Clinical trial NCT02246127
Conditions: Neuroendocrine Tumors
Keywords: advanced pNET everolimus STZ-5FU treatment sequence
Sponsor: Grupo Espanol de Tumores Neuroendocrinos
Start date: 2014-10-27; Completion date: 2021-07-12
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare streptozotocin (STZ) vs everolimus as first line treatment for advanced pNET and to elucidate which sequence of STZ based chemotherapy and the mammalian Target of Rapamycin (mTOR) inhibitor, everolimus, gives better results in terms of second Progression Free Survival (PFS) in well differentiated and advanced pancreatic NETs.

Detailed description:
STZ plus 5-Fuorouracil (5FU) is the actual standard of care for advanced pancreatic Neuroendocrine tumours (pNETS) in the European Union. Everolimus has been recently approved for its use in advanced pNETs by the Food and Drug Administration (FDA) and in Europe by the European Medical Agency (EMA).

A randomized study is needed to have a clear knowledge about the best sequence for its administration; this is, before or after palliative chemotherapy.

There may or may not be any benefits from giving first each other treatment of the study. The information obtained from this study will help the physician improve the treatment and management of patients with advanced pNET.

This study was planned to compare STZ-5FU chemotherapy followed by everolimus upon progression versus the reverse sequence. However sequential studies with pNETs are hard to be managed in terms of time and costs. Therefore the protocol was amended to have PFS1 (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression free survival after both STZ based chemotherapy and Everolimus or the reverse order) as secondary endpoint. This information will be extremely valuable for the day to day clinical practice of pNETs oncologists

Arms: arm 1: Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). arm 2: STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)
Interventions: intervention 1: Drug: Everolimus intervention 2: STZ-5FU
Intervention descriptions: intervention 1: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. intervention 2: 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-5 every 6 weeks (Moertel) or 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-3, and then 1 day with 1g/m2 and 1 day 400mg/m2 5-FU every 3 weeks (Uppsala).

Number of Cycles: until progression or unacceptable toxicity develops.

Protocol documents:
Prot_SAP_000.pdf: 
‭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
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‭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
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‭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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‭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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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭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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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭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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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭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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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭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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‭SEQTOR Study                                                                                 Protocol code GETNE1206‬
‭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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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭●‬ ‭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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‭SEQTOR Study                                                                                     Protocol code GETNE1206‬
‭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.‬
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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.‬
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‭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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‭Page‬‭1‬‭of‬‭68‬


‭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
‭SEQTOR‬
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‭Page‬‭2‬‭of‬‭68‬


‭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
‭SEQTOR‬
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‭Page‬‭3‬‭of‬‭68‬


‭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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‭Page‬‭4‬‭of‬‭68‬


‭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
‭SEQTOR‬
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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:‬
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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.‬
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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
‭SEQTOR‬
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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
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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
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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
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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
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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)‬
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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
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‭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
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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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