭progression,‬ ‭versus‬ ‭the‬ ‭reverse‬ ‭sequence,‬ ‭in‬ ‭terms‬ ‭of‬ ‭second‬
‭progression‬ ‭free‬ ‭survival‬ ‭(PFS2nd)‬ ‭rate‬ ‭at‬ ‭140+/-8‬ ‭weeks‬ ‭of‬ ‭treatment,‬‭based‬‭on‬
‭assessments‬ ‭by‬ ‭local‬ ‭investigator‬ ‭using‬ ‭RECIST‬ ‭criteria‬ ‭1.0‬ ‭(secondary‬ ‭objective‬
‭regarding protocol version V4.0, primary objective regarding protocol version V3.0)‬
‭●‬ ‭to‬‭describe‬‭the‬‭efficacy‬‭of‬‭the‬‭two‬‭treatment‬‭arms‬‭as‬‭a‬‭continuous‬‭variable‬‭Hazard‬
‭Ratio‬‭and‬‭obtaining‬‭the‬‭survival‬‭estimation‬‭of‬‭PFS1‬‭for‬‭the‬‭two‬‭arms‬‭at‬‭12‬‭months‬
‭(main‬‭analysis‬‭time‬‭point‬‭regarding‬‭protocol‬‭version‬‭V4.0)‬‭and‬‭at‬‭140‬‭weeks‬‭(main‬
‭analysis time point regarding protocol version V3.0)‬
‭●‬ ‭to‬ ‭determine,‬ ‭whether‬ ‭the‬ ‭overall‬ ‭survival‬ ‭(OS)‬ ‭could‬ ‭be‬ ‭modified‬ ‭by‬ ‭the‬ ‭upfront‬
‭administration‬‭of‬‭each‬‭other‬‭treatment,‬‭STZ-5FU‬‭and‬‭Everolimus,‬‭respectively,‬‭upon‬
‭progression‬
‭●‬ ‭to‬‭compare‬‭the‬‭clinical‬‭activity‬‭of‬‭STZ-5FU‬‭and‬‭Everolimus‬‭given‬‭in‬‭1‬‭st‬‭or‬‭2‬‭nd‬‭place‬‭in‬
‭terms‬ ‭of‬ ‭time‬ ‭to‬ ‭first‬ ‭(TTP1)‬ ‭and‬ ‭to‬ ‭second‬ ‭progression‬ ‭(TTP2nd),‬‭response‬‭rate‬
‭(RR),‬ ‭and‬ ‭early‬ ‭biochemical‬ ‭response‬ ‭(4‬ ‭week‬ ‭CgA‬ ‭levels),‬ ‭Quality‬ ‭of‬ ‭Life‬ ‭and‬
‭Cost-effectiveness‬ ‭of‬ ‭each‬ ‭sequence‬ ‭and‬ ‭to‬ ‭investigate‬ ‭the‬ ‭criteria‬‭for‬‭measuring‬
‭PFS‬‭(RECIST‬‭1.0,‬‭RECIST‬‭1.1,‬‭composite‬‭RECIST‬‭1.0‬‭and‬‭composite‬‭RECIST‬‭1.1)‬
‭that correlates better with OS‬
‭●‬ ‭to‬ ‭compare‬ ‭the‬ ‭safety‬ ‭and‬ ‭tolerability‬ ‭of‬ ‭upfront‬ ‭administration‬ ‭of‬ ‭each‬ ‭of‬ ‭the‬
‭treatments, STZ-5FU and Everolimus, respectively, upon progression‬
‭●‬ ‭to‬‭compare‬‭the‬‭cost-effectiveness‬‭of‬‭upfront‬‭administration‬‭of‬‭each‬‭of‬‭the‬‭treatments,‬
‭STZ-5FU and Everolimus, respectively, upon progression‬
‭The‬‭secondary endpoints‬‭of the study are:‬
‭●‬ ‭PFS2nd‬ ‭rates‬ ‭at‬ ‭140‬ ‭+/-‬ ‭8‬ ‭weeks‬ ‭of‬ ‭the‬ ‭combination‬ ‭STZ-5FU‬ ‭chemotherapy‬
‭followed‬ ‭by‬‭Everolimus‬‭upon‬‭progression,‬‭versus‬‭the‬‭reverse‬‭sequence,‬‭based‬‭on‬
‭assessments‬ ‭by‬ ‭local‬ ‭investigator‬ ‭using‬ ‭RECIST‬ ‭criteria‬ ‭1.0‬ ‭(secondary‬ ‭endpoint‬
‭regarding protocol version V4.0, primary endpoint regarding protocol version V3.0)‬
‭●‬ ‭PFS2nd as a continuous time variable of the two treatment arms‬
‭●‬ ‭PFS1 as a continuous time variable (secondary endpoint regarding protocol version‬
‭V3.0)‬
‭●‬ ‭Progression‬ ‭free‬ ‭survival‬ ‭course‬ ‭2‬‭(PFS2)‬‭(secondary‬‭endpoint‬‭regarding‬‭protocol‬
‭version V3.0)‬
‭●‬ ‭TTP1 of the two treatment arms‬
‭●‬ ‭TTP2nd of the two treatment arms‬
‭●‬ ‭Time‬‭from‬‭first‬‭progression‬‭to‬‭second‬‭progression‬‭of‬‭the‬‭two‬‭treatment‬‭arms‬‭RR‬‭of‬
‭the two treatment arms assessed every 12 weeks‬
‭●‬ ‭Quality‬‭of‬‭life‬‭score‬‭at‬‭baseline,‬‭upon‬‭progression‬‭and‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬
‭study treatment (both treatment arms)‬
‭●‬ ‭CgA levels at baseline and at 4 weeks of treatment start‬
‭●‬ ‭Correlation‬‭between‬‭the‬‭four‬‭criteria‬‭for‬‭PFS‬‭2‬‭(RECIST‬‭1.0,‬‭RECIST‬‭1.1,‬‭composite‬
‭RECIST 1.0 and composite RECIST 1.1) and Kendall tau variables‬
‭●‬ ‭OS of patients on treatment with the two treatment arms‬
‭●‬ ‭Number‬ ‭of‬ ‭adverse‬‭events‬‭(AEs),‬‭dose‬‭reductions‬‭and‬‭total‬‭dose‬‭administered‬‭on‬
‭patients‬ ‭treated‬ ‭with‬ ‭the‬ ‭two‬ ‭treatment‬ ‭arms.‬ ‭Cost‬ ‭per‬ ‭PFS‬ ‭gained:‬ ‭Incremental‬
‭cost-effectiveness‬ ‭ratio‬ ‭(ICER)‬ ‭of‬ ‭the‬ ‭difference‬ ‭of‬ ‭costs‬ ‭incurred‬ ‭on‬ ‭by‬ ‭the‬ ‭two‬
‭treatment arms Relevant Documents‬
‭Following documents have been used for the creation of the SAP:‬
‭SEQTOR‬
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‭●‬ ‭Study protocol GETNE1206, version 3.0, 26 November 2014‬
‭●‬ ‭Study protocol GETNE1206, version 4.0, 07 August 2018‬
‭●‬ ‭Study protocol GETNE1206, working protocol version 4.02, 30th of July 2019‬
‭●‬ ‭Electronic Case Report Form, version 3.3, 21 February 2018‬
‭●‬ ‭Data Management Plan, version 2.0, 16 January 2018‬
‭●‬ ‭Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 14 June‬
‭2010‬
‭●‬ ‭EORTC QLQ-C30 Scoring Manual, Third edition, 2001‬
‭●‬ ‭EORTC QLQ-GINET21 Module Scoring Manual‬
‭4‬ ‭Study Evaluations‬
‭4.1‬ ‭Population Characteristics‬
‭At the Screening/Baseline visit following data will be collected:‬
‭●‬ ‭Demographic‬‭data,‬‭i.e.‬‭age,‬‭gender,‬‭childbearing‬‭potential‬‭for‬‭females,‬‭Race‬‭(except‬‭for‬
‭France)‬
‭●‬ ‭Relevant medical or surgical history and current medical conditions‬
‭●‬ ‭Detailed‬‭disease‬‭diagnosis‬‭data,‬‭i.e.‬‭diagnosis‬‭and‬‭extension‬‭of‬‭advanced‬‭(unresectable‬
‭or‬‭metastatic)‬‭progressive‬‭pNET‬‭including‬‭date‬‭of‬‭first‬‭diagnosis‬‭and‬‭tumor‬‭location‬‭and‬
‭ENETS‬‭TNM‬‭classification‬‭and‬‭diagnosis‬‭details‬‭at‬‭inclusion‬‭in‬‭SEQTOR‬‭trial‬‭including‬
‭diagnosis confirmation date and tumor ENETS TNM classification and location‬
‭●‬ ‭Prior antineoplastic therapies with details of medications, radiotherapies and surgeries‬
‭●‬ ‭Physical‬‭examination‬‭per‬‭body‬‭system,‬‭vital‬‭signs‬‭including‬‭systolic‬‭and‬‭diastolic‬‭blood‬
‭pressure, heart rate, body temperature, respiration rate, body height and weight‬
‭●‬ ‭Local‬‭and‬‭centralized‬‭radiological‬‭tumor‬‭assessment‬‭including‬‭specification‬‭of‬‭target‬‭and‬
‭non-target lesions‬
‭4.2‬ ‭Study Medication‬
‭Patient‬ ‭will‬ ‭be‬ ‭treated‬ ‭with‬ ‭either‬ ‭Streptozotocin‬ ‭(STZ)‬‭in‬‭combination‬‭with‬‭5-Fluorouracil‬
‭(5_FU),‬ ‭i.e.‬ ‭STZ-5FU‬ ‭or‬ ‭with‬ ‭Everolimus‬ ‭as‬ ‭1‬‭st‬ ‭line‬ ‭treatment‬ ‭and‬ ‭switch‬ ‭to‬ ‭the‬ ‭2‬‭nd‬ ‭line‬
‭treatment‬ ‭(STZ-5FU‬ ‭or‬ ‭Everolimus,‬ ‭respectively)‬ ‭upon‬ ‭disease‬ ‭progression.‬ ‭Everolimus‬
‭consists‬‭of‬‭elongated‬‭white‬‭to‬‭off-white‬‭tablets‬‭for‬‭oral‬‭administration.‬‭STZ‬‭is‬‭administered‬
‭as‬‭a‬‭short‬‭(30–60‬‭min)‬‭infusion‬‭or‬‭rapid‬‭intravenous‬‭push‬‭and‬‭5-FU‬‭is‬‭given‬‭as‬‭intravenous‬
‭bolus‬‭injection.‬‭See‬‭section‬‭2‬‭for‬‭dosage‬‭details.‬‭Drug‬‭administration‬‭for‬‭STZ-5FU‬‭will‬‭be‬
‭documented‬ ‭separately‬ ‭for‬ ‭the‬ ‭two‬ ‭components‬ ‭including‬ ‭the‬ ‭dosage‬ ‭recommendation‬
‭mode,‬ ‭i.e.‬ ‭according‬ ‭to‬ ‭Uppsala‬ ‭or‬ ‭Moertel.‬ ‭For‬ ‭both‬ ‭study‬ ‭treatments‬ ‭Everolimus‬ ‭and‬
‭STZ-5FU,‬ ‭the‬ ‭administered‬ ‭dosage‬ ‭will‬ ‭be‬ ‭recorded‬ ‭including‬ ‭reason‬ ‭for‬ ‭changes‬ ‭or‬
‭discontinuation. Treatment interruptions will have to be recorded with 0 mg.‬
‭4.3‬ ‭Efficacy‬
‭Efficacy‬‭evaluation‬‭will‬‭be‬‭based‬‭on‬‭radiological‬‭tumor‬‭assessments.‬‭Tumor‬‭lesions‬‭should‬
‭be‬‭measured‬‭following‬‭RECIST‬‭criteria‬‭version‬‭1.0‬‭at‬‭each‬‭site.‬‭Main‬‭study‬‭endpoint‬‭will‬‭be‬
‭based‬‭on‬‭local‬‭assessment.‬‭ENETS‬‭Score‬‭will‬‭be‬‭assessed‬‭retrospectively‬‭by‬‭an‬‭ENETS‬
‭Central Radiological Commission in Paris.‬
‭SEQTOR‬
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‭●‬ ‭Local assessment following RECIST criteria version 1.0‬
‭Tumor‬‭lesions‬‭should‬‭be‬‭measured‬‭following‬‭RECIST‬‭criteria‬‭version‬‭1.0‬‭before‬‭the‬‭start‬‭of‬
‭each‬ ‭treatment‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks.‬ ‭All‬ ‭assessments‬ ‭performed‬ ‭during‬ ‭the‬ ‭study‬ ‭(at‬
‭baseline‬ ‭and‬ ‭every‬ ‭12‬ ‭weeks)‬ ‭should‬ ‭be‬ ‭done‬ ‭using‬ ‭the‬ ‭same‬ ‭method‬ ‭and‬ ‭the‬ ‭same‬
‭technique.‬‭Assessments‬‭and‬‭measurements‬‭should‬‭be‬‭performed‬‭by‬‭the‬‭same‬‭radiologist‬‭or‬
‭physician‬‭throughout‬‭the‬‭study.‬‭Therefore,‬‭each‬‭site‬‭must‬‭designate‬‭a‬‭radiologist‬‭or‬‭other‬
‭medical‬‭staff‬‭responsible‬‭for‬‭the‬‭interpretation‬‭of‬‭the‬‭radiographs‬‭and‬‭triphasic‬‭CT‬‭scans‬‭or‬
‭multiple-phase MRI.‬
‭●‬ ‭Retrospective centralized assessment of ENETS Score‬
‭An‬‭ENETS‬‭Central‬‭Radiological‬‭Commission‬‭will‬‭be‬‭set‬‭up‬‭for‬‭a‬‭centralized‬‭evaluation‬‭of‬
‭CTs.‬ ‭The‬ ‭radiological‬ ‭commission‬ ‭will‬ ‭perform‬ ‭tumor‬ ‭assessment‬ ‭according‬ ‭to‬ ‭the‬ ‭four‬
‭radiology‬ ‭criteria‬ ‭for‬ ‭response‬ ‭evaluation‬ ‭(RECIST‬ ‭versions‬ ‭1.0‬ ‭and‬ ‭1.1,‬ ‭and‬ ‭composite‬
‭Scores according to RECIST 1.0 and to RECIST 1.1)‬
‭Tumor‬‭response‬‭following‬‭Composite‬‭ENETS‬‭Score‬‭will‬‭be‬‭assessed‬‭following‬‭the‬‭modified‬
‭criteria of ENETS (based on Haesun Choi criteria), as defined on the table 1:‬
‭Table 1: ENETS Score‬
‭Response‬
‭Definition‬
‭CR*‬
‭- Disappearance of all lesions‬
‭- No new lesions‬
‭PR*‬
‭- A decrease in size of 30 %‬
‭or a decrease in tumor density (HU) of 15% on CT‬
‭- No new lesions‬
‭- No obvious progression of non-measurable disease‬
‭SD*‬
‭- Does not meet the criteria for CR, PR, or PD‬
‭PD‬
‭- An increase in tumor size of 20% and does not meet‬
‭criteria of PR by tumor density (HU) on CT‬
‭- New lesions‬
‭*‬‭Without‬‭symptomatic‬‭deterioration‬‭of‬‭general‬‭condition‬‭according‬‭to‬‭WHO‬‭scale‬‭or‬‭ECOG‬
‭(modified ENETS criteria).‬
‭4.4‬ ‭Safety‬
‭Safety‬‭assessments‬‭will‬‭be‬‭based‬‭on‬‭recording‬‭of‬‭Adverse‬‭Events,‬‭laboratory‬‭parameters‬
‭determined‬ ‭at‬ ‭screening/baseline‬ ‭and‬ ‭at‬ ‭the‬ ‭treatment‬ ‭cycles,‬‭physical‬‭examination,‬‭vital‬
‭signs‬ ‭and‬ ‭12-lead‬ ‭ECG,‬ ‭ECOG‬ ‭performance‬ ‭status.‬ ‭Furthermore,‬ ‭a‬ ‭30‬ ‭days‬ ‭follow-up‬
‭scheduled‬‭for‬‭30‬‭days‬‭after‬‭the‬‭last‬‭dose‬‭intake‬‭and‬‭survival‬‭follow‬‭ups‬‭scheduled‬‭at‬‭every‬‭3‬
‭months‬ ‭after‬ ‭the‬ ‭end‬ ‭of‬ ‭the‬ ‭treatment‬ ‭will‬ ‭be‬ ‭performed‬ ‭with‬ ‭details‬ ‭about‬ ‭anticancer‬
‭treatment given, adverse events and life status.‬
‭4.5‬ ‭Other Variables‬
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‭Chest‬‭X-ray‬‭(and/or‬‭if‬‭the‬‭disease‬‭is‬‭present‬‭in‬‭the‬‭chest,‬‭a‬‭chest‬‭CT)‬‭will‬‭be‬‭performed‬‭for‬
‭all‬ ‭patients.‬ ‭During‬ ‭the‬ ‭treatment‬ ‭period,‬ ‭chest‬ ‭X-ray‬ ‭will‬ ‭be‬ ‭performed‬ ‭every‬‭12‬‭weeks.‬
‭Pulmonary‬ ‭function‬ ‭tests‬ ‭will‬ ‭be‬ ‭performed‬ ‭if‬ ‭clinically‬ ‭necessary‬ ‭in‬ ‭case‬ ‭of‬ ‭evidence‬‭of‬
‭non-infectious‬ ‭pneumonitis.‬ ‭If‬ ‭non-infectious‬ ‭pneumonitis‬ ‭is‬ ‭diagnosed,‬ ‭pneumologist‬
‭consultation‬‭should‬‭be‬‭considered.‬‭When‬‭necessary‬‭to‬‭ensure‬‭patient‬‭care,‬‭a‬‭bronchoscopy‬
‭with biopsy and/or bronchoalveolar lavage (BAL) will be performed.‬
‭Quality‬ ‭of‬ ‭life‬ ‭will‬ ‭be‬ ‭assessed‬ ‭based‬ ‭on‬ ‭the‬‭EORTC‬‭QLQ-C30‬‭questionnaire.‬‭QLQ-C30‬
‭Version‬‭3.0‬‭is‬‭the‬‭most‬‭recent‬‭version‬‭and‬‭it‬‭is‬‭supplemented‬‭by‬‭disease‬‭specific‬‭modules‬
‭for‬ ‭NET,‬ ‭the‬ ‭EORTC‬ ‭QLQ‬‭GINET21.‬‭EORTC‬‭QLQ-C30‬‭and‬‭the‬‭specific‬‭module‬‭for‬‭NET‬
‭EORTC‬‭QLQ‬‭GINET21‬‭will‬‭be‬‭administrated‬‭before‬‭the‬‭start‬‭of‬‭each‬‭treatment‬‭period,‬‭upon‬
‭progression‬ ‭or‬ ‭unacceptable‬ ‭toxicity,‬ ‭or‬ ‭at‬ ‭the‬ ‭end‬ ‭of‬ ‭second‬ ‭treatment‬ ‭period‬‭if‬‭second‬
‭period event (progression) is not reached.‬
‭Documentation‬ ‭of‬ ‭resource‬ ‭utilization‬ ‭will‬ ‭be‬ ‭based‬ ‭on‬ ‭recordings‬ ‭of‬ ‭hospitalizations,‬
‭outpatient visits and diagnostics and procedures performed related to adverse events.‬
‭5‬ ‭Type of Analysis‬
‭6‬ ‭General Statistical Considerations‬
‭6.1‬ ‭General Principles‬
‭The‬‭statistical‬‭evaluation‬‭will‬‭be‬‭performed‬‭by‬‭using‬‭the‬‭software‬‭package‬‭SAS‬‭release‬‭9.4‬
‭(SAS Institute Inc., Cary, NC, USA).‬
‭Any‬‭statistical‬‭testing‬‭will‬‭be‬‭applied‬‭two-sided‬‭with‬‭a‬‭significance‬‭level‬‭of‬‭α=0.05.‬‭No‬‭interim‬
‭analyses‬ ‭are‬ ‭planned.‬ ‭The‬ ‭analysis‬ ‭will‬ ‭be‬ ‭performed‬ ‭splitted‬ ‭into‬ ‭two‬ ‭parts:‬ ‭the‬ ‭main‬
‭analysis‬ ‭first‬ ‭and‬ ‭the‬ ‭final‬ ‭analysis‬‭second.‬‭All‬‭data‬‭included‬‭in‬‭the‬‭main‬‭analysis‬‭will‬‭be‬
‭cleaned‬‭and‬‭locked‬‭at‬‭the‬‭timepoint‬‭of‬‭main‬‭analysis.‬‭Final‬‭analysis‬‭comprises‬‭all‬‭analyses‬
‭not‬ ‭yet‬ ‭performed‬ ‭within‬ ‭the‬ ‭main‬ ‭analysis.‬ ‭With‬ ‭this‬ ‭approach,‬ ‭inconsistencies‬ ‭of‬ ‭data‬
‭between‬ ‭main‬ ‭and‬ ‭final‬ ‭analysis‬ ‭and‬ ‭multiple‬ ‭testing‬ ‭of‬ ‭the‬ ‭same‬ ‭parameter‬ ‭caused‬ ‭by‬
‭splitted analyses will be avoided.‬
‭Sample size justification‬
‭As‬‭per‬‭protocol‬‭version‬‭4.0‬‭it‬‭is‬‭assumed‬‭that‬‭Everolimus‬‭achieves‬‭first‬‭progression‬‭free‬
‭survival‬ ‭of‬ ‭50‬ ‭%‬ ‭at‬ ‭52‬ ‭weeks‬ ‭(arm‬ ‭A:‬ ‭Everolimus‬ ‭followed‬ ‭by‬ ‭STZ-5-FU‬ ‭upon‬
‭progression)‬‭and‬‭arm‬‭B,‬‭the‬‭reverse‬‭sequence,‬‭achieves‬‭first‬‭progression‬‭free‬‭survival‬
‭of‬ ‭75‬‭%‬‭at‬‭52‬‭weeks.‬‭As‬‭per‬‭protocol‬‭version‬‭3.0‬‭it‬‭is‬‭assumed‬‭that‬‭treatment‬‭arm‬‭A‬
‭(Everolimus‬ ‭followed‬ ‭by‬ ‭STZ-5-FU‬ ‭upon‬ ‭progression)‬ ‭achieves‬‭a‬‭second‬‭progression‬
‭free‬ ‭survival‬ ‭of‬ ‭50‬ ‭%‬ ‭at‬ ‭140‬ ‭weeks‬ ‭and‬ ‭arm‬‭B,‬‭the‬‭reverse‬‭sequence,‬‭achieves‬‭first‬
‭progression‬‭free‬‭survival‬‭of‬‭75‬‭%‬‭at‬‭140‬‭weeks(data‬‭based‬‭on‬‭RADIANT-3‬‭results‬‭of‬‭11‬
‭months or 48 weeks; Yao et al, NEJM 201113).‬
‭The‬ ‭null‬ ‭hypothesis‬ ‭in‬ ‭this‬ ‭study‬ ‭is‬ ‭defined‬ ‭as‬ ‭H‬‭0‬‭:‬ ‭P‬‭B‬‭-P‬‭A‬ ‭=‬ ‭0‬ ‭and‬ ‭the‬ ‭alternative‬
‭hypothesis is defined as H‬‭1‬‭: P‬‭B‬‭-P‬‭A‬‭≠ 0.‬
‭A‬ ‭two-sided‬ ‭binomial‬ ‭test‬ ‭of‬ ‭proportion‬ ‭differences‬ ‭has‬ ‭been‬ ‭run‬ ‭to‬ ‭determine‬ ‭the‬
‭sample size.‬
‭According‬ ‭to‬‭protocol‬‭version‬‭4.0,‬‭setting‬‭type‬‭I‬‭error‬‭(alpha)‬‭level‬‭to‬‭0.05‬‭and‬‭type‬‭II‬
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‭error‬‭(beta)‬‭to‬‭0.20,‬‭a‬‭minimum‬‭sample‬‭size‬‭of‬‭132‬‭patients‬‭is‬‭required‬‭(Fleiss‬‭1980).‬
‭Assuming‬ ‭that‬ ‭5%‬‭of‬‭patients‬‭could‬‭be‬‭lost‬‭by‬‭several‬‭reasons,‬‭the‬‭proposed‬‭sample‬
‭size is 140 patients (70 patients per study arm).‬
‭According‬ ‭to‬‭protocol‬‭version‬‭3.0,‬‭setting‬‭type‬‭I‬‭error‬‭(alpha)‬‭level‬‭to‬‭0.05‬‭and‬‭type‬‭II‬
‭error‬‭(beta)‬‭to‬‭0.10,‬‭a‬‭minimum‬‭sample‬‭size‬‭of‬‭170‬‭patients‬‭is‬‭required‬‭(Fleiss‬‭1980).‬
‭Assuming‬ ‭that‬ ‭5%‬‭of‬‭patients‬‭could‬‭be‬‭lost‬‭by‬‭several‬‭reasons,‬‭the‬‭proposed‬‭sample‬
‭size is 180 patients (90 patients per study arm).‬
‭With 141 currently included patients, with at least 70 patients per treatment arm, the‬
‭actual power amounts 83% at alpha-level of 5% and 75% at alpha-level of 2.5‬‭%.‬
‭6.2‬ ‭Handling of Loss to Follow-up and Premature Discontinuation‬
‭Patients‬‭can‬‭be‬‭discontinued‬‭from‬‭study‬‭treatments‬‭(i.e.‬‭Everolimus‬‭and/or‬‭STZ-5FU)‬‭and/or‬
‭withdraw‬‭completely‬‭from‬‭the‬‭study.‬‭In‬‭case‬‭of‬‭treatment‬‭discontinuation,‬‭“End‬‭of‬‭Course‬‭1”‬
‭and‬ ‭/or‬ ‭“End‬ ‭of‬ ‭Course‬ ‭2”‬ ‭forms‬ ‭are‬ ‭to‬ ‭be‬ ‭completed‬ ‭and‬ ‭containing,‬ ‭amongst‬ ‭others,‬
‭laboratory‬ ‭data‬ ‭and‬ ‭physical‬ ‭examination.‬ ‭Reasons‬ ‭for‬ ‭drug‬ ‭discontinuation‬ ‭will‬ ‭be‬
‭documented‬‭at‬‭the‬‭drug‬‭administration‬‭sections,‬‭reason‬‭for‬‭withdrawal‬‭from‬‭the‬‭study‬‭will‬‭be‬
‭documented at the End of Study/Final Status Form.‬
‭Sample‬ ‭size‬ ‭and‬ ‭disposition‬ ‭information‬ ‭at‬ ‭each‬ ‭analysis‬ ‭time‬ ‭point,‬ ‭as‬‭well‬‭as‬‭the‬‭final‬
‭status‬‭of‬‭patients‬‭including‬‭reasons‬‭for‬‭withdrawal‬‭from‬‭the‬‭study‬‭or‬‭treatment,‬‭respectively,‬
‭will‬‭be‬‭displayed‬‭in‬‭frequency‬‭tables.‬‭Relative‬‭frequency‬‭calculation‬‭will‬‭be‬‭based‬‭in‬‭general‬
‭on‬ ‭the‬ ‭total‬ ‭population‬ ‭of‬ ‭patients‬ ‭(total‬ ‭population‬ ‭of‬ ‭stratum‬ ‭for‬ ‭subgroup-analysis,‬
‭respectively) at any analysis time point, who have not dropped out until this time.‬
‭6.3‬ ‭Data Rules‬
‭6.3.1‬ ‭General Definitions‬
‭●‬ ‭Baseline: measurements documented at the screening visit will be considered as‬
‭baseline values‬
‭●‬ ‭1‬‭st‬‭line treatment: study treatment administered as‬‭the first treatment of the randomized‬
‭sequence‬
‭●‬ ‭2‬‭nd‬‭line treatment: study treatment administered as‬‭the second treatment of the‬
‭randomized sequence after discontinuation of the 1‬‭st‬‭line treatment‬
‭6.3.2‬ ‭Definition of Derived Variables‬
‭a)‬ ‭Following algorithms will be used to calculate derived variables‬
‭Table 2: Derived variables‬
‭Variable‬
‭Derivation‬
‭Duration‬
‭-‬
‭of first dose of prior‬
‭antineoplastic therapies,‬
‭medications‬
‭End date (of last dose) – start date (of first dose) + 1‬
‭In case only month and year are documented, the 1‬‭st‬‭of month will be imputed for the‬
‭start date and the last of month will be imputed for the end date. No duration will be‬
‭calculated in case only the year is documented.‬
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‭-‬
‭of antineoplastic therapies,‬
‭radiotherapies‬
‭Time from‬
‭-‬
‭date of first diagnosis of‬
‭advanced pNET to date of‬
‭ICF signature‬
‭-‬
‭date of confirmation of‬
‭diagnosis to date of ICF‬
‭signature‬
‭Date of ICF signature - date of first / confirmation of diagnosis‬
‭In case only month and year are documented for the date of diagnosis, imputation with‬
‭1‬‭st‬‭of the month will be performed. No calculation‬‭will be done in case only the year is‬
‭documented.‬
‭Time from date of ICF to‬
‭collection date of paraffin‬
‭embedded tumor block‬
‭Date of ICF signature - date of collection date of paraffin embedded tumor block‬
‭Duration of observation period‬
‭Date of last documented visit / date of end of study / date of last contact (whichever‬
‭occurred last) – date of screening visit + 1‬
‭Duration of treatment before‬
‭discontinuation‬
‭Date of last intake of study drug / date of final status (end of treatment) – date of first‬
‭intake + 1‬
‭Time between visits [days]‬
‭●‬
‭Duration of 1‬‭st‬‭(2‬‭nd‬‭) line treatment:‬
‭Date of end of course 1 (end of course 2) visit – date of cycle 1 visit of 1‬‭st‬‭(2‬‭nd‬‭) line‬
‭treatment + 1‬
‭●‬
‭Duration of resting period [days]‬
‭Date of cycle 1 of 2‬‭nd‬‭line treatment / date of first‬‭intake of 2‬‭nd‬‭line treatment – date of‬
‭last documented cycle of 1‬‭st‬‭line treatment / date‬‭of last intake of 1‬‭st‬‭line treatment -1‬
‭●‬
‭Days between Screening and Cycle 1 of 1‬‭st‬‭line treatment:‬
‭Date of cycle 1 of 1‬‭st‬‭line treatment – date of screening‬‭visit‬
‭●‬
‭Days between end of treatment and 30-days FU‬
‭Date of 30 days FU – date of end of treatment‬
‭BMI [kg/m²]‬
‭Weight in kg / (height in m)²‬
‭12 lead-ECG worst diagnosis‬
‭In case several 12 lead-ECG assessments are documented for one analysis time point,‬
‭only the one with the worst diagnosis will be taken, with‬
‭abnormal, clinically significant‬‭defined as the worst,‬‭followed by‬‭abnormal, not clinically‬
‭significant,‬‭followed by‬‭normal‬‭, followed by‬‭non-evaluable‬
‭Change from baseline‬
‭Measurement value at any post baseline visit - measurement value at baseline‬
‭Average actual daily dose [mg/kg]‬
‭Sum of all dosages multiplied with exposure duration in days of that dosage / total‬
‭exposure duration, excluding off-days (days on interruption documented as 0 mg)‬
‭Dosing interruption‬
‭Dosages with a daily dose documented as 0 mg/kg‬
‭Dosing increase‬
‭Dosage increase compared to previously prescribed dose of same treatment, excluding‬
‭doses documented as 0 mg/kg (interruption)‬
‭Dosing decrease‬
‭Dosage decrease compared to previously prescribed dose of same treatment, excluding‬
‭doses documented as 0 mg/kg (interruption)‬
‭Duration of interruptions [days]‬
‭Sum of (End date of interruption – start date of interruption + 1)‬
‭Duration of exposure [days]‬
‭Sum of (date of last intake - date of first intake +1 - days with interruptions) by treatment‬
‭arm‬
‭Treatment emergent adverse‬
‭events (TEAE)‬
‭AEs with onset on or after the date of first exposure to study drug are considered as‬
‭treatment emergent.‬
‭AEs with onset date on or after the date of first exposure to the 1‬‭st‬‭line treatment or‬
‭occurred during the treatment resting period are considered as treatment emergent for‬
‭the 1‬‭st‬‭line treatment.‬
‭For patients receiving the 2‬‭nd‬‭line treatment and‬‭AEs with onset on or after the date of‬
‭first exposure to the 2‬‭nd‬‭line treatment will be allocated‬‭treatment emergent to the 2‬‭nd‬‭line‬
‭treatment.‬
‭Assignment of treatment emergent status in case of AE start and end date are‬
‭completely or partially missing:‬
‭●‬
‭If the start date of event is completely or partially missing and the event end date is‬
‭before first exposure to 1‬‭st‬‭line treatment the AE‬‭will be assigned as not treatment‬
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‭emergent. In case end dates are partially provided, the respective month and year‬
‭parts will be compared to the first exposure to 1‬‭st‬‭line treatment and if before, AE‬
‭will be assigned as not treatment emergent.‬
‭●‬
‭If end dates are equal to or after the first exposure to 1‬‭st‬‭line treatment or missing:‬
‭o‬
‭If the start date is completely missing, the AE will be considered as‬
‭treatment emergent for the 1‬‭st‬‭line treatment‬
‭o‬
‭If the only the start year of the event is documented being equal or after‬
‭the first exposure to 1‬‭st‬‭line treatment, the AE will‬‭be assigned as treatment‬
‭emergent to the 1‬‭st‬‭line treatment.‬
‭o‬
‭If only the start day of the event is missing but start month and year of the‬
‭event are equal or after first exposure to 1‬‭st‬‭line‬‭treatment, the AE will be‬
‭assigned as treatment emergent for the 1‬‭st‬‭line treatment.‬‭For patients‬
‭receiving the 2‬‭nd‬‭line treatment: in case the month‬‭and year are equal or‬
‭after the first exposure of the 2‬‭nd‬‭line treatment‬‭the AE will be assigned as‬
‭treatment emergent to the 2‬‭nd‬‭line treatment, unless‬‭the end date is‬
‭indicating that the event stopped before the first exposure of the 2‬‭nd‬‭line‬
‭treatment. In case of any other possible unclarity regarding assignment to‬
‭either the first or 2‬‭nd‬‭line treatment, the event‬‭will be assigned as treatment‬
‭emergent for the 1‬‭st‬‭line treatment.‬
‭Related adverse event‬
‭An AE with relationship documented by the reporter as missing, unknown, yes, not‬
‭assessable, or not applicable will be analyzed as a related AE. AEs with relationship‬
‭documented as no by the reporter are defined as not related AEs.‬
‭Duration of AE [days]‬
‭End Date of AE - Start Date of AE + 1‬
‭Duration will only be calculated, if complete event start and end dates are documented,‬
‭no imputation will be performed.‬
‭Time between onset of AE and‬
‭first treatment administration‬
‭Start Date of AE – date of first administration of study drug‬
‭In case patient received 2‬‭nd‬‭line treatment and AE‬‭is treatment emergent to the 2‬‭nd‬‭line‬
‭treatment, difference will be related to the 2‬‭nd‬‭line‬‭treatment.‬
‭Duration will only be calculated, if complete event start and end dates are documented,‬
‭no imputation will be performed.‬
‭Prior and concomitant medication‬
‭or significant non-drug therapies‬
‭Therapies with onset before the first exposure to 1‬‭st‬‭line treatment will be classified as‬
‭prior (also records with missing/unknown start date). Therapies which did not stop‬
‭before the first exposure to 1‬‭st‬‭line treatment (stop‬‭date on or later than date of first‬
‭exposure to 1‬‭st‬‭line treatment, stop date missing/unknown‬‭or ‘ongoing’) will be classified‬
‭as concomitant.‬
‭Relevant prior and concomitant‬
‭medical / surgical history /‬
‭medical conditions‬
‭Conditions which are documented as ongoing will be derived as concomitant, conditions‬
‭documented as not ongoing will be derived as prior. In case of missing ongoing status,‬
‭condition will be derived as concomitant.‬
‭First progression free survival‬
‭(PFS1R12m) rate at 12 months‬
‭PFS1R12m rate will be based on the overall response assessments by local‬
‭investigators using RECIST criteria version 1.0. Those assessments are to take place‬
‭every 12 weeks. The derivation of evaluation weeks is described in section 9.1, table 6.‬
‭Week 52 will correspond to 1 year after randomization, e.g. if randomization took place‬
‭on 05Mar2016, as per below mentioned definitions the 52nd week timepoint (TP52w)‬
‭will correspond to 05Mar2017.‬
‭PFS1 rate is the proportion of patients who are alive and progression free according to‬
‭the below:‬
‭Main definition of PFS1R12m‬
‭Definition of progression free:‬
‭-‬
‭Patient is alive and progression free (i.e. CR, PR or SD documented) at the week‬
‭60 evaluation and no disease progression is documented up to the week 60‬
‭evaluation.‬
‭-‬
‭First disease progression is documented at the week 60 evaluation, but the patient‬
‭was progression free (i.e. CR, PR or SD documented) at week 48 evaluation and‬
‭patient is receiving at least one cycle of 1‬‭st‬‭line‬‭treatment posterior week 52‬
‭-‬
‭Patient died between week 52 and the theoretical date of the week 60 evaluation‬
‭with main cause of death NOT documented as toxicity or primary disease.‬
‭Furthermore, no disease progression was documented up to the date of death‬
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‭Disease progression is defined as‬
‭-‬
‭First disease progression is documented before or at the week 48 evaluations‬
‭-‬
‭First disease progression is documented at the week 60 evaluations, but patient is‬
‭not receiving 1‬‭st‬‭line treatment posterior week 52‬
‭-‬
‭Patient died before week 52‬
‭-‬
‭Patient died between week 52 and the theoretical date of the week 60 evaluations‬
‭with main cause of death documented as toxicity or primary disease.‬
‭In case of week 48 evaluation is not available or not unique, the last available tumor‬
‭evaluation between week 46 and TP52w will be taken into account.‬
‭In case of week 60 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP52w will be taken into account.‬
‭Conservative definition of PFS1R12m‬
‭Patient is to be considered progression free, if patient is alive and progression free (i.e.‬
‭CR, PR or SD documented) at the week 60 evaluations and no disease progression is‬
‭documented up to the week 60 evaluations. Death of any cause or first disease‬
‭progression until including the week 60 evaluation will be considered as disease‬
‭progression.‬
‭In case of week 60 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP52w will be taken into account.‬
‭Optimistic definition of PFS1R12m‬
‭Patient is to be considered progression free, if‬
‭-‬
‭Patient is alive and progression free (i.e. CR, PR or SD documented) at the week‬
‭60 evaluations. No disease progression is documented up to the week 60‬
‭evaluation.‬
‭-‬
‭First disease progression is documented at the week 60 evaluations, but the patient‬
‭was progression free (i.e. CR, PR or SD documented) at week 48 evaluations.‬
‭-‬
‭Patient died due to any cause between week 52 and the theoretical date of the‬
‭week 60 evaluation. Furthermore, no disease progression was documented up to‬
‭the date of death‬
‭Disease progression is defined as‬
‭-‬
‭First disease progression is documented before or at the week 48 evaluations‬
‭-‬
‭First disease progression is documented at the week 60 evaluation and the week‬
‭48 evaluations is not CR, PR or SD or not available.‬
‭-‬
‭Patient died before week 52‬
‭In case of week 48 evaluation is not available or not unique, the last available tumor‬
‭evaluation between week 46 and TP52w will be taken into account.‬
‭In case of week 60 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP52w will be taken into account.‬
‭Second progression free survival‬
‭(PFS2nd) rate at 140 weeks +/- 8‬
‭weeks‬
‭PFS2nd rate will be based in analogy of PFS1R12m on the overall response‬
‭assessments by local investigators using RECIST criteria version 1.0. It refers to the‬
‭timepoint 140 weeks (=980days) after randomization (TP140w). PFS2nd rate is the‬
‭proportion of patients who are alive and had at least one progression according to the‬
‭below mentioned definitions:‬
‭Main definition of PFS2nd‬
‭Definition of progression free:‬
‭-‬
‭Patient is alive and progression free (at least) at cycle 2 of the 2‬‭nd‬‭line treatment (i.e.‬
‭CR, PR or SD documented) at the week 144 evaluation and no 2nd disease‬
‭progression is documented up to the week 144 evaluation.‬
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‭-‬
‭2nd disease progression is documented at the week 144 evaluation, but the patient‬
‭was progression free (i.e. CR, PR or SD documented) at week 132 evaluation and‬
‭patient is receiving at least one cycle of 2nd line treatment posterior week 140‬
‭-‬
‭Patient died between week 140 and the theoretical date of the week 144 evaluation‬
‭with main cause of death NOT documented as toxicity or primary disease.‬
‭Furthermore, no disease progression was documented up to the date of death‬
‭Disease progression is defined as‬
‭-‬
‭2nd disease progression is documented before or at the week 132 evaluations‬
‭-‬
‭2nd disease progression is documented at the week 144 evaluations, but patient is‬
‭not receiving 2‬‭nd‬‭line treatment posterior week 140‬
‭-‬
‭Patient died before week 140‬
‭-‬
‭Patient died between week 140 and the theoretical date of the week 144‬
‭evaluations with main cause of death documented as toxicity or primary disease.‬
‭In case of week 132 evaluation is not available or not unique, the last available tumor‬
‭evaluation between week 132 and TP140w will be taken into account.‬
‭In case of week 144 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP140w will be taken into account.‬
‭Conservative definition of PFS2nd‬
‭Patient is to be considered progression free, if patient is alive and progression free (i.e.‬
‭CR, PR or SD documented) at the week 144 evaluations and no disease progression is‬
‭documented up to the week 144 evaluations. Death of any cause or first disease‬
‭progression until including the week 144 evaluation will be considered as disease‬
‭progression.‬
‭In case of week 144 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP140w will be taken into account.‬
‭Optimistic definition of PFS2nd‬
‭Patient is to be considered progression free, if‬
‭-‬
‭Patient is alive and progression free‬‭(at least) at‬‭cycle 2 of the 2‬‭nd‬‭line treatment‬
‭(i.e. CR, PR or SD documented) at the week 144 evaluations. No 2nd disease‬
‭progression is documented up to the week 144 evaluation.‬
‭-‬
‭2nd disease progression is documented at the week 144 evaluations, but the‬
‭patient was progression free (at least) at cycle 2 (i.e. CR, PR or SD documented) at‬
‭week 132 evaluations.‬
‭-‬
‭Patient died due to any cause between week 140 and the theoretical date of the‬
‭week 60 evaluation. Furthermore, no disease progression was documented up to‬
‭the date of death‬
‭Disease progression is defined as‬
‭-‬
‭2nd disease progression is documented before or at the week 132 evaluations‬
‭-‬
‭2nd disease progression is documented at the week 144 evaluation and the week‬
‭132 evaluations is not CR, PR or SD or not available.‬
‭-‬
‭Patient died before week 140‬
‭-‬
‭In case of week 132 evaluation is not available or not unique, the last available tumor‬
‭evaluation between week 132 and TP140w will be taken into account.‬
‭In case of week 144 tumor evaluation is not available or not unique, the first available‬
‭evaluation at or after TP140w will be taken into account.‬
‭Second progression free survival‬
‭(PFS2nd) according to local‬
‭assessment using RECIST 1.0‬
‭Date of second disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 or date of death from any cause (whichever occurred‬
‭earlier) - date of randomization +1‬
‭Patients without second progression will be censored at the date of last tumor‬
‭evaluation. Patients without tumor evaluations will be censored at day 1.‬
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‭First Progression free survival‬
‭(PFS1) according to local‬
‭assessment using RECIST 1.0‬
‭Date of first disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 or date of death from any cause (whichever occurred‬
‭earlier) - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭First Progression free survival‬
‭(PFS1) according to central‬
‭assessment using RECIST 1.0‬
‭Date of first disease progression based on central assessment using RECIST criteria‬
‭version 1.0 or date of death from any cause (whichever occurred earlier) - date of‬
‭randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭First Progression free survival‬
‭(PFS1) according to central‬
‭assessment using RECIST 1.1‬
‭Date of first disease progression based on central assessment using RECIST criteria‬
‭version 1.1 or date of death from any cause (whichever occurred earlier) - date of‬
‭randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭First Progression free survival‬
‭(PFS1) according to central‬
‭assessment using ENETS‬
‭SCORE RECIST 1.0‬
‭Date of first disease progression based on central assessment using ENETS SCORE‬
‭RECIST criteria version 1.0 or date of death from any cause (whichever occurred‬
‭earlier) - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭First Progression free survival‬
‭(PFS1) according to central‬
‭assessment using ENETS‬
‭SCORE RECIST 1.1‬
‭Date of first disease progression based on central assessment using ENETS SCORE‬
‭RECIST criteria version 1.1 or date of death from any cause (whichever occurred‬
‭earlier) - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Progression free survival course‬
‭2 (PFS2) according to local‬
‭assessment using RECIST 1.0‬
‭Date of second disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 or date of death from any cause (whichever occurred‬
‭earlier) - date of first intake of 2nd line treatment‬
‭Patients without second progression will be censored at the date of last tumor‬
‭evaluation. Patients without tumor evaluations will be censored at day 1.‬
‭Time to first progression (TTP1)‬
‭according to local assessment‬
‭using RECIST 1.0‬
‭Date of first disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Time to first progression (TTP1)‬
‭according to central assessment‬
‭using RECIST 1.0‬
‭Date of first disease progression based on central assessment using RECIST criteria‬
‭version 1.0 - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Time to first progression (TTP1)‬
‭according to local assessment‬
‭using RECIST 1.1‬
‭Date of first disease progression based on central assessment using RECIST criteria‬
‭version 1.1 - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Time to first progression (TTP1)‬
‭according to local assessment‬
‭using ENETS SCORE RECIST‬
‭1.0‬
‭Date of first disease progression based on central assessment using ENETS SCORE‬
‭RECIST criteria version 1.0 - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Time to first progression (TTP1)‬
‭according to local assessment‬
‭using ENETS SCORE RECIST‬
‭1.1‬
‭Date of first disease progression based on central assessment using ENETS SCORE‬
‭RECIST criteria version 1.1 - date of randomization +1‬
‭Patients without progression will be censored at the date of last tumor evaluation.‬
‭Patients without tumor evaluations will be censored at day 1.‬
‭Time to second progression‬
‭(TTP2nd) according to local‬
‭assessment using RECIST 1.0‬
‭Date of second disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 - date of randomization +1‬
‭Patients without second progression will be censored at the date of last tumor‬
‭evaluation. Patients without tumor evaluations will be censored at day 1.‬
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‭Time from first progression to‬
‭second progression‬
‭Date of second disease progression based on assessment by local investigator using‬
‭RECIST criteria version 1.0 - date of first disease progression based on assessment by‬
‭local investigator using RECIST criteria version 1.0‬
‭Patients without second progression will be censored at the date of last tumor‬
‭evaluation. Patients without tumor evaluations will be censored at day 1‬
‭Objective response rate (ORR)‬
‭according to local assessment‬
‭Rate of objective response (CR+PR+SD)‬‭according to‬‭local assessment measured by‬
‭RECIST criteria version 1.0‬
‭Calculation will be performed by evaluation following the regular 12-week basis. The‬
‭derivation of evaluation weeks is described in section 9.1, table 6‬
‭Objective response rate (ORR)‬
‭according to central assessment‬
‭Rate of objective response (CR+PR+SD)‬‭according to‬‭central assessment measured by‬
‭RECIST criteria version 1.0‬
‭Calculation will be performed by evaluation following the regular 12-week basis. The‬
‭derivation of evaluation weeks is described in section 9.1, table 6‬
‭Overall response rate‬
‭Rate of patients that have observed during all evaluations as a best response CR or PR‬
‭or SD‬
‭Overall survival (OS)‬
‭Date of death – date of randomization +1‬
‭Patients alive or lost to follow up will be censored at the last date known to be alive.‬
‭Patients without any documentation post randomization will be censored with day 1.‬
‭Incremental Cost-Effectiveness‬
‭(ICER)‬
‭𝐶𝑜𝑠𝑡𝑠‬‭ ‬‭𝐸𝑣𝑒𝑟𝑜𝑙𝑖𝑚𝑢𝑠‬‭ ‬‭𝑎𝑠‬‭ ‬‭1‬‭𝑠𝑡‬‭ ‬‭𝑙𝑖𝑛𝑒‬‭ ‬‭𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡‬‭ ‬‭–‬‭ ‬‭𝐶𝑜𝑠𝑡𝑠‬‭ ‬‭𝑆𝑇𝑍‬−‭5‬‭𝐹𝑈‬‭ ‬‭𝑎𝑠‬‭ ‬‭1‬‭𝑠𝑡‬‭ ‬‭𝑙𝑖𝑛𝑒‬‭ ‬‭𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡‬
‭𝑃𝐹𝑆‬‭1‬‭ ‬‭𝑜𝑓‬‭ ‬‭𝐸𝑣𝑒𝑟𝑜𝑙𝑖𝑚𝑢𝑠‬‭ ‬‭𝑎𝑠‬‭ ‬‭1‬‭𝑠𝑡‬‭ ‬‭𝑙𝑖𝑛𝑒‬‭ ‬‭𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡‬−‭ ‬‭𝑃𝐹𝑆‬‭1‬‭ ‬‭𝑜𝑓‬‭ ‬‭𝑆𝑇𝑍‬−‭5‬‭𝐹𝑈𝑎𝑠‬‭ ‬‭1‬‭𝑠𝑡‬‭ ‬‭𝑙𝑖𝑛𝑒‬‭ ‬‭𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡‬
‭Details for calculation of cost effectiveness will be defined in a separate statistical‬
‭analysis plan‬
‭CTCAE grades (if possible, grades will be derived based on original documented units and values and not on converted to SI‬
‭units)‬
‭Anemia‬
‭Grade 1: Hemoglobin <LLN - 10.0 g/dL; <LLN - 6.2 mmol/L; <LLN - 100 g/L‬
‭Grade 2: Hemoglobin <10.0 - 8.0 g/dL; <6.2 - 4.9 mmol/L; <100 - 80g/L‬
‭Grade 3: Hemoglobin <8.0 g/dL; <4.9 mmol/L; <80 g/L‬
‭Grade 4: -‬
‭Hemoglobin increased‬
‭Grade 1: Increase in >0 - 2 gm/dL above ULN or above baseline if baseline is above‬
‭ULN‬
‭Grade 2: Increase in >2 - 4 gm/dL above ULN or above baseline if baseline is above‬
‭ULN‬
‭Grade 3:  Increase in >4 gm/dL above ULN or above baseline if baseline is above ULN‬
‭Grade 4: -‬
‭Leukocytosis‬
‭Grade 1: -‬
‭Grade 2: -‬
‭Grade 3: WBC count >100,000/mm3‬
‭Grade 4: -‬
‭Alanine aminotransferase (ALT)‬
‭increased‬
‭Grade 1: >ULN - 3.0 x ULN‬
‭Grade 2: >3.0 - 5.0 x ULN‬
‭Grade 3: >5.0 - 20.0 x ULN‬
‭Grade 4: >20.0 x ULN‬
‭Alkaline phosphatase increased‬
‭Grade 1: >ULN - 2.5 x ULN‬
‭Grade 2: >2.5 - 5.0 x ULN‬
‭Grade 3: >5.0 - 20.0 x ULN‬
‭Grade 4: >20.0 x ULN‬
‭Aspartate aminotransferase‬
‭(AST) increased‬
‭Grade 1: >ULN - 3.0 x ULN‬
‭Grade 2: >3.0 - 5.0 x ULN‬
‭Grade 3: >5.0 - 20.0 x ULN‬
‭Grade 4: >20.0 x ULN‬
‭Blood bilirubin increased‬
‭Grade 1: >ULN - 1.5 x ULN‬
‭Grade 2: >1.5 - 3.0 x ULN‬
‭Grade 3: >3.0 - 10.0 x ULN‬
‭Grade 4: >10.0 x ULN‬
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‭Cholesterol high‬
‭Grade 1: >ULN - 300 mg/dL; >ULN - 7.75 mmol/L‬
‭Grade 2: >300 - 400 mg/dL; >7.75 - 10.34 mmol/L‬
‭Grade 3: >400 - 500 mg/dL; >10.34 - 12.92 mmol/L‬
‭Grade 4: >500 mg/dL; >12.92 mmol/L‬
‭Creatinine increased‬
‭Grade 1: >1 - 1.5 x baseline; >ULN - 1.5 x ULN‬
‭Grade 2: >1.5 - 3.0 x baseline; >1.5 - 3.0 x ULN‬
‭Grade 3: >3.0 baseline; >3.0 - 6.0 x ULN‬
‭Grade 4: >6.0 x ULN‬
‭Lymphocyte count decreased‬
‭Grade 1: <LLN - 800/mm‬‭3‬‭; <LLN - 0.8 x 10‬‭9‬‭/L‬
‭Grade 2: <800 - 500/mm‬‭3‬‭; <0.8 - 0.5 x 10‬‭9‬‭/L‬
‭Grade 3: <500 - 200/mm‬‭3‬‭; <0.5 - 0.2 x 10‬‭9‬‭/L‬
‭Grade 4: <200/mm‬‭3‬‭; <0.2 x 10‬‭9‬‭/L‬
‭Lymphocyte count increased‬
‭Grade 1: -‬
‭Grade 2: >4000/mm3 - 20,000/mm3‬
‭Grade 3: >20,000/mm3‬
‭Grade 4: -‬
‭Neutrophil count decreased‬
‭Grade 1: <LLN - 1500/mm‬‭3‬‭; <LLN - 1.5 x 10‬‭9‬‭/L‬
‭Grade 2: <1500 - 1000/mm‬‭3‬‭; <1.5 - 1.0 x 10‬‭9‬‭/L‬
‭Grade 3: <1000 - 500/mm‬‭3‬‭; <1.0 - 0.5 x 10‬‭9‬‭/L‬
‭Grade 4: <500/ mm‬‭3‬‭; <0.5 x 10‬‭9‬‭/L‬
‭Platelet count decreased‬
‭Grade 1: <LLN - 75,000/mm‬‭3‬‭; <LLN - 75.0 x 10‬‭9‬‭/L‬
‭Grade 2: <75,000 - 50,000/mm‬‭3‬‭; <75.0 - 50.0 x 10‬‭9‬‭/L‬
‭Grade 3: <50,000 - 25,000/mm‬‭3‬‭; <50.0 - 25.0 x 10‬‭9‬‭/L‬
‭Grade 4: <25,000/mm‬‭3‬‭; <25.0 x 10‬‭9‬‭/L‬
‭White blood cell decreased‬
‭Grade 1: <LLN - 3000/mm‬‭3‬‭; <LLN - 3.0 x 10‬‭9‬‭/L‬
‭Grade 2: <3000 - 2000/mm‬‭3‬‭; <3.0 - 2.0 x 10‬‭9‬‭/L‬
‭Grade 3: <2000 - 1000/mm‬‭3‬‭; <2.0 - 1.0 x 10‬‭9‬‭/L‬
‭Grade 4: <1000/mm‬‭3‬‭; <1.0 x 10‬‭9‬‭/L‬
‭Hyperglycemia‬
‭Grade 1: Fasting glucose value >ULN - 160 mg/dL; Fasting glucose value >ULN - 8.9‬
‭mmol/L‬
‭Grade 2: Fasting glucose value >160 - 250 mg/dL; Fasting glucose value >8.9 - 13.9‬
‭mmol/L‬
‭Grade 3: Fasting glucose value >250 - 500 mg/dL; >13.9 - 27.8 mmol/L‬
‭Grade 4: Fasting glucose value >500 mg/dL; >27.8 mmol/L‬
‭Hypoglycemia‬
‭Grade 1: Fasting glucose value <LLN - 55 mg/dL; <LLN - 3.0 mmol/L‬
‭Grade 2: Fasting glucose value <55 - 40 mg/dL; <3.0 - 2.2 mmol/L‬
‭Grade 3: Fasting glucose value <40 - 30 mg/dL; <2.2 - 1.7 mmol/L‬
‭Grade 4: Fasting glucose value‬
‭Hyperkalemia‬
‭Grade 1: Potassium >ULN - 5.5 mmol/L‬
‭Grade 2: Potassium >5.5 - 6.0 mmol/L‬
‭Grade 3: Potassium >6.0 - 7.0 mmol/L‬
‭Grade 4: Potassium >7.0 mmol/L‬
‭Hypokalemia‬
‭Grade 1: Potassium <LLN - 3.0 mmol/L‬
‭Grade 2: Potassium <LLN - 3.0 mmol/L‬
‭Grade 3: Potassium <3.0 - 2.5 mmol/L‬
‭Grade 4: Potassium <2.5 mmol/L‬
‭Hypermagnesemia‬
‭Grade 1: Magnesium >ULN - 3.0 mg/dL; >ULN - 1.23 mmol/L‬
‭Grade 2: -‬
‭Grade 3: Magnesium >3.0 - 8.0 mg/dL; >1.23 - 3.30 mmol/L‬
‭Grade 4: Magnesium >8.0 mg/dL; >3.30 mmol/L‬
‭Hypomagnesemia‬
‭Grade 1: Magnesium <LLN - 1.2 mg/dL; <LLN - 0.5 mmol/L‬
‭Grade 2: Magnesium <1.2 - 0.9 mg/dL; <0.5 - 0.4 mmol/L‬
‭Grade 3: Magnesium <0.9 - 0.7 mg/dL; <0.4 - 0.3 mmol/L‬
‭Grade 4: Magnesium <0.7 mg/dL; <0.3 mmol/L;‬
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‭Hypernatremia‬
‭Grade 1: Sodium >ULN - 150 mmol/L‬
‭Grade 2: Sodium >150 - 155 mmol/L‬
‭Grade 3: Sodium >155 - 160 mmol/L‬
‭Grade 4: Sodium >160 mmol/L‬
‭Hyponatremia‬
‭Grade 1: Sodium <LLN - 130 mmol/L‬
‭Grade 2: -‬
‭Grade 3: <130 - 120 mmol/L‬
‭Grade 4: <120 mmol/L;‬
‭Hypertriglyceridemia‬
‭Grade 1: 150 mg/dL - 300 mg/dL; 1.71 mmol/L - 3.42 mmol/L‬
‭Grade 2: >300 mg/dL - 500 mg/dL; >3.42 mmol/L - 5.7 mmol/L‬
‭Grade 3: >500 mg/dL - 1000 mg/dL; >5.7 mmol/L - 11.4 mmol/L‬
‭Grade 4: >1000 mg/dL; >11.4 mmol/L‬
‭Hypoalbuminemia‬
‭Grade 1: <LLN - 3 g/dL; <LLN - 30 g/L‬
‭Grade 2: <3 - 2 g/dL; <30 - 20 g/L‬
‭Grade 3: <2 g/dL; <20 g/L‬
‭Grade 4: -‬
‭Hypophosphatemia‬
‭Grade 1: <LLN - 2.5 mg/dL; <LLN - 0.8 mmol/L‬
‭Grade 2: <2.5 - 2.0 mg/dL; <0.8 - 0.6 mmol/L‬
‭Grade 3: <2.0 - 1.0 mg/dL; <0.6 - 0.3 mmol/L‬
‭Grade 4: <1.0 mg/dL; <0.3 mmol/L‬
‭b)‬ ‭Conversion factors for laboratory recordings:‬
‭For‬ ‭laboratory‬ ‭parameters‬ ‭different‬ ‭units‬ ‭can‬ ‭be‬ ‭documented‬ ‭in‬ ‭the‬ ‭eCRF.‬ ‭Following‬
‭conversion factors will be used to obtain SI units for summarization of the results:‬
‭Table 3 Conversation factors for laboratory parameters‬
‭Parameter‬
‭SI Unit for‬
‭analysis‬
‭Alternative eCRF‬
‭Units‬
‭Conversion factors‬
‭Haemoglobin‬
‭g/L‬
‭mmol/L‬
‭g/dL‬
‭1g/L = 1mmol/L / 16.1‬
‭1g/L = 0.1g/dL‬
‭Haematocrit‬
‭L/L‬
‭%‬
‭1L/L = 100%‬
‭Platelets‬
‭10‬‭9‬‭/L‬
‭10‬‭3‬‭/µL‬
‭1/µL (= 1/mm‬‭3‬‭)‬
‭10‬‭3‬‭/µL = 10‬‭9‬‭/L‬
‭10‬‭9‬‭/L = 1000/µL‬
‭Red Blood Cell Count, total‬
‭10‬‭12‬‭/L‬
‭10‬‭9‬‭/L‬
‭10‬‭3‬‭/mm‬‭3‬
‭10‬‭3‬‭/µL‬
‭10‬‭12‬‭/L = 1000*10‬‭9‬‭/L‬
‭10‬‭3‬‭/mm‬‭3‬‭= 10‬‭3‬‭/µL = 10‬‭9‬‭/L‬
‭White Blood Cell Count, total‬
‭10‬‭9‬‭/L‬
‭10‬‭3‬‭/mm‬‭3‬
‭10‬‭3‬‭/µL‬
‭10‬‭9‬‭/L = 10‬‭3‬‭/mm‬‭3‬‭= 10‬‭3‬‭/µL‬
‭Absolute Neutrophil Count (ANC)‬
‭Lymphocyte Count‬
‭Monocyte Count‬
‭Eosinophil Count‬
‭Basophil Count‬
‭1/µL (= 1/mm‬‭3‬‭)‬
‭10‬‭9‬‭/L‬
‭10‬‭3‬‭/µL‬
‭1/µL = 10‬‭9‬‭/L / 1000‬
‭10‬‭3‬‭/µL = 10‬‭9‬‭/L‬
‭Sodium‬
‭mmol/L‬
‭mEq/L‬
‭mval/L‬
‭mg/dL‬
‭mmol/L = mEq/L = mval/L‬
‭1mmol/L= 1mg/dL / 0.435‬
‭Potassium‬
‭mmol/L‬
‭mEq/L‬
‭mval/L‬
‭mg/dL‬
‭mmol/L = mEq/L = mval/L‬
‭1mmol/L= 1mg/dL / 0.256‬
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‭Ion Chloride‬
‭mmol/L‬
‭mEq/L‬
‭mval/L‬
‭mg/dL‬
‭1mmol/L= 1mg/dL / 0.2821‬
‭Bicarbonate‬
‭mmol/L‬
‭mEq/L‬
‭mval/L‬
‭mg/dL‬
‭mmol/L = mEq/L = mval/L‬
‭mmol/L = mg/dL / 0.1639‬
‭Creatinine‬
‭µmol/L‬
‭mg/dL‬
‭mg/L‬
‭1µmol/l = 1mg/dl × 88.4‬
‭1µmol/l = 1mg/l × 884‬
‭Albumin‬
‭g/L‬
‭mmol/L‬
‭g/dL‬
‭1g/L = 1mmol/L × 66.46‬
‭1g/L = g/dL / 10‬
‭Protein, total‬
‭g/L‬
‭g/dL‬
‭1g/L = 1g/dL / 10‬
‭AST (SGOT)‬
‭ALT (SGPT)‬
‭Alkaline Phosphatase‬
‭U/L‬
‭µmol/Ls‬
‭µkat/L‬
‭1U/L = 1µkat/L / 60‬
‭µkat/L = µmol/Ls‬
‭Bilirubin, total‬
‭µmol/L‬
‭mmol/L‬
‭mg/dL‬
‭mg/L‬
‭1µmol/l =1mmol/L / 1000‬
‭1µmol/l = 1mg/dl / 17.1‬
‭1µmol/l = 1mg/L / 1.71‬
‭Uric Acid‬
‭µmol/L‬
‭mmol/L‬
‭mg/dL‬
‭mg/L‬
‭1µmol/l = 1mmol/L / 1000‬
‭1µmol/l = 1mg/dL / 59.5‬
‭1µmol/l = 1mg/L / 5.95‬
‭Urea‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.166‬
‭Blood Urea Nitrogen (BUN)‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL/ 0.3561‬
‭Calcium‬
‭mmol/L‬
‭mEq/L‬
‭mval/L‬
‭mg/dL‬
‭1mmol/L = 1mEq/L / 0.50‬
‭1mmol/L = 1mval/L / 0.50‬
‭1mmol/L = 1mg/dL / 0.25‬
‭Magnesium‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.411‬
‭Phosphate‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L  = 1mg/dL / 0.323‬
‭LDH, total‬
‭µkat/L‬
‭µmol/L‬
‭U/L‬
‭1µkat/L = 1µmol/L × 60‬
‭1µkat/L = 1U/L / 0.0167‬
‭Glucose, fasting‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/l = 1mg/dl / 0.0555‬
‭Urine – Proteins‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL × #‬
‭Urine – Glucose‬
‭mg/dL‬
‭mmol/L‬
‭1mg/dL = 1mmol/L / 18.02‬
‭Urine - Blood‬
‭Categories‬
‭negative/1/2/3 or‬
‭4‬
‭Urine – Ketones‬
‭mg/dL‬
‭mmol/L‬
‭1mg/dL = 1mmol/L / 10‬
‭Urine - White Blood Cell Count‬
‭/µL‬
‭1e+9/L‬
‭10‬‭3‬‭/mm‬‭3‬
‭10‬‭3‬‭/µL‬
‭1/µL = 1e+9/L / 1000‬
‭1/µL = 103/µL /1000‬
‭103/mm3 = 103/µL‬
‭PTT‬
‭sec‬
‭1/1‬
‭(no conversion, separate‬
‭analysis)‬
‭Total Cholesterol‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.0259‬
‭Triglycerides‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.0113‬
‭LDL‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.0259‬
‭HDL‬
‭mmol/L‬
‭mg/dL‬
‭1mmol/L = 1mg/dL / 0.0259‬
‭Vitamin B‬‭12‬
‭pmol/L‬
‭pg/mL‬
‭1pmol/L = 1pg/mL / 0.7378‬
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‭c)‬ ‭Scoring instructions for EORTC QLQ-C30 including GINET21 module:‬
‭Scoring of EORTC QLQ-C30:‬
‭The‬ ‭QLQ-C30‬ ‭is‬ ‭composed‬ ‭of‬ ‭both‬ ‭multi-item‬ ‭scales‬ ‭and‬ ‭single-item‬ ‭measures.‬ ‭These‬
‭include‬‭five‬‭functional‬‭scales,‬‭three‬‭symptom‬‭scales,‬‭a‬‭global‬‭health‬‭status‬‭/‬‭QoL‬‭scale‬‭and‬
‭six‬ ‭single‬ ‭items.‬ ‭Each‬ ‭of‬ ‭the‬ ‭multi-item‬ ‭scales‬‭includes‬‭a‬‭different‬‭set‬‭of‬‭items‬‭-‬‭no‬‭item‬
‭occurs in more than one scale.‬
‭All‬‭of‬‭the‬‭scales‬‭and‬‭single-item‬‭measures‬‭range‬‭in‬‭score‬‭from‬‭0‬‭to‬‭100.‬‭A‬‭high‬‭scale‬‭score‬
‭represents‬‭a‬‭higher‬‭response‬‭level.‬‭Thus,‬‭a‬‭high‬‭score‬‭for‬‭a‬‭functional‬‭scale‬‭represents‬‭a‬
‭high‬‭/‬‭healthy‬‭level‬‭of‬‭functioning,‬‭a‬‭high‬‭score‬‭for‬‭the‬‭global‬‭health‬‭status‬‭/‬‭QoL‬‭represents‬
‭a‬ ‭high‬ ‭QoL,‬ ‭but‬ ‭a‬ ‭high‬ ‭score‬ ‭for‬ ‭a‬ ‭symptom‬ ‭scale‬ ‭/‬ ‭item‬ ‭represents‬ ‭a‬ ‭high‬ ‭level‬ ‭of‬
‭symptomatology / problems.‬
‭The principle for scoring these scales is the same in all cases:‬
‭1.‬‭Estimate‬‭the‬‭average‬‭of‬‭the‬‭items‬‭that‬‭contribute‬‭to‬‭the‬‭scale;‬‭this‬‭is‬‭the‬‭raw‬‭score.‬‭For‬
‭each scale (see below for details) at least half of the items have to be answered.‬
‭2.‬‭Use‬‭a‬‭linear‬‭transformation‬‭to‬‭standardize‬‭the‬‭raw‬‭score,‬‭so‬‭that‬‭scores‬‭range‬‭from‬‭0‬
‭to‬ ‭100;‬ ‭a‬ ‭higher‬ ‭score‬ ‭represents‬ ‭a‬ ‭higher‬ ‭("better")‬ ‭level‬ ‭of‬ ‭functioning,‬ ‭or‬ ‭a‬ ‭higher‬
‭("worse") level of symptoms.‬
‭Technical summary of scoring:‬
‭In practical terms, if items‬‭I‬‭1‬‭,‬‭I‬‭2‬‭, ...,‬‭I‬‭n‬‭are included‬‭in a scale, the procedure is as follows:‬
‭Raw score‬
‭Calculate the raw score (i.e. mean of the items answers) if at least half of the items of a‬
‭scale are answered =‬‭RS = (I‬‭1‬‭+‬‭I‬‭2‬‭+ ... +‬‭I‬‭n‬‭) / n‬
‭Linear transformation‬
‭Apply the linear transformation to 0-100 to obtain the score‬‭S‬‭,‬
‭Functional scales:‬‭𝑆‬ = ‭1‬ −(‭𝑅𝑆‬−‭1‬)
‭𝑟𝑎𝑛𝑔𝑒‬
{
}‭×100‬
‭Symptom scales / items:‬‭𝑆‬ =
‭𝑅𝑆‬−‭1‬
‭𝑟𝑎𝑛𝑔𝑒‬
{
}‭×100‬
‭Global health status / QoL:‬‭ ‬‭𝑆‬ =
‭𝑅𝑆‬−‭1‬
‭𝑟𝑎𝑛𝑔𝑒‬
{
}‭×100‬
‭Range‬ ‭is‬ ‭the‬ ‭difference‬ ‭between‬ ‭the‬ ‭maximum‬ ‭possible‬ ‭value‬ ‭of‬ ‭RS‬ ‭and‬ ‭the‬ ‭minimum‬
‭possible‬ ‭value.‬ ‭The‬ ‭QLQ-C30‬ ‭has‬ ‭been‬ ‭designed‬ ‭so‬‭that‬‭all‬‭items‬‭in‬‭any‬‭scale‬‭take‬‭the‬
‭same‬‭range‬‭of‬‭values.‬‭Therefore,‬‭the‬‭range‬‭of‬‭RS‬‭equals‬‭the‬‭range‬‭of‬‭the‬‭item‬‭values.‬‭Most‬
‭items‬‭are‬‭scored‬‭1‬‭to‬‭4,‬‭giving‬‭range‬‭=‬‭3.‬‭The‬‭exceptions‬‭are‬‭the‬‭items‬‭contributing‬‭to‬‭the‬
‭global‬‭health‬‭status‬‭/‬‭QoL,‬‭which‬‭are‬‭7-point‬‭questions‬‭with‬‭range‬‭=‬‭6,‬‭and‬‭the‬‭initial‬‭yes/no‬
‭items on the earlier versions of the QLQ-C30 which have‬‭range‬‭= 1.‬
‭Table 4 Overview of scales:‬
‭Scale‬
‭Scale‬
‭abbreviation‬
‭Number of‬
‭items‬
‭Item‬
‭range*‬
‭Item numbers‬
‭Global health status / QoL‬
‭Global health status/QoL‬
‭(revised)†‬
‭QL2‬
‭2‬
‭6‬
‭29, 30‬
‭Functional scales‬
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‭Physical functioning (revised)†‬
‭PF2‬
‭5‬
‭3‬
‭1 to 5‬
‭Role functioning (revised)†‬
‭RF2‬
‭2‬
‭3‬
‭6, 7‬
‭Emotional functioning‬
‭EF‬
‭4‬
‭3‬
‭21 to 24‬
‭Cognitive functioning‬
‭CF‬
‭2‬
‭3‬
‭20, 25‬
‭Social functioning‬
‭SF‬
‭2‬
‭3‬
‭26, 27‬
‭Symptom scales / items‬
‭Fatigue‬
‭FA‬
‭3‬
‭3‬
‭10, 12, 18‬
‭Nausea and vomiting‬
‭NV‬
‭2‬
‭3‬
‭14, 15‬
‭Pain‬
‭PA‬
‭2‬
‭3‬
‭9, 19‬
‭Dyspnoea‬
‭DY‬
‭1‬
‭3‬
‭8‬
‭Insomnia‬
‭SL‬
‭1‬
‭3‬
‭11‬
‭Appetite loss‬
‭AP‬
‭1‬
‭3‬
‭13‬
‭Constipation‬
‭CO‬
‭1‬
‭3‬
‭16‬
‭Diarrhoea‬
‭DI‬
‭1‬
‭3‬
‭17‬
‭Financial difficulties‬
‭FI‬
‭1‬
‭3‬
‭28‬
‭*‬‭Item‬‭range‬‭is‬‭the‬‭difference‬‭between‬‭the‬‭possible‬‭maximum‬‭and‬‭the‬‭minimum‬‭response‬‭to‬‭individual‬
‭items;‬
‭most items take values from 1 to 4, giving‬‭range‬‭=‬‭3.‬
‭†‬‭(revised)‬‭scales‬‭are‬‭those‬‭that‬‭have‬‭been‬‭changed‬‭since‬‭version‬‭1.0,‬‭and‬‭their‬‭short‬‭names‬‭are‬
‭indicated in this manual by a suffix “2” – for example, PF2.‬
‭Dealing with missing data:‬
‭No‬ ‭imputation‬ ‭will‬ ‭be‬ ‭applied‬ ‭for‬ ‭unanswered‬ ‭questionnaire‬ ‭items.‬ ‭Instead,‬ ‭the‬ ‭following‬
‭procedure‬‭will‬‭be‬‭applied.‬‭For‬‭each‬‭scale,‬‭at‬‭least‬‭half‬‭of‬‭the‬‭items‬‭must‬‭be‬‭answered‬‭and‬
‭the‬ ‭unanswered‬ ‭item‬ ‭will‬‭be‬‭excluded‬‭(ignored)‬‭for‬‭the‬‭raw‬‭score‬‭calculation.‬‭That‬‭is,‬‭for‬
‭calculation‬‭of‬‭the‬‭EF‬‭scale‬‭at‬‭least‬‭2‬‭items‬‭must‬‭be‬‭answered,‬‭for‬‭the‬‭PF2‬‭scale‬‭at‬‭least‬‭3‬
‭items‬ ‭must‬‭be‬‭answered.‬‭In‬‭case‬‭not‬‭at‬‭least‬‭half‬‭of‬‭the‬‭items‬‭are‬‭answered‬‭for‬‭a‬‭scale,‬
‭scale score will be set to missing for a patient for the respective visit.‬
‭Examples:‬
‭Emotional functioning scale‬‭:‬
‭All 4 items answered:‬
‭Raw score‬‭= (Q‬‭21‬‭+ Q‬‭22‬‭+ Q‬‭23‬‭+ Q‬‭24‬‭) / 4‬
‭EF score: (1 - (RS - 1) / 3) x 100‬
‭Item Q‬‭23‬‭is missing:‬
‭Raw score‬‭= (Q‬‭21‬‭+ Q‬‭22‬‭+ Q‬‭24‬‭) / 3‬
‭EF score: (1 - (RS - 1) / 3) x 100‬
‭Scoring of EORTC QLQ-GINET21‬
‭The‬‭GINET21‬‭module‬‭for‬‭patients‬‭with‬‭G.I.‬‭related‬‭Neuroendocrine‬‭Tumors‬‭include‬‭21‬‭items,‬
‭conceptualized‬ ‭as‬ ‭consisting‬ ‭of‬ ‭5‬ ‭scales‬ ‭and‬‭4‬‭single‬‭items.‬‭The‬‭following‬‭section‬‭is‬‭the‬
‭scoring‬‭algorithm‬‭for‬‭the‬‭scales‬‭described‬‭in‬‭a‬‭similar‬‭fashion‬‭to‬‭the‬‭scoring‬‭for‬‭the‬‭EORTC‬
‭QLQ-C30.‬
‭Following scales are defined:‬
‭1.‬ ‭Endocrine scale (items 31, 32 and 33)‬
‭2.‬ ‭G.I. scale (items 34, 35, 36, 37 and 38)‬
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‭3.‬ ‭Treatment scale (items 39, 40 and 46)‬
‭4.‬ ‭Social function scale (items 42, 44 and 49)‬
‭5.‬ ‭Disease related worries scale (items 41, 43 and 47)‬
‭Technical summary of scoring:‬
‭Note‬‭for‬‭all‬‭scales‬‭a‬‭high‬‭score‬‭is‬‭equivalent‬‭to‬‭worse‬‭or‬‭more‬‭problems.‬‭For‬‭each‬‭scale,‬
‭calculate‬‭the‬‭raw‬‭score‬‭by‬‭the‬‭addition‬‭of‬‭item‬‭responses‬‭divided‬‭by‬‭the‬‭number‬‭of‬‭items.‬
‭Then‬‭a‬‭linear‬‭transformation‬‭is‬‭used‬‭to‬‭standardize‬‭the‬‭raw‬‭score,‬‭so‬‭that‬‭scores‬‭range‬‭from‬
‭0 to 100.‬
‭Score = (raw score - 1) / range x 100‬
‭Range‬ ‭is‬ ‭the‬ ‭difference‬ ‭between‬ ‭the‬ ‭maximum‬ ‭and‬ ‭minimum‬ ‭possible‬ ‭value‬ ‭of‬ ‭the‬ ‭raw‬
‭score. All items are scored from 1 to 4, giving a range = 3.‬
‭Multi items‬
‭1.‬ ‭Endocrine symptoms scale (items 31, 32 and 33)‬
‭a)‬ ‭Add‬‭questionnaire‬‭items‬‭31,‬‭32‬‭and‬‭33‬‭and‬‭divide‬‭this‬‭sum‬‭by‬‭the‬‭number‬‭of‬‭items‬
‭(3):‬
‭Endo= (Q‬‭31‬‭+ Q‬‭32‬‭+ Q‬‭33‬‭) / 3‬
‭b)‬ ‭Carry out linear transformation to convert to a 1-100 scale:‬
‭FinalEndo= (Endo - 1) / 3 x 100‬
‭2.‬ ‭G.I. symptoms scale (items 34, 35, 36, 37 and 38)‬
‭a)‬ ‭Add‬‭questionnaire‬‭items‬‭34,‬‭35,‬‭36,‬‭37‬‭and‬‭38‬‭and‬‭divide‬‭this‬‭sum‬‭by‬‭the‬‭number‬‭of‬
‭items (5):‬
‭GI= (Q‬‭34‬‭+ Q‬‭35‬‭+ Q‬‭36‬‭+ Q‬‭37‬‭+ Q‬‭38‬‭) / 5‬
‭b)‬ ‭Carry out linear transformation to convert to a 1-100 scale:‬
‭FinalGI = (GI - 1) / 3 x 100‬
‭3.‬ ‭Treatment related symptoms scale (items 39, 40 and 46)‬
‭a)‬ ‭Add‬‭questionnaire‬‭items‬‭39,‬‭40‬‭and‬‭46‬‭and‬‭divide‬‭this‬‭sum‬‭by‬‭the‬‭number‬‭of‬‭items‬
‭(3):‬
‭Treat= (Q‬‭39‬‭+ Q‬‭40‬‭+ Q‬‭46‬‭) / 3‬
‭b)‬ ‭Carry out linear transformation to convert to a 1-100 scale:‬
‭FinalTreat = (Treat - 1) / 3 x 100‬
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‭4.‬ ‭Social function scale (items 42, 44 and 49)‬
‭a)‬ ‭Add‬‭questionnaire‬‭items‬‭42,‬‭44‬‭and‬‭49‬‭and‬‭divide‬‭this‬‭sum‬‭by‬‭the‬‭number‬‭of‬‭items‬
‭(3):‬
‭Soc= (Q‬‭42‬‭+ Q‬‭44‬‭+ Q‬‭49‬‭) / 3‬
‭b)‬ ‭Carry out linear transformation to convert to a 1-100 scale:‬
‭FinalSoc = (Soc - 1) / 3 x 100‬
‭5.‬ ‭Disease related worries (items 41, 43 and 47)‬
‭a)‬ ‭Add‬‭questionnaire‬‭items‬‭41,‬‭43‬‭and‬‭47‬‭and‬‭divide‬‭this‬‭sum‬‭by‬‭the‬‭number‬‭of‬‭items‬
‭(3):‬
‭Dis= (Q‬‭41‬‭+ Q‬‭43‬‭+ Q‬‭47‬‭) / 3‬
‭b)‬ ‭Carry out linear transformation to convert to a 1-100 scale:‬
‭FinalDis = (Dis - 1) / 3 x 100‬
‭Single items‬
‭These items are treated individually. They should be linearly transformed to a 0-100 scale.‬
‭1.‬ ‭Muscle /bone pain symptom (item 48)‬
‭Pain= (Q‬‭48‬‭- 1) / 3 x 100‬
‭2.‬ ‭Sexual function (item 51)‬
‭Sx = (Q‬‭51‬‭- 1) / 3 x 100‬
‭3.‬ ‭Information/communication function (item 50)‬
‭Inf= (Q‬‭50‬‭- 1) / 3 x 100‬
‭4.‬ ‭Body Image (item 45)‬
‭BI= (Q‬‭45‬‭- 1) / 3 x 100‬
‭Dealing with missing data:‬
‭It‬ ‭is‬ ‭possible‬ ‭to‬ ‭estimate‬ ‭the‬ ‭missing‬ ‭score.‬ ‭A‬ ‭simple‬ ‭method‬ ‭for‬ ‭imputing‬ ‭items‬ ‭from‬
‭multi-item scales, which has been used by many QoL instruments, is the following:‬
‭●‬ ‭If‬‭at‬‭least‬‭half‬‭of‬‭the‬‭items‬‭from‬‭the‬‭scale‬‭have‬‭been‬‭answered‬‭then‬‭use‬‭all‬‭the‬‭items‬‭that‬
‭were‬‭completed‬‭and‬‭apply‬‭the‬‭standard‬‭equation‬‭for‬‭calculating‬‭the‬‭raw‬‭score.‬‭Ignore‬‭the‬
‭missing values when making the calculations.‬
‭●‬ ‭It‬‭is‬‭not‬‭possible‬‭to‬‭estimate‬‭missing‬‭answers‬‭for‬‭single‬‭items‬‭or‬‭for‬‭scales‬‭where‬‭less‬
‭then ½ items have been completed. Result invalid for scale on that patient.‬
‭Not applicable box (items 39, 40, 47 and 51)‬
‭For descriptive purposes it is important to distinguish between missing data and items which‬
‭are not applicable. For calculations, N/A data should be managed as for missing data.‬
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‭6.3.3‬ ‭Handling of Data Inconsistencies‬
‭To‬ ‭ensure‬ ‭integrity‬ ‭and‬ ‭quality‬‭of‬‭data,‬‭multiple‬‭validation‬‭checks‬‭are‬‭implemented‬‭in‬‭the‬
‭electronic‬ ‭data‬ ‭capture‬ ‭(EDC)‬ ‭system.‬ ‭Data‬ ‭directly‬ ‭entered‬ ‭into‬ ‭the‬ ‭EDC‬ ‭system‬ ‭are‬
‭checked‬ ‭automatically‬ ‭during‬ ‭data‬ ‭entry.‬ ‭The‬ ‭process‬ ‭of‬ ‭data‬ ‭validation‬ ‭as‬ ‭well‬ ‭as‬ ‭the‬
‭specifications‬ ‭for‬ ‭the‬ ‭electronic‬ ‭and‬ ‭manual‬ ‭review‬ ‭of‬ ‭data‬ ‭are‬ ‭defined‬ ‭in‬ ‭the‬ ‭Data‬
‭Validation/Edit Check catalogue please refer to the DMP for further details.‬
‭6.3.4‬ ‭Handling of Missing Data‬
‭Missing‬‭data‬‭in‬‭the‬‭eCRF‬‭will‬‭be‬‭detected‬‭during‬‭data‬‭entry‬‭via‬‭automatic‬‭edit‬‭checks‬‭by‬‭the‬
‭EDC‬‭system‬‭to‬‭assess‬‭whether‬‭the‬‭information‬‭is‬‭available‬‭at‬‭the‬‭study‬‭sites.‬‭For‬‭data‬‭that‬
‭remain‬‭missing,‬‭no‬‭imputation‬‭of‬‭missing‬‭information‬‭will‬‭be‬‭applied.‬‭Number‬‭of‬‭patients‬‭with‬
‭missing‬‭data‬‭will‬‭be‬‭presented‬‭as‬‭separate‬‭category.‬‭Relative‬‭frequencies‬‭will‬‭be‬‭calculated‬
‭based‬‭on‬‭all‬‭values‬‭of‬‭the‬‭patient‬‭set‬‭including‬‭patients‬‭with‬‭missing‬‭data.‬‭In‬‭special‬‭cases,‬
‭where the basis differs from total population, this will be mentioned in the table titles.‬
‭6.3.5‬ ‭Decisions of the Data Review Meeting‬
‭Pending, to be included when available, i.e. after the Data Review Meeting (DRM).‬
‭6.4‬
‭Coding‬
‭The‬‭most‬‭recent‬‭Medical‬‭Dictionary‬‭of‬‭Regulatory‬‭Activities‬‭(MedDRA)‬‭version‬‭will‬‭be‬‭used‬
‭for‬ ‭coding‬ ‭of‬ ‭medical‬ ‭history,‬ ‭adverse‬ ‭events‬ ‭and‬ ‭the‬ ‭specification‬ ‭of‬ ‭the‬ ‭physical‬
‭examination.‬
‭Coding‬ ‭of‬ ‭prior‬ ‭and‬‭concomitant‬‭medications‬‭will‬‭be‬‭performed‬‭by‬‭the‬‭most‬‭recent‬‭World‬
‭Health Organization (WHO) Drug Dictionary.‬
‭7‬ ‭Patient Enrolment and Analysis Sets‬
‭It‬‭is‬‭planned‬‭to‬‭recruit‬‭140‬‭adult‬‭patients‬‭with‬‭a‬‭diagnosis‬‭of‬‭advanced‬‭pNET‬‭in‬‭8‬‭European‬
‭countries.‬‭Patients‬‭will‬‭be‬‭assigned‬‭to‬‭the‬‭following‬‭analysis‬‭sets‬‭for‬‭statistical‬‭analysis‬‭with‬
‭the following criteria:‬
‭The‬‭Safety Analysis Set (SAF)‬‭will consist of patients‬‭who fulfil the following criteria:‬
‭●‬ ‭Patient has been randomized‬
‭●‬ ‭At‬‭least‬‭one‬‭dose‬‭of‬‭the‬‭two‬‭study‬‭treatments‬‭has‬‭been‬‭documented,‬‭i.e.‬‭STZ-5FU‬‭or‬
‭Everolimus‬
‭●‬ ‭Availability‬ ‭of‬ ‭post-baseline‬ ‭safety‬ ‭data‬ ‭of‬ ‭any‬ ‭kind‬ ‭(i.e.‬ ‭documentation‬ ‭of‬
‭post-baseline‬ ‭physical‬ ‭examination,‬ ‭post-baseline‬ ‭ECOG‬ ‭performance‬ ‭status,‬
‭post-baseline‬‭laboratory‬‭data‬‭of‬‭any‬‭kind,‬‭post-baseline‬‭12-lead‬‭ECG,‬‭post-baseline‬
‭vital signs or experience of AEs)‬
‭The‬ ‭Intention-To-Treat‬ ‭Analysis‬ ‭Set‬ ‭(ITT)‬ ‭will‬ ‭consist‬ ‭of‬ ‭patients‬ ‭who‬ ‭fulfil‬ ‭the‬ ‭following‬
‭criteria:‬
‭●‬ ‭Patient has been randomized‬
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‭Patients‬‭in‬‭the‬‭ITT‬‭set‬‭will‬‭be‬‭analyzed‬‭as‬‭randomized‬‭irrespective‬‭of‬‭their‬‭actual‬‭intake‬‭of‬
‭study treatment.‬
‭The‬‭Per-Protocol Set‬‭(PP) will consist of patients‬‭who fulfil the following criteria:‬
‭●‬ ‭Included in the ITT set‬
‭●‬ ‭No major protocol deviation documented‬
‭The main analysis of efficacy will be based on the ITT population set.‬
‭Patients‬ ‭who‬ ‭have‬ ‭been‬ ‭included‬ ‭into‬ ‭the‬ ‭study‬ ‭despite‬ ‭of‬ ‭a‬ ‭violation‬ ‭of‬ ‭inclusion‬ ‭or‬
‭exclusion‬‭criterion‬‭or‬‭who‬‭show‬‭other‬‭protocol‬‭deviations‬‭in‬‭the‬‭course‬‭of‬‭the‬‭study‬‭will‬‭be‬
‭compiled‬ ‭in‬ ‭a‬ ‭list‬ ‭of‬ ‭protocol‬ ‭deviations.‬ ‭A‬ ‭classification‬ ‭of‬‭these‬‭protocol‬‭deviations‬‭into‬
‭major/minor‬‭and‬‭decisions‬‭how‬‭to‬‭handle‬‭these‬‭subjects‬‭will‬‭take‬‭place‬‭in‬‭a‬‭Data‬‭Review‬
‭Meeting‬‭(DRM).‬‭The‬‭DRM‬‭will‬‭take‬‭place‬‭after‬‭data‬‭collection‬‭is‬‭completed‬‭and‬‭the‬‭database‬
‭is‬‭clean‬‭(soft‬‭lock),‬‭but‬‭prior‬‭to‬‭database‬‭lock‬‭(hard‬‭lock).‬‭Results‬‭of‬‭the‬‭DRM‬‭will‬‭be‬‭outlined‬
‭in Data Review Meeting minutes to be created after the DRM.‬
‭Outcome‬‭of‬‭the‬‭selection‬‭process‬‭and‬‭for‬‭general‬‭study‬‭overview,‬‭following‬‭frequency‬‭tables‬
‭will be prepared, for details see section 12.1:‬
‭●‬ ‭Number of participating sites‬
‭●‬ ‭Screening and randomization of patients‬
‭●‬ ‭Analysis sets‬
‭Furthermore,‬‭patients‬‭discontinued‬‭from‬‭the‬‭study,‬‭protocol‬‭deviations‬‭and‬‭patients‬‭excluded‬
‭from the efficacy analyses will be displayed in a listing.‬
‭8‬ ‭Statistical Analysis‬
‭8.1‬
‭Presentation of Analysis Results‬
‭Continuous‬‭data‬‭will‬‭be‬‭described‬‭by‬‭the‬‭total‬‭number‬‭of‬‭patients‬‭in‬‭the‬‭respective‬‭analysis‬
‭set/subgroup,‬ ‭number‬ ‭of‬ ‭non-missing‬ ‭and‬ ‭missing‬ ‭values,‬ ‭mean,‬ ‭standard‬ ‭deviation,‬
‭median,‬‭minimum,‬‭maximum‬‭as‬‭well‬‭as‬‭lower‬‭and‬‭upper‬‭quartiles.‬‭Unless‬‭otherwise‬‭noted,‬
‭mean,‬‭median‬‭and‬‭percentiles‬‭of‬‭a‬‭set‬‭of‬‭values‬‭will‬‭be‬‭printed‬‭out‬‭to‬‭one‬‭more‬‭decimal‬‭than‬
‭the original value, the standard deviation to two more decimals than the original value.‬
‭Categorical‬ ‭data‬ ‭including‬ ‭categories‬ ‭of‬ ‭continuous‬ ‭data‬ ‭will‬ ‭be‬ ‭presented‬ ‭in‬ ‭frequency‬
‭tables‬ ‭containing‬ ‭absolute‬‭and‬‭relative‬‭frequencies.‬‭All‬‭table‬‭percentages‬‭will‬‭be‬‭reported‬
‭with‬ ‭one‬ ‭decimal‬ ‭point‬ ‭unless‬ ‭otherwise‬ ‭noted.‬ ‭Frequency‬ ‭tables‬ ‭will‬ ‭include‬ ‭the‬ ‭total‬
‭number‬‭of‬‭observations‬‭and‬‭the‬‭number‬‭of‬‭missing‬‭values‬‭as‬‭additional‬‭categories.‬‭Multiple‬
‭response data will be presented as distribution of single entries‬
‭If‬ ‭applicable,‬ ‭95%‬‭confidence‬‭intervals‬‭(CIs)‬‭will‬‭be‬‭displayed‬‭for‬‭the‬‭mean‬‭of‬‭continuous‬
‭data‬ ‭or‬ ‭frequencies,‬ ‭respectively.‬ ‭Details‬ ‭on‬ ‭analyses‬ ‭including‬ ‭CIs‬ ‭and‬ ‭the‬ ‭calculated‬
‭method will be specified in the respective in section 9.2.‬
‭Results will be summarized treatment arm, as applicable.‬
‭Table 5 Assignment of treatment groups for TFL output‬
‭Detailed treatment description‬
‭Name for TFL output‬
‭STZ-5FU according to Moertel or Uppsala Code List‬
‭STZ-5FU‬
‭Everolimus 10 mg per day‬
‭Everolimus‬
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‭Treatment arm:‬
‭STZ-5FU – Everolimus 10 mg per day‬
‭Everolimus 10 mg per day - STZ-5FU according to Moertel or‬
‭Uppsala Code List‬
‭STZ-5FU - Everolimus‬
‭Everolimus - STZ-5FU‬
‭All‬‭variables‬‭documented‬‭at‬‭different‬‭analysis‬‭time‬‭points‬‭/‬‭cycles‬‭will‬‭be‬‭summarized‬‭by‬‭the‬
‭available cycle, as defined in table below.‬
‭Table 6 Assignments of visits for TFL output‬
‭Visit in EDC‬
‭Visit name for TFL output‬
‭Screening (Day -28 to 0)‬
‭Baseline‬
‭Everolimus / STZ-5FU Cycle 1 to Cycle X‬
‭with X corresponding to the maximum cycle number‬
‭documented‬
‭Cycle 1 to Cycle X, 1‬‭st‬‭line / 2‬‭nd‬‭line‬
‭with X corresponding to the maximum‬
‭cycle number documented‬
‭End of Course 1 or End of Course 2‬
‭EoT‬
‭assigning end of treatment for the‬
‭respective treatment‬
‭Survival Follow-Ups:‬
‭30 days following end of treatment‬
‭3 months following end of treatment‬
‭6 months following end of treatment‬
‭[…]‬
‭30 months following end of treatment‬
‭Interim-/additional follow-up‬
‭FU 30 days‬
‭FU 3 months‬
‭FU 6 months‬
‭[…]‬
‭FU 30 months‬
‭FU Add. No. X‬
‭with X corresponding to the maximum FU‬
‭number documented‬
‭Biomarkers evaluation (CgA), CTC, NETest‬
‭Screening‬
‭At 4 weeks in course 1‬
‭Cycle 1 of 2‬‭nd‬‭treatment* / Before start of 2‬‭nd‬‭treatment**‬
‭At 4 weeks at course 2* **‬
‭*only for Biomarkers‬
‭** only for NETest‬
‭Baseline‬
‭At 4 weeks‬
‭Cycle 1 2‬‭nd‬‭line* / Before start of 2‬‭nd‬‭line**‬
‭At 4 weeks 2‬‭nd‬‭line* **‬
‭*only for Biomarkers‬
‭** only for NETest‬
‭Presentation by evaluation week for assessments‬
‭performed every 12 weeks and not documented during the‬
‭treatment visits‬
‭Evaluation will be assigned to respective week in relation to‬
‭the baseline visit with a range of +/- 14 days‬
‭Baseline‬
‭Week 12‬
‭Week 24‬
‭Week 36‬
‭Week 48‬
‭Week 60‬
‭…‬
‭Week X‬
‭with X corresponding to the maximum‬
‭week number documented‬
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‭8.2‬ ‭Analysis variables‬
‭8.2.1‬ ‭Population Characteristics‬
‭Demographic‬ ‭data‬ ‭including‬ ‭vital‬ ‭signs,‬‭physical‬‭examination,‬‭ECOG‬‭performance‬‭status,‬
‭12-lead-ECG,‬ ‭height‬ ‭in‬ ‭cm,‬ ‭weight‬ ‭in‬ ‭kg‬ ‭and‬ ‭BMI‬ ‭at‬ ‭the‬ ‭Screening/Baseline‬‭visit‬‭will‬‭be‬
‭summarized in frequency tables or with descriptive statistics, as appropriate.‬
‭Relevant‬ ‭medical/surgical‬‭history‬‭and‬‭medical‬‭conditions‬‭will‬‭be‬‭summarized‬‭in‬‭frequency‬
‭tables‬ ‭containing‬ ‭the‬ ‭number‬ ‭and‬ ‭percentage‬ ‭of‬ ‭patients‬ ‭with‬ ‭no‬ ‭and‬ ‭with‬ ‭any‬
‭condition/disease‬‭and‬‭broken‬‭down‬‭by‬‭diagnosis‬‭displayed‬‭as‬‭MedDRA‬‭SOC/PT,‬‭separately‬
‭for‬ ‭prior‬ ‭and‬ ‭for‬ ‭concomitant‬ ‭diseases.‬ ‭Records‬ ‭documented‬ ‭as‬ ‭not‬ ‭ongoing‬ ‭will‬ ‭be‬
‭classified‬ ‭as‬ ‭prior,‬ ‭records‬ ‭documented‬ ‭as‬ ‭ongoing‬ ‭will‬ ‭be‬ ‭classified‬ ‭as‬ ‭concomitant.‬
‭Records‬‭leading‬‭to‬‭same‬‭MedDRA‬‭PT‬‭for‬‭the‬‭same‬‭patient‬‭with‬‭same‬‭ongoing‬‭status‬‭will‬‭be‬
‭counted only once.‬
‭Prior‬ ‭antineoplastic‬ ‭therapies‬ ‭(i.e.‬ ‭medications,‬ ‭radiotherapies,‬ ‭surgeries‬ ‭and‬ ‭non-drug‬
‭therapies)‬‭will‬‭be‬‭summarized‬‭separately‬‭per‬‭therapy‬‭type‬‭as‬‭patient-based‬‭and‬‭event-based‬
‭analyses.‬‭Patient‬‭based‬‭analyses‬‭will‬‭contain‬‭the‬‭total‬‭number‬‭and‬‭percentage‬‭of‬‭patients‬
‭with‬ ‭any‬ ‭and‬ ‭with‬‭no‬‭prior‬‭antineoplastic‬‭therapies‬‭based‬‭on‬‭the‬‭total‬‭number‬‭of‬‭patients‬
‭included‬‭in‬‭the‬‭analyzed‬‭population‬‭set.‬‭For‬‭medications,‬‭WHO‬‭DD‬‭ATC‬‭level‬‭1‬‭and‬‭3‬‭coding‬
‭will‬‭be‬‭included.‬‭Further‬‭details,‬‭like‬‭setting,‬‭location,‬‭number‬‭of‬‭cycles,‬‭duration,‬‭reason‬‭for‬
‭discontinuation,‬‭best‬‭response‬‭etc.,‬‭will‬‭be‬‭tabulated‬‭event‬‭based‬‭with‬‭absolute‬‭and‬‭relative‬
‭frequencies or descriptive statistics based on the total number of therapies documented.‬
‭Documented‬‭records‬‭for‬‭prior‬‭and‬‭concomitant‬‭medications‬‭and‬‭non-drug‬‭therapies‬‭will‬‭be‬
‭classified‬‭as‬‭prior‬‭or‬‭concomitant‬‭as‬‭specified‬‭in‬‭section‬‭7.3.2‬‭and‬‭summarized‬‭separately‬
‭for‬ ‭these‬ ‭two‬ ‭groups‬ ‭including‬ ‭the‬ ‭number‬ ‭and‬ ‭percentage‬ ‭of‬ ‭patients‬ ‭with‬ ‭any‬ ‭and‬ ‭no‬
‭therapy,‬‭including‬‭WHO‬‭DD‬‭ATC‬‭level‬‭1‬‭and‬‭3‬‭coding‬‭of‬‭the‬‭specified‬‭therapies‬‭based‬‭on‬‭the‬
‭total number of patients in the population under investigation.‬
‭Disease‬ ‭diagnosis‬ ‭data‬ ‭with‬ ‭details‬ ‭regarding‬ ‭the‬ ‭first‬ ‭diagnosis‬ ‭of‬ ‭pNET‬ ‭and‬ ‭diagnosis‬
‭confirmation‬‭at‬‭study‬‭inclusion‬‭will‬‭be‬‭summarized‬‭with‬‭descriptive‬‭statistics‬‭and‬‭frequency‬
‭tables‬‭as‬‭appropriate.‬‭Tumor‬‭assessments‬‭at‬‭baseline‬‭will‬‭be‬‭summarized‬‭separately‬‭for‬‭the‬
‭central‬ ‭and‬ ‭the‬ ‭local‬ ‭radiological‬ ‭assessment‬ ‭including‬ ‭details‬ ‭for‬ ‭target‬ ‭and‬ ‭non-target‬
‭lesions.‬
‭Demographic data and disease diagnosis data will also be displayed in a listing.‬
‭8.2.2‬ ‭Study Medication‬
‭Details‬‭of‬‭documented‬‭study‬‭medication‬‭administration‬‭will‬‭be‬‭summarized‬‭with‬‭descriptive‬
‭statistics‬‭or‬‭in‬‭frequency‬‭tables‬‭in‬‭terms‬‭of‬‭initial‬‭daily‬‭dose,‬‭average‬‭daily‬‭dose,‬‭number‬‭of‬
‭documented‬‭dose‬‭adjustments‬‭per‬‭patient‬‭including‬‭a‬‭differentiation‬‭of‬‭dose‬‭increases,‬‭dose‬
‭decreases‬ ‭and‬ ‭dose‬ ‭interruptions‬ ‭along‬ ‭with‬‭the‬‭documented‬‭reasons‬‭for‬‭the‬‭adaptation.‬
‭Furthermore,‬ ‭duration‬ ‭of‬ ‭interruptions‬ ‭and‬ ‭duration‬ ‭of‬ ‭exposure‬ ‭will‬ ‭be‬ ‭analyzed.‬ ‭As‬ ‭for‬
‭study‬‭treatment‬‭STZ-5FU‬‭details‬‭will‬‭be‬‭documented‬‭separately‬‭for‬‭the‬‭two‬‭components‬‭STZ‬
‭and‬‭5-FU,‬‭all‬‭analyses‬‭regarding‬‭study‬‭medication‬‭will‬‭be‬‭tabulated‬‭separately‬‭for‬‭these‬‭two‬
‭components.‬
‭See section 7.3.2 for derivation and definitions of the above-mentioned variables.‬
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‭8.2.3‬ ‭Efficacy‬
‭The‬ ‭main‬ ‭efficacy‬ ‭endpoints‬ ‭are‬ ‭the‬ ‭primary‬ ‭endpoints‬ ‭as‬ ‭described‬ ‭in‬ ‭chapter‬ ‭3.1.‬ ‭For‬
‭derivation‬‭see‬‭section‬‭7.3.2..‬‭The‬‭primary‬‭endpoints‬‭will‬‭be‬‭analyzed‬‭in‬‭a‬‭frequency‬‭table‬
‭displaying‬‭the‬‭number‬‭and‬‭percentage‬‭of‬‭patients‬‭who‬‭achieved‬‭and‬‭who‬‭did‬‭not‬‭achieve‬‭the‬
‭criterions‬ ‭for‬ ‭progression‬ ‭free‬ ‭survival‬ ‭according‬ ‭to‬ ‭the‬ ‭main,‬ ‭conservative‬ ‭and‬ ‭optimist‬
‭definition‬ ‭as‬ ‭stated‬ ‭in‬ ‭section‬ ‭7.3.2.‬ ‭P-value‬ ‭from‬ ‭the‬ ‭two-sided‬ ‭Chi-square‬ ‭test‬ ‭will‬ ‭be‬
‭displayed.‬‭If‬‭the‬‭expected‬‭cell‬‭count‬‭for‬‭any‬‭cell‬‭is‬‭less‬‭than‬‭5,‬‭Fisher’s‬‭exact‬‭test‬‭will‬‭be‬
‭applied instead.‬
‭Time-to‬‭event‬‭analysis‬‭will‬‭be‬‭performed‬‭for‬‭the‬‭PFS1,‬‭PFS2nd,‬‭PFS2,‬‭TTP1,‬‭TTP2nd‬ ‭and‬
‭OS‬‭(overall‬‭survival)‬‭and‬‭displayed‬‭with‬‭Kaplan-Meier‬‭summary‬‭statistics‬‭including‬‭p-value‬
‭from‬‭the‬‭log-rank‬‭test.‬‭PFS1‬‭and‬‭TTP1‬‭will‬‭be‬‭derived‬‭based‬‭on‬‭the‬‭local‬‭and‬‭the‬‭central‬
‭radiological assessments (see section 7.3.2).‬
‭Although‬ ‭sample‬ ‭size‬ ‭has‬ ‭not‬ ‭been‬ ‭calculated‬ ‭for‬ ‭these‬ ‭comparisons,‬ ‭it‬ ‭is‬ ‭planned‬ ‭to‬
‭perform a Cox regression (Cox 1972) for detecting possible influencing factors.‬
‭Correlation‬ ‭analysis‬ ‭will‬ ‭be‬ ‭performed‬ ‭for‬ ‭the‬ ‭OS‬ ‭and‬ ‭the‬ ‭PFS1‬ ‭and‬ ‭displayed‬ ‭in‬ ‭a‬
‭scatterplot including Pearson’s correlation coefficient.‬
‭Listings‬ ‭will‬ ‭be‬ ‭prepared‬ ‭with‬ ‭tumor‬ ‭assessments‬ ‭of‬ ‭central‬ ‭and‬ ‭local‬ ‭radiological‬
‭assessments including details for target and non-target lesions.‬
‭Response‬ ‭Rate‬ ‭is‬ ‭defined‬ ‭as‬ ‭the‬ ‭rate‬ ‭of‬ ‭objective‬ ‭response‬ ‭(CR+PR+SD)‬ ‭measured‬ ‭by‬
‭RECIST‬ ‭criteria‬ ‭version‬ ‭1.0.‬‭It‬‭will‬‭be‬‭derived‬‭separately‬‭for‬‭local‬‭and‬‭central‬‭radiological‬
‭assessments‬ ‭and‬ ‭by‬ ‭tumor‬ ‭evaluation‬ ‭following‬ ‭the‬ ‭regular‬ ‭12-week‬ ‭basis‬ ‭with‬ ‭its‬
‭confidence interval at level 95 %.‬
‭Overall‬‭response‬‭rate‬‭will‬‭be‬‭analyzed‬ ‭and‬ ‭a‬‭logistic‬‭regression‬‭will‬‭be‬‭performed‬‭with‬‭an‬
‭exploratory aim in order to detect factors that influence this rate.‬
‭Regressions‬‭will‬‭be‬‭performed‬‭with‬‭the‬‭following‬‭factors‬‭included‬‭in‬‭the‬‭model:‬‭Age,‬‭Gender,‬
‭Race,‬‭Location,‬‭Prior‬‭surgery‬‭(yes‬‭–‬‭curative‬‭–‬‭Non‬‭residual‬‭disease,‬‭Yes-curative-residual‬
‭disease,‬ ‭Yes-‬ ‭other‬ ‭than‬ ‭curative,‬ ‭No‬ ‭surgery),‬ ‭Baseline‬ ‭ecog,‬ ‭CgA,‬ ‭Translational‬ ‭and‬
‭biomarker‬ ‭parameters,‬ ‭TNM,‬ ‭Tumor‬ ‭histology,‬ ‭Mitotic‬ ‭Index,‬ ‭Ki67,‬ ‭Enets‬ ‭classification,‬
‭histopathological grade.‬
‭A recurrent event analysis will be performed in order to estimate the confidence interval‬
‭of the effect of the treatment in first progression and second progression (Juan R.‬
‭Gonzalez & Edsel A. Peña 2004). Recurrent event analysis will follow a cross-over‬
‭design; the other secondary endpoints will be analyzed following a parallel design.‬
‭8.2.4‬ ‭Safety‬
‭Safety‬ ‭analysis‬ ‭will‬ ‭be‬ ‭based‬ ‭on‬ ‭the‬ ‭analysis‬ ‭of‬ ‭adverse‬ ‭events‬ ‭and‬ ‭on‬ ‭post‬ ‭baseline‬
‭evaluations‬ ‭of‬ ‭laboratory‬ ‭assessments,‬ ‭physical‬ ‭examination,‬ ‭ECOG‬ ‭performance‬‭status,‬
‭12-Lead ECG and vital signs.‬
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‭1.1.1.1‬
‭Adverse events‬
‭Only treatment emergent adverse events (TEAEs) will be analyzed in summary tables which‬
‭are derived as stated in section 7.3.2. Non-treatment emergent AEs will be included in the‬
‭adverse event listings.‬
‭An‬‭overview‬‭summary‬‭of‬‭TEAEs‬‭will‬‭be‬‭prepared‬‭on‬‭a‬‭patient‬‭based‬‭and‬‭event-based‬‭level.‬
‭Event‬‭based‬‭summary‬‭of‬‭TEAE‬‭will‬‭contain‬‭the‬‭total‬‭number‬‭of‬‭TEAEs,‬‭number‬‭of‬‭related‬
‭TEAEs‬ ‭(all,‬ ‭serious‬ ‭and‬ ‭non-serious),‬ ‭number‬ ‭of‬ ‭TEAEs‬ ‭leading‬ ‭to‬ ‭permanent‬
‭discontinuation‬ ‭from‬ ‭treatment‬ ‭(all,‬ ‭serious‬ ‭and‬ ‭non-serious)‬ ‭and‬ ‭TEAEs‬ ‭with‬ ‭outcome‬
‭death.‬‭The‬‭patient-based‬‭summary‬‭will‬‭contain‬‭the‬‭number‬‭of‬‭patients‬‭without‬‭any‬‭TEAE,‬
‭with‬‭at‬‭least‬‭one‬‭TEAE‬‭(all,‬‭serious‬‭and‬‭non-serious),‬‭the‬‭number‬‭of‬‭patients‬‭with‬‭related‬
‭TEAEs‬‭(all,‬‭serious‬‭and‬‭non-serious),‬‭number‬‭of‬‭patients‬‭with‬‭at‬‭least‬‭one‬‭TEAEs‬‭leading‬‭to‬
‭permanent‬‭discontinuation‬‭from‬‭treatment‬‭(all,‬‭serious‬‭and‬‭non-serious)‬‭and‬‭the‬‭number‬‭of‬
‭patients with TEAE with the outcome death.‬
‭TEAEs‬ ‭will‬ ‭also‬ ‭be‬ ‭summarized‬ ‭by‬ ‭MedDRA‬ ‭SOC‬ ‭and‬ ‭PT‬ ‭as‬ ‭patient-based‬ ‭and‬
‭event-based.‬‭For‬‭the‬‭patient-based‬‭analyses,‬‭multiple‬‭occurrences‬‭of‬‭a‬‭specific‬‭event‬‭within‬
‭one‬‭patient‬‭(i.e.‬‭leading‬‭to‬‭same‬‭SOC/PT),‬‭the‬‭event‬‭will‬‭be‬‭counted‬‭only‬‭once.‬‭Both,‬‭the‬
‭patient-based‬‭and‬‭event‬‭based‬‭analyses‬‭will‬‭be‬‭performed‬‭for‬‭all‬‭TEAEs‬‭(all,‬‭serious‬‭and‬
‭non-serious),‬ ‭related‬ ‭TEAEs‬ ‭(all,‬ ‭serious‬ ‭and‬ ‭non-serious),‬ ‭TEAEs‬ ‭by‬ ‭relationship‬ ‭(all,‬
‭serious‬‭and‬‭non-serious),‬‭TEAEs‬‭by‬‭CTCAE‬‭grade‬‭(all,‬‭serious‬‭and‬‭non-serious),‬‭TEAEs‬‭by‬
‭action‬ ‭taken‬ ‭(all,‬ ‭serious‬ ‭and‬‭non-serious),‬‭TEAEs‬‭resulting‬‭in‬‭permanent‬‭discontinuation‬
‭from study drug (all, serious and non-serious) and TEAEs leading to death.‬
‭1.1.1.2‬
‭Laboratory data‬
‭Post‬ ‭baseline‬ ‭laboratory‬ ‭assessments‬ ‭will‬ ‭be‬ ‭summarized‬ ‭in‬ ‭the‬ ‭SI‬ ‭unit‬ ‭with‬ ‭descriptive‬
‭summary‬ ‭statistics‬ ‭or‬ ‭in‬ ‭frequency‬ ‭tables,‬ ‭as‬ ‭appropriate,‬ ‭separately‬ ‭per‬ ‭laboratory‬
‭parameter‬‭and‬‭evaluation‬‭time‬‭point.‬‭Furthermore,‬‭where‬‭applicable,‬‭change‬‭from‬‭baseline‬
‭results‬‭will‬‭also‬‭be‬‭summarized.‬‭For‬‭each‬‭parameter,‬‭where‬‭applicable,‬‭it‬‭will‬‭be‬‭determined‬
‭whether‬‭the‬‭value‬‭(original,‬‭not‬‭converted)‬‭is‬‭within,‬‭below‬‭or‬‭above‬‭the‬‭documented‬‭normal‬
‭range‬ ‭for‬ ‭that‬ ‭parameter‬ ‭and‬ ‭the‬ ‭number‬ ‭of‬ ‭values‬ ‭within,‬ ‭below‬ ‭and‬ ‭above‬ ‭will‬ ‭be‬
‭summarized‬‭per‬‭evaluation‬‭time‬‭point‬‭in‬‭a‬‭frequency‬‭table.‬‭In‬‭addition,‬‭CTCAE‬‭grades‬‭will‬
‭be‬‭derived‬‭as‬‭stated‬‭in‬‭section‬‭7.3.2‬‭and‬‭the‬‭frequency‬‭and‬‭percentages‬‭of‬‭CTCAE‬‭grades‬
‭will be summarized per CTCAE term and evaluation time point.‬
‭For‬ ‭the‬ ‭change‬ ‭from‬ ‭baseline‬ ‭in‬ ‭CgA‬ ‭values‬ ‭the‬ ‭p-value‬ ‭from‬ ‭Wilcoxon‬ ‭rank-sum‬ ‭test‬
‭(Mann–Whitney‬ ‭U‬ ‭test)‬ ‭for‬ ‭the‬ ‭difference‬ ‭between‬ ‭the‬ ‭two‬ ‭study‬ ‭treatments‬ ‭will‬ ‭be‬
‭presented.‬
‭1.1.1.3‬
‭Other safety data‬
‭Post‬ ‭baseline‬ ‭assessments‬ ‭of‬ ‭physical‬ ‭examination,‬ ‭ECOG‬ ‭performance‬ ‭status,‬ ‭12‬
‭lead-ECG,‬ ‭weight,‬ ‭BMI‬ ‭and‬ ‭vital‬ ‭signs‬ ‭including‬ ‭change‬ ‭from‬ ‭baseline‬ ‭results‬ ‭will‬ ‭be‬
‭summarized‬ ‭per‬ ‭evaluation‬ ‭timepoint‬ ‭with‬ ‭descriptive‬ ‭statistics‬ ‭or‬‭in‬‭frequency‬‭tables,‬‭as‬
‭appropriate.‬
‭1.1.2‬ ‭Other Variables‬
‭Scores‬ ‭from‬ ‭the‬ ‭EORTC‬ ‭QLQ-C30‬ ‭and‬ ‭the‬ ‭disease‬ ‭specific‬ ‭EORTC‬ ‭QLQ-GINEt21‬
‭questionnaire‬ ‭will‬ ‭be‬ ‭derived‬ ‭as‬ ‭described‬ ‭in‬ ‭section‬ ‭7.3.2‬ ‭summarized‬ ‭with‬ ‭descriptive‬
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‭statistics‬‭per‬‭score‬‭and‬‭evaluation‬‭time‬‭point.‬‭In‬‭addition,‬‭answers‬‭to‬‭the‬‭single‬‭items‬‭will‬‭be‬
‭displayed in frequency tables.‬
‭Resource‬‭utilization‬‭data‬‭will‬‭be‬‭tabulated‬‭with‬‭descriptive‬‭statistics‬‭or‬‭frequency‬‭tables,‬‭as‬
‭appropriate‬ ‭separately‬ ‭for‬ ‭hospitalizations,‬ ‭outpatient‬ ‭visits,‬ ‭diagnostics‬ ‭and‬ ‭procedures‬
‭related‬ ‭to‬ ‭AEs.‬ ‭Further‬ ‭calculation‬ ‭of‬ ‭cost‬ ‭effectiveness‬ ‭will‬ ‭be‬ ‭described‬ ‭in‬ ‭a‬ ‭separate‬
‭statistical analysis plan.‬
‭1.2‬ ‭Subgroup Analysis and Stratifications‬
‭All‬ ‭data‬ ‭will‬ ‭be‬ ‭examined‬ ‭by‬ ‭treatment‬ ‭arm‬ ‭and‬ ‭if‬ ‭applicable‬ ‭in‬ ‭total‬ ‭for‬ ‭the‬ ‭respective‬
‭analysis‬‭population‬‭as‬‭defined‬‭in‬‭column‬‭“Subgroup/Strata”‬‭in‬‭section‬‭12.1.‬‭Apart‬‭from‬‭these‬
‭subgroups/strata, no further stratifications or subgroup analyses will be performed.‬
‭2‬ ‭Changes to Planned Analyses‬
‭This section is to be finalized and specified in more detail when above mentioned analyses‬
‭are fixed and open comments are resolved. Following deviations are currently‬
‭applicable/possible:‬
‭●‬ ‭CgA levels will be analyzed using a paired Wilcoxon test comparing baseline and‬
‭four weeks values. -> no paired design‬
‭●‬ ‭No cross over design as stated at several parts of the protocol. Treatment switch only‬
‭in case of progression and not mandatory like in a cross over design, patient does‬
‭not serve as his own comparator, but parallel comparison of treatments‬
‭●‬ ‭Cut off of data collection time for analysis, but data collection not truncated.‬
‭●‬ ‭Correlation analysis of OS/PFS and display Kendall’s Tau (only for paired analyses),‬
‭here parallel design‬
‭3‬ ‭References‬
‭Not applicable.‬
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‭4‬ ‭Appendix‬
‭4.1‬ ‭Tables, Figures and Listings (TFLs)‬
‭The‬‭structure‬‭and‬‭organization‬‭of‬‭the‬‭TFLs,‬‭variable‬‭names‬‭or‬‭categories‬‭might‬‭be‬‭changed,‬
‭as‬‭deemed‬‭necessary,‬‭during‬‭programming,‬‭without‬‭requiring‬‭a‬‭separate‬‭SAP‬‭amendment‬
‭or new SAP version.‬
‭Table Name‬
‭Statistics / Categories‬
‭Subgroup / Strata‬
‭14.1 Study Patients and Demographic Data‬
‭Disposition of sites and patients, analysis sets, study and treatment discontinuation‬
‭Number of participating sites‬
‭Number of participating sites‬
‭Number of sites with at least one patient screened (ICF signed)‬
‭Number of sites with at least one patient randomized‬
‭Number of sites with at least one patient included in SAF‬
‭Number of sites with at least one patient included in ITT‬
‭Number of sites with at least one patient included in PP‬
‭Number of sites with at least one patient treated with STZ-5FU‬
‭Number of sites with at least one patient treated with Everolimus‬
‭In total and by country‬
‭Screening and randomization of‬
‭patients‬
‭Number of patients screened (ICF signed)‬
‭Number of not randomized patients‬
‭Number of patients randomized‬
‭Number of patients randomized to treatment sequence STZ-5FU‬
‭– Everolimus‬
‭Number of patients randomized to treatment sequence‬
‭Everolimus – STZ-5FU‬
‭In total and by country‬
‭and site‬
‭Reason for screening failure‬
‭Inclusion-/Exclusion criteria not fulfilled‬
‭Patient rejects participation on the trial‬
‭Patient decided to retract from participation before random‬
‭allocation‬
‭Patient did not come to screening visit‬
‭Other‬
‭Subgroup of patients‬
‭assigned as screening‬
‭failure at end of study‬
‭form‬
‭Final status at end of treatment‬
‭Final status at end of treatment‬
‭Total‬
‭Treatment/Study completion according to Protocol (incl Disease‬
‭Progression)‬
‭Withdrawal 1‬‭st‬‭treatment‬
‭Withdrawal 2‬‭nd‬‭treatment‬
‭If withdrawal is ticked, primary reason:‬
‭Total‬
‭Missing‬
‭Adverse Event‬
‭Death‬
‭Protocol Violation‬
‭Lost to Follow-Up‬
‭Withdrawal of Consent‬
‭Investigator Discretion‬
‭Sponsor Discretion‬
‭Other‬
‭If death, main cause of death:‬
‭Total‬
‭Missing‬
‭Primary Disease‬
‭Toxicity‬
‭Chronic disease not related to an AE or to progression‬
‭SAF, ITT, PP‬
‭By treatment arm‬
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‭Other cause‬
‭Does the Subject agree to be followed for post treatment‬
‭evaluations?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Does the Subject agree to be followed for survival?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes, reason for study end‬
‭Total‬
‭Missing‬
‭Death‬
‭Lost to Follow-Up‬
‭Withdrawal of Consent for survival data collection‬
‭Investigator Discretion‬
‭Sponsor Discretion‬
‭Other‬
‭Analysis sets‬
‭Number of patients screened (ICF signed)‬
‭Number of patients in SAF‬
‭Number of patients excluded from the SAF‬
‭Reasons for exclusion from SAF‬
‭Number of patients in ITT‬
‭Number of patients excluded from the ITT‬
‭Reasons for exclusion from ITT‬
‭Number of patients in PP‬
‭Number of patients excluded from the PP‬
‭Reasons for exclusion from PP‬
‭In total and by‬
‭treatment arm‬
‭Violation of eligibility criteria at‬
‭randomization‬
‭Number of patients violated any eligibility criterion at‬
‭randomization‬
‭Number of patients per violated inclusion and exclusion criterion‬
‭Subgroup of patients‬
‭who did not meet all‬
‭eligibility criteria at‬
‭randomization‬
‭Violation of eligibility criteria‬
‭post randomization (end of first‬
‭line treatment)‬
‭Did the subject meet all eligibility criteria?‬
‭Total‬
‭Yes‬
‭No‬
‭If no:‬
‭Number of patients violated any eligibility criterion at post‬
‭randomization‬
‭Number of patients per violated inclusion and exclusion criterion‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Number of patients per‬
‭treatment‬
‭Total number of patients in respective population‬
‭Number of patients treated with STZ-5FU‬
‭Number of patients treated according to Moertel‬
‭Number of patients treated according to Uppsala‬
‭Number of patients treated with STZ-5FU as 1‬‭st‬‭line‬
‭Number of patients treated according to Moertel‬
‭Number of patients treated according to Uppsala‬
‭Number of patients treated with STZ-5FU as 2‬‭nd‬‭line‬
‭Number of patients treated according to Moertel‬
‭Number of patients treated according to Uppsala‬
‭SAF, ITT, PP‬
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‭Number of patients treated with Everolimus‬
‭Number of patients treated with Everolimus as 1‬‭st‬‭line‬
‭Number of patients treated with Everolimus as 2‬‭nd‬‭line‬
‭Primary reason for permanent‬
‭discontinuation of study‬
‭treatment‬
‭Primary reason for discontinuation of study treatment‬
‭Total‬
‭Progressive disease‬
‭Adverse Event‬
‭Patient decision (retrieval of consent)‬
‭Other‬
‭Duration of treatment before discontinuation [days]‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭who discontinued study‬
‭treatment permanently‬
‭SAF, ITT, PP‬
‭By treatment, by‬
‭treatment arm‬
‭Number of patients per‬
‭cycle/follow up visit‬
‭Total‬
‭Baseline‬
‭Cycle 1‬
‭Cycle 2‬
‭…‬
‭Cycle X‬
‭EoT‬
‭FU 30 days‬
‭…‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Observation period [days]‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Time between visits [days]‬
‭Days between Screening and Cycle 1 of 1‬‭st‬‭line treatment‬
‭Duration of 1‬‭st‬‭line treatment‬
‭Days between end of treatment and 30-days FU‬
‭Only for patients receiving 2‬‭nd‬‭line treatment:‬
‭Duration of resting period‬
‭Duration of 2‬‭nd‬‭line treatment‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Demographic data and other baseline characteristics‬
‭Gender‬
‭Total‬
‭Missing‬
‭Male‬
‭Female‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Age‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Childbearing potential‬
‭Total‬
‭Child bearing potential‬
‭Surgically sterile‬
‭Post menopausal‬
‭Subgroup of females‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Race‬
‭Total‬
‭Asian‬
‭Black or African American‬
‭White‬
‭Other‬
‭Not for French patients‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Physical examination at‬
‭baseline‬
‭Performance of physical examination at baseline‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes:‬
‭Separately by body system‬
‭General Appearance‬
‭Skin‬
‭[…]‬
‭SAF, ITT, PP‬
‭by treatment arm‬
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‭Basic Nervous System‬
‭Other (MedDRA PT)‬
‭Total‬
‭Missing‬
‭Normal‬
‭Abnormal, not clinically significant‬
‭Abnormal, clinically significant‬
‭Not done‬
‭Height, weight and BMI at‬
‭baseline‬
‭Body height at baseline [cm]‬
‭Body weight at baseline [kg]‬
‭BMI [kg/m²] at baseline‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Vital signs at baseline‬
‭Performance of vital signs assessment at baseline‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes:‬
‭Separately by measurement‬
‭Systolic blood pressure [mmHg]‬
‭Diastolic blood pressure [mmHg]‬
‭Heart rate [beats per minute]‬
‭Body temperature [°C]‬
‭Respiration Rate [breaths per minute]‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭ECOG performance status at‬
‭baseline‬
‭Total‬
‭Missing‬
‭0: Fully active […]‬
‭1: Restricted in physically strenuous activity […]‬
‭2: Ambulatory and capable of all selfcare […]‬
‭3: Capable of only limited selfcare […]‬
‭4: Completely disabled […]‬
‭5: Dead‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭12 lead-ECG worst documented‬
‭diagnosis at baseline‬
‭Total‬
‭Missing‬
‭Normal‬
‭Abnormal, not clinically significant‬
‭Abnormal, clinically significant‬
‭Non-evaluable‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Medical history, prior or concomitant therapies‬
‭Medical and surgical history and medical conditions‬
‭Relevant prior medical / surgical‬
‭history / medical conditions‬
‭Total‬
‭Total number of patients with no prior medical condition or event‬
‭Total number of patients with any prior medical condition or‬
‭event‬
‭MedDRA SOC and PT‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Relevant concomitant medical /‬
‭surgical history / medical‬
‭conditions‬
‭Total‬
‭Total number of patients with no concomitant medical condition‬
‭or event‬
‭Total number of patients with any concomitant medical condition‬
‭or event‬
‭MedDRA SOC and PT‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Prior antineoplastic therapies‬
‭Prior antineoplastic therapies, medications‬
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‭Incidences of prior‬
‭antineoplastic therapies,‬
‭medications‬
‭Total‬
‭Total number of patients with no prior antineoplastic therapies,‬
‭medications‬
‭Total number of patients with any prior antineoplastic therapies,‬
‭medications‬
‭WHO DD ATC level 1 and 3‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by therapy‬
‭type‬
‭Prior antineoplastic therapies,‬
‭medications – details (event‬
‭based)‬
‭Total number of prior antineoplastic therapies, medications‬
‭Setting‬
‭Missing‬
‭Adjuvant‬
‭Neoadjuvant‬
‭Therapeutic‬
‭Prevention‬
‭Palliative‬
‭Other‬
‭Number of cycles‬
‭Quantitative statistical parameters‬
‭Duration‬
‭Quantitative statistical parameters‬
‭Reason for discontinuation‬
‭Missing‬
‭Adverse event(s) not related to toxicity‬
‭Adverse event(s)‬
‭Toxicity‬
‭Completed prescribed regimen‬
‭Disease Progression‬
‭Patient’s decision‬
‭Lost to follow-up‬
‭Unknown‬
‭Other‬
‭Best response‬
‭Missing‬
‭Complete response‬
‭Partial response‬
‭Stable disease‬
‭Progressive disease‬
‭Complete response/unconfirmed‬
‭Unknown‬
‭Not applicable‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by therapy‬
‭type‬
‭Prior antineoplastic therapies, radiotherapies‬
‭Incidences of prior‬
‭antineoplastic therapies,‬
‭radiotherapies‬
‭Total‬
‭Total number of patients with no prior antineoplastic therapies,‬
‭radiotherapies‬
‭Total number of patients with any prior antineoplastic therapies,‬
‭radiotherapies‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by type‬
‭Prior antineoplastic therapies,‬
‭radiotherapies – details (event‬
‭based)‬
‭Total number of prior antineoplastic therapies, radiotherapies‬
‭Location (multiple response)‬
‭Missing‬
‭Pancreas‬
‭Liver‬
‭[…]‬
‭Breast‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by type‬
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‭Other‬
‭Duration‬
‭Quantitative statistical parameters‬
‭Setting‬
‭Missing‬
‭Adjuvant‬
‭Neoadjuvant‬
‭Therapeutic‬
‭Prevention‬
‭Palliative‬
‭Other‬
‭Reason for discontinuation‬
‭Missing‬
‭Adverse event(s) not related to toxicity‬
‭Adverse event(s)‬
‭Toxicity‬
‭Completed prescribed regimen‬
‭Disease Progression‬
‭Patient’s decision‬
‭Lost to follow-up‬
‭Unknown‬
‭Other‬
‭Best response‬
‭Missing‬
‭Complete response‬
‭Partial response‬
‭Stable disease‬
‭Progressive disease‬
‭Complete response/unconfirmed‬
‭Unknown‬
‭Not applicable‬
‭Prior antineoplastic therapies, surgeries‬
‭Incidences of prior‬
‭antineoplastic therapies,‬
‭surgeries‬
‭Total‬
‭Total number of patients with no prior antineoplastic therapies,‬
‭surgeries‬
‭Total number of patients with any prior antineoplastic therapies,‬
‭surgeries‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by surgery‬
‭type‬
‭Prior antineoplastic therapies,‬
‭surgeries – details (event‬
‭based)‬
‭Total number of prior antineoplastic therapies, surgeries‬
‭Reason for surgery‬
‭Missing‬
‭Curative‬
‭Palliative‬
‭Biopsy‬
‭Prophylaxis‬
‭Unknown‬
‭Other‬
‭Residual disease‬
‭Yes‬
‭No‬
‭Unknown‬
‭Not applicable‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭in total and by surgery‬
‭type‬
‭Prior and concomitant medication or significant non-drug therapies‬
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‭Prior medication or significant‬
‭non-drug therapies‬
‭Total‬
‭Number of patients with no prior medication or significant‬
‭non-drug therapies‬
‭Number of patients with any prior medication or significant‬
‭non-drug therapies‬
‭WHO DD level 1 and 3‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Concomitant medication or‬
‭significant non-drug therapies‬
‭Total‬
‭Number of patients with no concomitant medication or significant‬
‭non-drug therapies‬
‭Number of patients with any concomitant medication or‬
‭significant non-drug therapies‬
‭WHO DD level 1 and 3‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Disease diagnosis data‬
‭Diagnosis and extension of‬
‭advanced (unresectable or‬
‭metastatic) progressive pNET‬
‭Time from date of first diagnosis of advanced pNET to date‬
‭of ICF signature‬
‭Quantitative statistical parameters‬
‭Primary site of tumor (multiple response)‬
‭Total‬
‭Missing‬
‭Pancreas‬
‭Peritoneum‬
‭Other (adhoc codes)‬
‭ENETS TNM Classification (Rindi, 2010):‬
‭T – Primary tumor‬
‭Missing‬
‭Tx Cannot be assessed‬
‭T0 No evidence of primary tumor‬
‭T1 Confined to pancreas and < 2 cm‬
‭T2 Confined to pancreas and 2 -4 cm‬
‭T3 Confined to pancreas and > 4 cm; or invasion of‬
‭duodenum or bile duct‬
‭T4 Invasion of adjacent organs or major vessels‬
‭N – Regional lymph nodes‬
‭Missing‬
‭Nx Cannot be assessed‬
‭N0 No regional lymph node metastases‬
‭N1 Regional lymph node metastases‬
‭M – Distant metastases‬
‭Missing‬
‭Mx Cannot be assessed‬
‭M0 No distant metastases‬
‭M1 Distant metastases‬
‭If M1 Distant metastases is ticked:‬
‭Location of Tumor Metastasis (multiple response)‬
‭Missing‬
‭Pancreas‬
‭Liver‬
‭Peritoneum‬
‭Lung‬
‭Bone‬
‭Other (adhoc codes)‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Diagnosis at inclusion in‬
‭SEQTOR trial‬
‭Time from date of confirmation of diagnosis to date of ICF‬
‭signature‬
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‭Quantitative statistical parameters‬
‭ENETS TNM Classification (Rindi, 2010):‬
‭T – Primary tumor‬
‭Missing‬
‭T1 Confined to pancreas and < 2 cm‬
‭T2 Confined to pancreas and 2 -4 cm‬
‭T3 Confined to pancreas and > 4 cm; or invasion of‬
‭duodenum or bile duct‬
‭T4 Invasion of adjacent organs or major vessels‬
‭Tx Cannot be assessed‬
‭N – Regional lymph nodes‬
‭Missing‬
‭Nx Cannot be assessed‬
‭N0 No regional lymph node metastases‬
‭N1 Regional lymph node metastases‬
‭M – Distant metastases‬
‭Missing‬
‭Mx Cannot be assessed‬
‭M0 No distant metastases‬
‭M1 Distant metastases‬
‭If M1 Distant metastases is ticked:‬
‭Location of Tumor Metastasis (multiple response)‬
‭Missing‬
‭Pancreas‬
‭Liver‬
‭Peritoneum‬
‭Lung‬
‭Bone‬
‭Other (adhoc coded)‬
‭Type of tissue‬
‭Missing‬
‭Primary tumor‬
‭Metastasis‬
‭Other (adhoc codes)‬
‭Mitotic Index assessed?‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes, Mitotic Index [%]‬
‭Quantitative statistical parameters‬
‭Ki67 assessed?‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes, Ki67 [%]‬
‭Quantitative statistical parameters‬
‭ENETS / WHO Classification‬
‭Missing‬
‭G1: <2 mitoses per 2 mm2 and/or Ki-67 index ≤ 2%‬
‭G2: 2–20 mitoses per 2 mm2 and/or Ki-67 index >2% and ≤ 20%‬
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‭Unknown‬
‭Tumor assessments at baseline‬
‭Type and location of tumor‬
‭assessment at baseline, local‬
‭radiological tumor assessment‬
‭Total number of tumor assessments‬
‭Type of tumor assessment‬
‭Missing‬
‭Triphasic CT‬
‭Multiple-phase MRI‬
‭Other (adhoc codes)‬
‭Location of tumor assessment‬
‭Missing‬
‭CNS supratentorial‬
‭CNS infratentorial‬
‭[…]‬
‭Gall bladder‬
‭Other (adhoc codes)‬
‭Overall response following RECIST 1.0‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Type and location of tumor‬
‭assessment at baseline,‬
‭centralized radiological tumor‬
‭assessment‬
‭Total number of tumor assessments‬
‭Type of tumor assessment‬
‭Missing‬
‭Triphasic CT‬
‭Multiple-phase MRI‬
‭Other (adhoc codes)‬
‭Location of tumor assessment‬
‭Missing‬
‭CNS supratentorial‬
‭CNS infratentorial‬
‭[…]‬
‭Gall bladder‬
‭Other (adhoc codes)‬
‭Tumor density‬
‭Quantitative statistical parameters‬
‭Overall response following RECIST 1.0‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭Overall response following RECIST 1.1‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭ENETS Score following RECIST 1.0‬
‭SAF, ITT, PP‬
‭by treatment arm‬
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‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭ENETS Score following RECIST 1.1‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭Target lesion definition at‬
‭baseline, local radiological‬
‭tumor assessment‬
‭Total number of target lesions‬
‭Location of target lesion‬
‭Missing‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭Status of lesion‬
‭Missing‬
‭New Lesion / Baseline Lesion‬
‭Splitted Lesion‬
‭Merged Lesion‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Target lesion definition at‬
‭baseline, local radiological‬
‭tumor assessment, patient‬
‭based analysis‬
‭Number of target lesions per patient‬
‭Quantitative statistical parameters‬
‭Location of target lesion (multiple response)‬
‭Total‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭Status of lesion (multiple response)‬
‭Tota‬
‭New Lesion / Baseline Lesion‬
‭Splitted Lesion‬
‭Merged Lesion‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Target lesion definition at‬
‭baseline, centralized‬
‭radiological tumor assessment‬
‭Total number of target lesions‬
‭Location of target lesion‬
‭Missing‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭Status of lesion‬
‭Missing‬
‭New Lesion / Baseline Lesion‬
‭Splitted Lesion‬
‭Merged Lesion‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Target lesion definition at‬
‭baseline, centralized‬
‭radiological tumor assessment,‬
‭patient based analysis‬
‭Number of target lesions per patient‬
‭Quantitative statistical parameters‬
‭Location of target lesion (multiple response)‬
‭Total‬
‭CNS supratentorial‬
‭[…]‬
‭SAF, ITT, PP‬
‭By treatment arm‬
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‭Other (adhoc codes)‬
‭Status of lesion (multiple response)‬
‭Tota‬
‭New Lesion / Baseline Lesion‬
‭Splitted Lesion‬
‭Merged Lesion‬
‭Non-target lesion definition at‬
‭baseline, local radiological‬
‭tumor assessment‬
‭Total number of non target lesions‬
‭Location of non-target lesion‬
‭Missing‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Non-target lesion definition at‬
‭baseline, local radiological‬
‭tumor assessment, patient‬
‭based analysis‬
‭Number of non-target lesions per patient‬
‭Quantitative statistical parameters‬
‭Location of non-target lesion (multiple response)‬
‭Total‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Non-target lesion definition at‬
‭baseline, centralized‬
‭radiological tumor assessment‬
‭Total number of non-target lesions‬
‭Location of non-target lesion‬
‭Missing‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Non-target lesion definition at‬
‭baseline, centralized‬
‭radiological tumor assessment,‬
‭patient based analysis‬
‭Number of non-target lesions per patient‬
‭Quantitative statistical parameters‬
‭Location of non-target lesion (multiple response)‬
‭Total‬
‭CNS supratentorial‬
‭[…]‬
‭Other (adhoc codes)‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Extent of exposure and drug concentration data‬
‭Initial daily dose administered‬
‭[mg]‬
‭Quantitative statistical parameters‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Average actual daily dose‬
‭[mg/kg] (excluding interruptions)‬
‭Quantitative statistical parameters‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Number of dose adjustment per‬
‭patient (excluding interruptions)‬
‭Quantitative statistical parameters‬
‭In categories:‬
‭Missing‬
‭No dose adjustments‬
‭1 dose adjustment‬
‭2 dose adjustments‬
‭3 dose adjustments‬
‭More than 3 dose adjustment‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Number of dose increases per‬
‭patient (excluding interruptions)‬
‭Quantitative statistical parameters‬
‭In categories:‬
‭Missing‬
‭SAF, ITT, PP‬
‭By treatment arm‬
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‭No dose increases‬
‭1 dose increase‬
‭2 dose increases‬
‭3 dose increases‬
‭More than 3 dose increases‬
‭For STZ-5FU patient separately for the two components‬
‭Reason for dose increase‬
‭(excluding interruptions)‬
‭Total number of documented increases‬
‭Reason for dose increase‬
‭Missing‬
‭Adverse Event/Toxicity‬
‭Dosing error‬
‭Other‬
‭Not applicable/Initial dose‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Number of dose decreases per‬
‭patient (excluding interruptions)‬
‭Quantitative statistical parameters‬
‭In categories:‬
‭Missing‬
‭No dose decreases‬
‭1 dose decrease‬
‭2 dose decreases‬
‭3 dose decreases‬
‭More than 3 dose decreases‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Reason for dose decrease‬
‭(excluding interruptions)‬
‭Total number of documented decreases‬
‭Reason for dose‬‭de‬‭crease‬
‭Missing‬
‭Adverse Event/Toxicity‬
‭Dosing error‬
‭Other‬
‭Not applicable/Initial dose‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Number of dosage interruptions‬
‭per patient‬
‭Quantitative statistical parameters‬
‭In categories:‬
‭Missing‬
‭No dose interruptions‬
‭1 dose interruption‬
‭2 dose interruptions‬
‭3 dose interruptions‬
‭More than 3 dose interruptions‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Reason for dose interruptions‬
‭(excluding interruptions)‬
‭Total number of documented interruptions‬
‭Reason for dose‬‭de‬‭crease‬
‭Missing‬
‭Adverse Event/Toxicity‬
‭Dosing error‬
‭Other‬
‭Not applicable/Initial dose‬
‭For STZ-5FU patient separately for the two components‬
‭Subgroup of patients‬
‭with interruptions‬
‭SAF, ITT, PP‬
‭By treatment arm‬
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‭Duration of interruptions [days]‬
‭Quantitative statistical parameters‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭Duration of exposure [days]‬
‭Quantitative statistical parameters‬
‭For STZ-5FU patient separately for the two components‬
‭SAF, ITT, PP‬
‭By treatment arm‬
‭14.2 Efficacy Data‬
‭Progression free survival rate at‬
‭12 months (PFS1R12m)‬
‭according to RECIST criteria 1.0‬
‭Missing‬
‭Yes‬
‭No‬
‭Separately for‬
‭Main analysis‬
‭Conservative analysis‬
‭Optimistic analysis‬
‭Including p-value‬
‭ITT, PP‬
‭by treatment arm‬
‭Progression free survival to 1‬‭st‬
‭line treatment (PFS1) according‬
‭to local assessment using‬
‭RECIST criteria version 1.0‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Progression free survival to 1‬‭st‬
‭line treatment (PFS1) according‬
‭to central assessment using‬
‭RECIST criteria version 1.0‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Progression free survival to 1‬‭st‬
‭line treatment (PFS1) according‬
‭to central assessment using‬
‭RECIST criteria version 1.1‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Progression free survival to 1‬‭st‬
‭line treatment (PFS1) according‬
‭to central assessment using‬
‭ENETS SCORE RECIST criteria‬
‭version 1.0‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Progression free survival to 1‬‭st‬
‭line treatment (PFS1) according‬
‭to central assessment using‬
‭ENETS SCORE RECIST criteria‬
‭version 1.1‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Time to first progression (TTP1)‬
‭according to local assessment‬
‭using RECIST criteria version‬
‭1.0‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Time to first progression (TTP1)‬
‭according to central assessment‬
‭Time to events analysis‬
‭ITT, PP‬
‭by treatment arm‬
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‭using RECIST criteria version‬
‭1.0‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭Time to first progression (TTP1)‬
‭according to central assessment‬
‭using RECIST criteria version‬
‭1.1‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Time to first progression (TTP1)‬
‭according to central assessment‬
‭using ENETS SCORE RECIST‬
‭criteria version 1.0‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Time to first progression (TTP1)‬
‭according to central assessment‬
‭using ENETS SCORE RECIST‬
‭criteria version 1.1‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Overall survival (OS)‬
‭Time to events analysis‬
‭Descriptive summaries of Kaplan-Meier estimates (Number of‬
‭events, number of censored, 25%, 50% and 75% quartiles‬
‭including 95% CI)‬
‭Kaplan-Meier curve‬
‭Including p-value from log rank test‬
‭ITT, PP‬
‭by treatment arm‬
‭Correlation of OS and PFS1‬
‭according to local assessment‬
‭using RECIST criteria version‬
‭1.0‬
‭Scatterplot and correlation coefficient‬
‭ITT, PP‬
‭by treatment arm‬
‭Correlation of OS and PFS1‬
‭according to central assessment‬
‭using RECIST criteria version‬
‭1.0‬
‭Scatterplot and correlation coefficient‬
‭ITT, PP‬
‭by treatment arm‬
‭Correlation of OS and PFS1‬
‭according to central assessment‬
‭using RECIST criteria version‬
‭1.1‬
‭Scatterplot and correlation coefficient‬
‭ITT, PP‬
‭by treatment arm‬
‭Correlation of OS and PFS1‬
‭according to central assessment‬
‭using ENETS SCORE RECIST‬
‭criteria version 1.0‬
‭Scatterplot and correlation coefficient‬
‭ITT, PP‬
‭by treatment arm‬
‭Correlation of OS and PFS1‬
‭according to central assessment‬
‭using ENETS SCORE RECIST‬
‭criteria version 1.1‬
‭Scatterplot and correlation coefficient‬
‭ITT, PP‬
‭by treatment arm‬
‭Objective response rate (ORR)‬
‭according to local assessment‬
‭Missing‬
‭Yes‬
‭No‬
‭ITT, PP‬
‭by treatment arm, by‬
‭evaluation following the‬
‭regular 12-week basis‬
‭Objective response rate (ORR)‬
‭according to central assessment‬
‭Missing‬
‭Yes‬
‭No‬
‭ITT, PP‬
‭by treatment arm, by‬
‭evaluation following the‬
‭regular 12-week basis‬
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‭Overall response rate according‬
‭to local assessment‬
‭Quantitative statistical parameters‬
‭Results of the logistic regression‬
‭ITT, PP‬
‭By treatment arm‬
‭Overall response rate according‬
‭to central assessment‬
‭Quantitative statistical parameters‬
‭Results of the logistic regression‬
‭ITT, PP‬
‭By treatment arm‬
‭Type and location of tumor‬
‭assessment post-baseline, local‬
‭radiological tumor assessment‬
‭Total number of tumor assessments‬
‭Type of tumor assessment‬
‭Missing‬
‭Triphasic CT‬
‭Multiple-phase MRI‬
‭Other (adhoc codes)‬
‭Location of tumor assessment‬
‭Missing‬
‭CNS supratentorial‬
‭CNS infratentorial‬
‭[…]‬
‭Gall bladder‬
‭Other (adhoc codes)‬
‭Overall response following RECIST 1.0‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭ITT, PP‬
‭by treatment arm‬
‭by evaluation week‬
‭Type and location of tumor‬
‭assessment post-baseline,‬
‭centralized radiological tumor‬
‭assessment‬
‭Total number of tumor assessments‬
‭Type of tumor assessment‬
‭Missing‬
‭Triphasic CT‬
‭Multiple-phase MRI‬
‭Other (adhoc codes)‬
‭Location of tumor assessment‬
‭Missing‬
‭CNS supratentorial‬
‭CNS infratentorial‬
‭[…]‬
‭Gall bladder‬
‭Other (adhoc codes)‬
‭Tumor density‬
‭Quantitative statistical parameters‬
‭Overall response following RECIST 1.0‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭Overall response following RECIST 1.1‬
‭Missing‬
‭CR – Complete Response‬
‭ITT, PP‬
‭by treatment arm‬
‭by evaluation week‬
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‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭ENETS Score following RECIST 1.0‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭ENETS Score following RECIST 1.1‬
‭Missing‬
‭CR – Complete Response‬
‭PR – Partial Response‬
‭SD – Stable Disease‬
‭PD – Progression of Disease‬
‭Not applicable / Not assessable / Unknown‬
‭14.3 Safety Data‬
‭14.3.1 Adverse Events‬
‭Event based summary of‬
‭TEAEs‬
‭Total number of TEAE‬
‭Number of related TEAEs‬
‭Number of TEAEs resulting in permanent discontinuation of‬
‭study drug‬
‭Number of non-serious TEAEs‬
‭Number of non-serious related TEAEs‬
‭Number of non-serious TEAEs resulting in permanent‬
‭discontinuation of study drug‬
‭Number of serious TEAEs‬
‭Number of serious related TEAEs‬
‭Number of serious TEAEs resulting in permanent discontinuation‬
‭of study drug‬
‭Number of TEAEs with outcome death‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based summary of‬
‭TEAEs‬
‭Total number of patients‬
‭Number of patients without any TEAE‬
‭Number of patients with at least one TEAE‬
‭Number of patients with at least one related TEAE‬
‭Number of patients with at least one TEAE resulting in‬
‭permanent discontinuation of study drug‬
‭Number of patients with at least one non-serious TEAEs‬
‭Number of patients with at least one non-serious related TEAEs‬
‭Number of patients with at least one non-serious TEAEs‬
‭resulting in permanent discontinuation of study drug‬
‭Number of patients with at least one serious TEAEs‬
‭Number of patients with at least one serious related TEAEs‬
‭Number of patients with at least one serious TEAEs resulting in‬
‭permanent discontinuation of study drug‬
‭Number of patients with TEAEs with outcome death‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
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‭Classification of TEAE‬
‭Total number of TEAEs‬
‭SAE‬
‭Yes‬
‭No‬
‭If yes, serious criteria (multiple response)‬
‭Death‬
‭Life-threatening‬
‭Hospitalization or prolongation of existing hospitalization‬
‭Persistent or significant disability or incapacity‬
‭Congenital abnormality or birth defect‬
‭Other medically important condition‬
‭CTCAE Grade/Severity‬
‭Missing‬
‭CTCAE grade 1‬
‭CTCAE grade 2‬
‭CTCAE grade 3‬
‭CTCAE grade 4‬
‭CTCAE grade 5‬
‭CTCAE not defined**‬
‭Mild*‬
‭Moderate*‬
‭Severe*‬
‭Unknown*‬
‭Not assessable*‬
‭*: only to be documented if “CTCAE grade” documented as “not‬
‭defined”;‬
‭**: only if severity is missing in case “CTCAE grade” is‬
‭documented as “not defined”‬
‭Relationship by reporter‬
‭Missing‬
‭Yes‬
‭No‬
‭Unknown‬
‭Not assessable‬
‭Not applicable‬
‭Action taken with study drug‬
‭Missing‬
‭None‬
‭Discontinued‬
‭Reduced/interrupted‬
‭Dosage increased‬
‭Unknown‬
‭Not applicable‬
‭Outcome‬
‭Missing‬
‭Ongoing‬
‭Resolved‬
‭Recovered with sequelae‬
‭Fatal‬
‭Unknown‬
‭Not assessable‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs by‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
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‭Event based related TEAEs by‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs by‬
‭relationship, MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs by CTCAE‬
‭grade, MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs by‬
‭MedDRA SOC and PT resulting‬
‭in permanent discontinuation of‬
‭study drug by MedDRA SOC‬
‭and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs by action‬
‭taken, MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious‬
‭TEAEs by MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious related‬
‭TEAEs by MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious‬
‭TEAEs by relationship,‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious‬
‭TEAEs by CTCAE grade,‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious‬
‭TEAEs resulting in permanent‬
‭discontinuation of study drug by‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based non-serious‬
‭TEAEs by action taken,‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based TEAEs by‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based TEAEs by‬
‭relationship, MedDRA SOC and‬
‭PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based TEAEs by‬
‭CTCAE grade, MedDRA SOC‬
‭and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based TEAEs by‬
‭MedDRA SOC and PT resulting‬
‭in permanent discontinuation of‬
‭study drug by MedDRA SOC‬
‭and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient t based TEAEs by action‬
‭taken, MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based non-serious‬
‭TEAEs by MedDRA SOC and‬
‭PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
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‭Patient based non-serious‬
‭related TEAEs by MedDRA‬
‭SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based non-serious‬
‭TEAEs by relationship,‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based non-serious‬
‭TEAEs by CTCAE grade,‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based non-serious‬
‭TEAEs resulting in permanent‬
‭discontinuation of study drug by‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based non-serious‬
‭TEAEs by action taken,‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭14.3.2 Deaths, Other Serious and Significant Adverse Events‬
‭Event based serious TEAEs by‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based serious related‬
‭TEAEs by MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based serious TEAEs by‬
‭relationship, MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based serious TEAEs by‬
‭CTCAE grade, MedDRA SOC‬
‭and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based serious TEAEs‬
‭resulting in permanent‬
‭discontinuation of study drug by‬
‭MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based TEAEs leading to‬
‭death by MedDRA SOC and PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Event based serious TEAEs by‬
‭action taken, MedDRA SOC and‬
‭PT‬
‭Total number of TEAEs‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based serious TEAEs by‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based serious related‬
‭TEAEs by MedDRA SOC and‬
‭PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based serious TEAEs by‬
‭relationship, MedDRA SOC and‬
‭PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based serious TEAEs by‬
‭CTCAE grade, MedDRA SOC‬
‭and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based serious TEAEs‬
‭resulting in permanent‬
‭discontinuation of study drug by‬
‭MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭Patient based TEAEs leading to‬
‭death by MedDRA SOC and PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
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‭Patient based serious TEAEs by‬
‭action taken, MedDRA SOC and‬
‭PT‬
‭Total number of patients‬
‭MedDRA SOC and PT‬
‭SAF‬
‭In total and by‬
‭treatment arm‬
‭14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events‬
‭No TFL output, only heading for report‬
‭14.3.4 Laboratory Data and Other Safety Variables‬
‭Laboratory data‬
‭Laboratory – sampling and‬
‭fasting condition‬
‭Were any lab samples obtained?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Was Patient fasting?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Unknown‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – pregnancy test‬
‭Were any lab samples for pregnancy test obtained?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes:‬
‭Sample‬
‭Total‬
‭Serum‬
‭Urine‬‭(not at Baseline visit)‬
‭Result of pregnancy test‬
‭Total‬
‭Missing‬
‭Negative‬
‭Positive‬
‭Subgroup of females‬
‭with child bearing‬
‭potential‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit (only those‬
‭visits where pregnancy‬
‭test is mandatory or‬
‭optional performed‬
‭tests)‬
‭Laboratory – Hematology‬
‭sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Hematology‬
‭results‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Hematology‬
‭results, change from baseline‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Hematology‬
‭results, categorical analysis‬
‭Per laboratory parameter‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
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‭Laboratory – Serum‬
‭Biochemistry sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum‬
‭Biochemistry results‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum‬
‭Biochemistry results, change‬
‭from baseline‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum‬
‭Biochemistry results, categorical‬
‭analysis‬
‭Per laboratory parameter‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Urinalysis sample‬
‭collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Urinalysis results‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Urinalysis results,‬
‭change from baseline‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Urinalysis results‬
‭results, categorical analysis‬
‭Per laboratory parameter‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Dipstick Urinalysis‬
‭sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Dipstick Urinalysis‬
‭results‬
‭pH‬
‭Total‬
‭Missing‬
‭<=4.5‬
‭5.0‬
‭5.5‬
‭6.0‬
‭6.5‬
‭7.0‬
‭7.5‬
‭>=8.0‬
‭Proteins, Glucose, Blood, Ketones, WBC‬
‭Total‬
‭Missing‬
‭Negative‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
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‭Trace‬
‭1+‬
‭2+‬
‭3+‬
‭4+‬
‭Laboratory – Coagulation‬
‭sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Coagulation‬
‭results‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Coagulation‬
‭results, change from baseline‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Coagulation‬
‭results, categorical analysis‬
‭Per laboratory parameter‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum Lipide‬
‭profile sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum Lipide‬
‭profile results‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum Lipide‬
‭profile results, change from‬
‭baseline‬
‭Per laboratory parameter in SI unit‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Serum Lipide‬
‭profile results, categorical‬
‭analysis‬
‭Per laboratory parameter‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Vitamin B‬‭12‬‭test‬
‭sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Vitamin B‬‭12‬‭test‬
‭results‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Vitamin B‬‭12‬‭test,‬
‭change from baseline‬
‭Quantitative statistical parameters‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭SEQTOR‬
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‭Laboratory – Vitamin B‬‭12‬‭test,‬
‭categorical analysis‬
‭Total‬
‭LLN‬
‭Normal‬
‭ULN‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Abnormal laboratory values‬
‭CTCAE grades 1-4‬
‭Per CTCAE Term (as specified in section 7.3.2)‬
‭Total‬
‭Grade 1‬
‭Grade 2‬
‭Grade 3‬
‭Grade 4‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – CgA‬
‭Quantitative statistical parameters‬
‭ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – CgA, change from‬
‭baseline‬
‭Quantitative statistical parameters‬
‭including p-value‬
‭ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Circulating tumor‬
‭cells‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭by central assessor‬
‭Laboratory – Circulating tumor‬
‭cells, change from baseline‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭by central assessor‬
‭Laboratory – NETest score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭by central assessor‬
‭Laboratory – NETest score,‬
‭change from baseline‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭by central assessor‬
‭Laboratory – Hepatitis viremia‬
‭sample collection‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Laboratory – Hepatitis viremia‬
‭results‬
‭Per laboratory parameter‬
‭Total‬
‭Missing‬
‭negative‬
‭positive‬
‭Only at Screening:‬
‭Is Patient being monitored routinely for HBV-DNA?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Not applicable‬
‭Is Patient being monitored routinely for HCV-RNA?‬
‭Total‬
‭Missing‬
‭Yes‬
‭Subgroup of patients‬
‭with collected sample‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
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‭No‬
‭Not applicable‬
‭Collection of paraffin embedded‬
‭tumor block at screening‬
‭Was a Paraffin Embedded Tumour Block collected?‬
‭(Inclusion criteria No.4)‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Time from date of ICF to collection date of Paraffin‬
‭Embedded Tumour Block‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Other safety data‬
‭Physical examination post‬
‭baseline‬
‭Performance of physical examination post baseline‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Any changes from the previous visit?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes:‬
‭Separately by body system‬
‭General Appearance‬
‭Skin‬
‭[…]‬
‭Basic Nervous System‬
‭Other (MedDRA PT)‬
‭Total‬
‭Missing‬
‭Normal‬
‭Abnormal, not clinically significant‬
‭Abnormal, clinically significant‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭ECOG performance status post‬
‭baseline‬
‭Total‬
‭Missing‬
‭0: Fully active […]‬
‭1: Restricted in physically strenuous activity […]‬
‭2: Ambulatory and capable of all selfcare […]‬
‭3: Capable of only limited selfcare […]‬
‭4: Completely disabled […]‬
‭5: Dead‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭12 lead-ECG worst documented‬
‭diagnosis post baseline‬
‭Total‬
‭Missing‬
‭Normal‬
‭Abnormal, not clinically significant‬
‭Abnormal, clinically significant‬
‭Non-evaluable‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Weight and BMI post baseline‬
‭and change from baseline‬
‭Body weight [kg]‬
‭Body weight [kg] – change from baseline‬
‭BMI [kg/m²]‬
‭BMI [kg/m²] – change from baseline‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
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‭Vital signs post baseline and‬
‭change from baseline‬
‭Performance of vital signs assessment‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If yes:‬
‭Separately by measurement‬
‭Systolic blood pressure [mmHg]‬
‭Systolic blood pressure [mmHg] – change from baseline‬
‭Diastolic blood pressure [mmHg]‬
‭Diastolic blood pressure [mmHg] – change from baseline‬
‭Heart rate [beats per minute]‬
‭Heart rate [beats per minute] – change from baseline‬
‭Body temperature [°C]‬
‭Body temperature [°C] – change from baseline‬
‭Respiration Rate [breaths per minute]‬
‭Respiration Rate [breaths per minute] – change from‬
‭baseline‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Follow up (30 days and survival)‬
‭Kind of follow-up‬
‭Missing‬
‭Visit‬
‭Phone Contact‬
‭Other‬
‭Is the Subject alive‬
‭Missing‬
‭Yes‬
‭No‬
‭Unknown‬
‭If no, cause of death:‬
‭Total‬
‭Missing‬
‭Disease Progression‬
‭Toxicity‬
‭Chronic disease not related to an AE or to progression‬
‭Other cause (adhoc codes)‬
‭If yes, did the subject receive any anticancer treatment after‬
‭discontinuation of study treatment / since last visit?‬
‭Total‬
‭Yes‬
‭No‬
‭Unknown‬
‭If yes, specify therapy type:‬
‭Total‬
‭Biotherapy‬
‭Chemotherapy‬
‭Hormonal therapy‬
‭Immunotherapy‬
‭Targeted therapy‬
‭Peptide Receptor Radionucleic Therapy (PRRT)‬
‭Radiofrequency ablation (RFA)‬
‭Radioembolization (SIRF)‬
‭Selective Chemo embolization (TACE)‬
‭Cryoablation‬
‭Biopsy‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭SEQTOR‬
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‭Other‬
‭14.4 Other data‬
‭Number of patients consented‬
‭per protocol version‬
‭Total‬
‭Missing‬
‭Version 2.0, 30th of January 2014‬
‭Version 2.01, 1st of September 2014‬
‭Version 3.0, 26th of November 2014‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Did the Subject sign the‬
‭Informed Consent for the‬
‭optional CTC and NETest Sub‬
‭Studies?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Not applicable (starting only with Prot. Vers. 3.0)‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Chest X-Ray‬
‭Total‬
‭Missing‬
‭Normal‬
‭Clinically insignificant abnormality‬
‭Clinically significant abnormality‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Pulmonary function test‬
‭Spirometry done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If, yes:‬
‭Findings‬
‭Total‬
‭Missing‬
‭Normal‬
‭Clinically insignificant abnormality‬
‭Clinically significant abnormality‬
‭Other‬
‭Diffusion Capacity for CO (DLCO) done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If, yes:‬
‭Findings‬
‭Total‬
‭Missing‬
‭Normal‬
‭Clinically insignificant abnormality‬
‭Clinically significant abnormality‬
‭Other‬
‭Pulse Oximetry done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If, yes:‬
‭Findings‬
‭Total‬
‭Missing‬
‭Normal‬
‭Clinically insignificant abnormality‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭SEQTOR‬
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‭Clinically significant abnormality‬
‭Other‬
‭Bronchoscopy‬
‭Was Infection Agent identified?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Was Broncho-Alveloar Lavage (BAL) done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Was BAL Cell Count done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Was Alveolar Hemorrhage seen?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭Findings‬
‭Total‬
‭Missing‬
‭Normal‬
‭Clinically insignificant abnormality‬
‭Clinically significant abnormality‬
‭Other‬
‭Was Transbronchial Biopsy done?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭If, yes:‬
‭Findings‬
‭Total‬
‭Missing‬
‭Malignancy‬
‭Infection‬
‭Non-infectious Pneumonitis‬
‭Other‬
‭If, non-infectious Pneumonitis:‬
‭Specification of non-infectious Pneumonitis‬
‭Total‬
‭Missing‬
‭Lymphoid interstitial pneumonia (LIP)‬
‭Organizing Pneumonia‬
‭Other‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Patient questionnaires‬
‭Check for patient questionnaires‬
‭Was the EORTC QLQ-C30 completed by the patient?‬
‭Total‬
‭Missing‬
‭Yes‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭SEQTOR‬
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‭No‬
‭Was the EORTC QLQ GINET21 completed by the patient?‬
‭Total‬
‭Missing‬
‭Yes‬
‭No‬
‭EORTC QLQ-C30, global health‬
‭status / QoL score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, physical‬
‭functioning score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, role‬
‭functioning score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, emotional‬
‭functioning score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, cognitive‬
‭functioning score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, social‬
‭functioning score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, fatigue‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, nausea and vomiting‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, pain‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, dyspnoea‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, insomnia‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, appetite loss‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, constipation‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, diarrhoea‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, symptom‬
‭score, financial difficulties‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-C30, global health‬
‭status/ QoL frequency table‬
‭29. How would you rate your overall health during the past‬
‭week?‬
‭30. How would you rate your overall quality of life during the‬
‭past week?‬
‭Total‬
‭Missing‬
‭1 (very poor)‬
‭SEQTOR‬
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‭2‬
‭3‬
‭4‬
‭5‬
‭6‬
‭7 (excellent)‬
‭EORTC QLQ-C30, functional‬
‭scales, physical functioning‬
‭items frequency table‬
‭1.  Do you have any trouble doing strenuous activities, like‬
‭carrying a heavy shopping bag or a suitcase?‬
‭2. Do you have any trouble taking a long walk?‬
‭3.  Do you have any trouble taking a short walk outside of‬
‭the house?‬
‭4.  Do you need to stay in bed or a chair during the day?‬
‭5.  Do you need help with eating, dressing, washing yourself‬
‭or using the toilet?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, functional‬
‭scales, role functioning items‬
‭frequency table‬
‭6.‬ ‭Were you limited in doing either your work or‬‭other daily‬
‭activities?‬
‭7. Were you limited in pursuing your hobbies or other‬
‭leisure time activities?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, functional‬
‭scales, emotional functioning‬
‭items frequency table‬
‭21. Did you feel tense?‬
‭22.‬‭Did you worry?‬
‭23.‬‭Did you feel irritable?‬
‭24.‬‭Did you feel depressed?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, functional‬
‭scales, cognitive functioning‬
‭items frequency table‬
‭20.‬‭Have you had difficulty in concentrating on things,‬‭like‬
‭reading a newspaper or watching television?‬
‭25. Have you had difficulty remembering things?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, functional‬
‭scales, social functioning items‬
‭frequency table‬
‭26.‬‭Has your physical condition or medical treatment‬
‭interfered with your family life?‬
‭27.‬‭Has your physical condition or medical treatment‬
‭interfered with your social activities?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SEQTOR‬
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‭EORTC QLQ-C30, symptoms‬
‭scales, fatigue items frequency‬
‭table‬
‭10.‬‭Did you need to rest?‬
‭12.‬‭Have you felt weak?‬
‭18. Were you tired?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, nausea and vomiting‬
‭items frequency table‬
‭14. Have you felt nauseated?‬
‭15. Have you vomited?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, pain items frequency‬
‭table‬
‭9.  Have you had pain?‬
‭19. Did pain interfere with your daily activities?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, dyspnoea frequency‬
‭table‬
‭8. Were you short of breath?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, insomnia frequency‬
‭table‬
‭11. Have you had trouble sleeping?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, appetite loss frequency‬
‭table‬
‭13. Have you lacked appetite?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, constipation frequency‬
‭table‬
‭16. Have you been constipated?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-C30, symptoms‬
‭scales, diarrhoea frequency‬
‭table‬
‭17. Have you had diarrhea?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SEQTOR‬
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‭EORTC QLQ-C30, symptoms‬
‭scales, financial difficulties‬
‭frequency table‬
‭28. Has your physical condition or medical treatment‬
‭caused you financial difficulties?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭EORTC QLQ-GINET21,‬
‭endocrine symptoms score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, G.I.‬
‭symptoms score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21,‬
‭treatment related symptoms‬
‭score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, social‬
‭function score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, disease‬
‭related worries score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, muscle‬
‭/bone pain symptom score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, sexual‬
‭function score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21,‬
‭Information / communication‬
‭function score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, body‬
‭Image score‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21,‬
‭endocrine symptoms items‬
‭frequency table‬
‭31.‬‭Did you have hot flushes?‬
‭32. Have you noticed or been told by others that you looked‬
‭flushed/red?‬
‭33. Did you have night sweats?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, G.I.‬
‭symptoms items frequency table‬
‭34. Did you have abdominal discomfort?‬
‭35. Did you have a bloated feeling in your abdomen?‬
‭36. Have you had a problem with passing wind/gas‬
‭flatulence?‬
‭37. Have you had a acid indigestion or heartburn?‬
‭38. Have you had difficulties with eating?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭SEQTOR‬
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‭EORTC QLQ-GINET21,‬
‭treatment related symptoms‬
‭items frequency table‬
‭39. Have you had side-effects from your treatment?‬
‭40. Have you had a problem from repeated injections?‬
‭Total‬
‭Missing‬
‭N/A‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭46. Has weight gain been a problem for you?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, social‬
‭function items frequency table‬
‭42. Were you concerned about disruption of home life?‬
‭44. How distressing has your illness or treatment been to‬
‭those close to you?‬
‭49. Did you have any limitations in your ability to travel?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, disease‬
‭related worries items frequency‬
‭table‬
‭41. Were you worried about the tumor recurring in other‬
‭areas of the body?‬
‭43. Have you worried about your health in the future?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭47. Did your worry about the results of your tests?‬
‭Total‬
‭Missing‬
‭N/A‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, muscle‬
‭/bone pain symptom item‬
‭frequency table‬
‭48. Have you had aches or pains in your muscles or bones?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, sexual‬
‭function item frequency table‬
‭51. Has the disease or treatment affected your sex life (for‬
‭the worse)?‬
‭Total‬
‭Missing‬
‭N/A‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭SEQTOR‬
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‭Page‬‭65‬‭of‬‭68‬

‭EORTC QLQ-GINET21,‬
‭Information / communication‬
‭function item frequency table‬
‭50. Have you had problems receiving adequate information‬
‭about  your disease and treatment?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭EORTC QLQ-GINET21, body‬
‭image item frequency table‬
‭45. Has weight loss been a problem for you?‬
‭Total‬
‭Missing‬
‭Not at all‬
‭A little‬
‭Quite a bit‬
‭Very much‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭by visit‬
‭Resource utilization‬
‭Resource utilization -‬
‭hospitalization‬
‭Total number of documented hospital admissions‬
‭Main reason for hospitalization‬
‭Missing‬
‭Treatment‬
‭AE‬
‭Other‬
‭Hospital wards‬
‭Missing‬
‭Oncology‬
‭Internal Medicine‬
‭Neurology‬
‭Intensive Care Unit‬
‭Step down ward‬
‭Chemotherapy administration‬
‭Pneumology‬
‭Gastroenterology/Digestive‬
‭Cardiology‬
‭Other‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Resource utilization -‬
‭hospitalization‬
‭Number of nights‬
‭Quantitative statistical parameters‬
‭SAF, ITT, PP‬
‭by treatment arm, by‬
‭hospital ward‬
‭Resource utilization – outpatient‬
‭visit‬
‭Total number of documented outpatient visits‬
‭Main reason for visit‬
‭Missing‬
‭Treatment‬
‭AE‬
‭Other‬
‭Physician speciality‬
‭Missing‬
‭Oncologist‬
‭General medicine‬
‭Pneumologist‬
‭Hematologist‬
‭Cardiologist‬
‭Gastroenterologist‬
‭Endocrinologist‬
‭Nurse (Oncology, general medicine)‬
‭Other‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭SEQTOR‬
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‭Resource utilization –‬
‭diagnostics related to AEs‬
‭Total number of documented diagnostics related to AEs‬
‭Diagnostics performed (multiple response)‬
‭Missing‬
‭Broncoscopy‬
‭Pulmonary function test‬
‭Biopsy‬
‭CT Scan‬
‭RMN‬
‭Chest X- ray‬
‭Chest CT‬
‭ECG‬
‭Laboratory test‬
‭Physical examination‬
‭Other‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭Resource utilization –‬
‭procedures related to AEs‬
‭Total number of documented procedures related to AEs‬
‭Procedures performed (multiple response)‬
‭Missing‬
‭Surgery‬
‭Dialysis‬
‭Drug prescription and treatment‬
‭Study treatment interruption‬
‭Other‬
‭SAF, ITT, PP‬
‭by treatment arm‬
‭16.2 Patient Data Listings‬
‭Listing of patients discontinued‬
‭from study‬
‭Center, Patient number, randomized treatment sequence,‬
‭treatment before discontinuation, sex, age, reason for‬
‭discontinuation‬
‭Listing of protocol deviations‬
‭Center, Patient number, randomized treatment sequence, sex,‬
‭age, description of protocol deviation‬
‭Listing of patients excluded from‬
‭the efficacy analysis‬
‭Center, Patient number, randomized treatment sequence, sex,‬
‭age, reason from exclusion from the analysis populations‬
‭Listing of demographic and‬
‭disease diagnosis data‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, race, inclusion into analysis sets, first diagnosis data (date‬
‭of first diagnosis, primary site of tumor, ENETS TMN‬
‭classification), diagnosis data at study entry (date of‬
‭confirmation, ENETS TNM classification, location of tumor)‬
‭Listing of local radiological‬
‭tumor assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, evaluation timepoint, date of assessment, type, location,‬
‭overall response according to RECIST 1.0‬
‭Listing of central radiological‬
‭tumor assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, evaluation timepoint, date of assessment, type, location,‬
‭tumor density, , overall response according to RECIST‬
‭1.0/1.1/ENETS score 1.0/1.1,‬
‭Listing of target lesions of local‬
‭radiological tumor assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, location, status, date, longest diameter, reappearance,‬
‭disappearance‬
‭Listing of target lesions of‬
‭central radiological tumor‬
‭assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, location, status, date, longest diameter, short axis,‬
‭reappearance, disappearance‬
‭Listing of non-target lesions of‬
‭local radiological tumor‬
‭assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, date, status‬
‭Listing of non-target lesions of‬
‭central radiological tumor‬
‭assessments‬
‭Center, Patient number, randomized treatment sequence, age,‬
‭sex, date, status‬
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‭Listing of adverse events‬
‭Center, Patient number, randomized treatment sequence,‬
‭treatment age, sex, AE term including MedDRA PT, start date,‬
‭end date, duration, TEAE, time since first intake of treatment to‬
‭AE onset, SAE and details, CTCAE grade/severity, relationship,‬
‭action taken, additional therapy, dechallenge, rechallenge,‬
‭outcome‬
‭Listing of serious adverse‬
‭events‬
‭Center, Patient number, randomized treatment sequence,‬
‭treatment age, sex, AE term including MedDRA PT, start date,‬
‭end date, duration, TEAE, time since first intake of treatment to‬
‭AE onset, SAE and details, CTCAE grade/severity, relationship,‬
‭action taken, additional therapy, dechallenge, rechallenge,‬
‭outcome‬
‭Listing of deaths‬
‭Center, Patient number, randomized treatment sequence,‬
‭treatment age, sex, AE term including MedDRA PT, start date,‬
‭end date, duration, TEAE, time since first intake of treatment to‬
‭AE onset, SAE and details, CTCAE grade/severity, relationship,‬
‭action taken, additional therapy, dechallenge, rechallenge,‬
‭outcome‬
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