Sequentiality of Everolimus and STZ-5FU in Advanced Pancr... | NCT02246127

NCT02246127

ID	Type	Description	Link
2013-000726-66	EudraCT Number

Status Module

Sponsor/Collaborators Module

Name	Class
European Neuroendocrine Tumor Society	UNKNOWN
Kantar Health	INDUSTRY
Novartis Pharmaceuticals	INDUSTRY

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sequence A, drug: everolimus first	Active Comparator	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).	Drug: Drug: Everolimus Drug: STZ-5FU
Sequence B, drug: STZ - 5FU first	Experimental	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)	Drug: Drug: Everolimus Drug: STZ-5FU

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Drug: Everolimus	Drug	10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.	Sequence A, drug: everolimus first Sequence B, drug: STZ - 5FU first

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
First Progression Free Survival (PFS1)	Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms Definitions for PFS rate for course 1 at 12 months: No: number (proportion) of patients who were not alive and progression free according to the respective definition (main, conservative, and optimistic); Yes: number (proportion) of patients who were alive and progression free according to the respective definition (main, conservative, and optimistic).	At 12 months

Secondary Outcomes

Measure	Description	Time Frame
Second Progression Free Survival (Second PFS)	PFS of Course 1 (PFS1) + interval between treatments + PFS of Course 2 (PFS2), where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2	Until the end of study every 12 weeks, approximately up to 5 years

Other Outcomes

Measure	Description	Time Frame
Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status	Patient self-reported quality of life (QoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the specific module for NETs, QLQ-GINET21. These questionnaires have a punctuation that ranges from 100 (best patient performance) to 0 (worse patient performance). Here we report the total QLQ-C30 score. Timepoints: Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT). Patients changed treatment line and ended both treatments after progression, therefore this outcome is not linked to specific reference timepoints but rather to a relevant disease stage which may happer early or latter in time. All assessments are performed obviously during trial duration, up to approximately 5 years.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.
Documented confirmation of pancreatic NET G1 or G2 as per European Neuroendocrine Society (ENETS) classification system.
Patients from whom a paraffin-embedded primary tumour or metastasis block is available and to be sent by Courier.
Before study inclusion, patients must show progressive disease documented by radiology 12 months prior to study inclusion. Treatment naive patients can be also included if the patient needs active treatment with either chemotherapy or everolimus.
Presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0, documented by a Triphasic Computed Tomography (CT) scan or multiphase MRI radiological assessment.
Previous treatment with somatostatin (SS) analogues is allowed. Only those patients with active functioning syndrome at entry can continue with SS analogues during the study.
Adequate bone marrow and renal functions, and serum fasting cholesterol
Women with child-bearing potential must have a negative serum pregnancy test.
Written Informed Consent obtained according to local regulations

Exclusion Criteria:

Previous treatment with chemotherapy and/or mTOR inhibitors or tyrosine kinase inhibitors.
Immune therapy or radiation therapy within 4 weeks prior to the patient entering the study.
Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/radiofrequency ablation of hepatic metastasis within 2 months of enrolment.
Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within the last 6 months and/or without progression following PRRT.
Uncontrolled diabetes mellitus.
Any severe and/or uncontrolled medical conditions.
Treatment with potent inhibitors or inducers of Cytochrome P450 3A4 (CYP3A) isoenzyme within 5 days immediately before the start of treatment.
Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.
Patients known to be HIV seropositive.
Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Known intolerance or hypersensitivity to 5FU or STZ or its excipients (notice that this criterion includes patients with known deficit of dihydropyrimidine dehydrogenase deficiency -DPD).
Pregnant, lactating women or fertile adults not using effective birth control methods.
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).

Contacts/Locations Module

Name	Affiliation	Role
Salazar Ramon, MD, PhD	Instituto Catalán de Oncologia, ICO-Hospitalet	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Aarhus Aarhus University Hospital NET Centre (AUH-NET)		Aarhus		8000	Denmark
Rigshospitalet NET CoE, University of Copenhagen

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Aug 7, 2018

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
BG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Median

Full Range

years

Title

Denominators

Categories

Title	Measurements
	OG00071.4(59.4 to 81.6) OG00161.8(49.2 to 73.3)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	significant differences between both arms is assumed in case p-val < 0.05	Regression, Cox		0.229		Odds Ratio (OR)	0.65			2-Sided	95	0.32	1.32					Superiority

Secondary

Second Progression Free Survival (Second PFS)

PFS of Course 1 (PFS1) + interval between treatments + PFS of Course 2 (PFS2), where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)

Posted

Median

95% Confidence Interval

months

Until the end of study every 12 weeks, approximately up to 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Progression-free Survival (PFS) to First Treatment

Time from the date of randomization to the date of first disease progression.

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)

Posted

Median

95% Confidence Interval

months

Throughout the study period every 12 weeks, approximately up to 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Adverse Events (AEs) Rate

Number of patients expiriencing adverse events, treatment-related AEs and serious adverse events (SAEs)

Patients who do not received study treatment were not included in the safety population to analyze safety.

The outcome is reported per arm, as the trial was designed to report which sequential strategy is the best in overall. Most patients with panNETs progress and therefore will require to go through both treatments. The main scientific interest is the overall safety/efficacy.

Posted

Number

Patients

Throughout the study period in continous monitoring at every visit for approximately up to 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Frequency of Dose Modifications to First Treatment

Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving study treatment.

Posted

Number

Patients

Throughout the study period, approximately up to 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Best Overall Response (BOR) to First Study Treatment

Best response achieved with the first study treatment according to RECIST V1.0

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving treatment.

Posted

Count of Participants

Participants

Throughout the study period, every 12 weeks up to approximately 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Objective Response Rate (ORR) to First Study Treatment

The ORR is defined as the number of patients having as their BOR to first treatment either Complete response (CR) or Partial Response (PR) measured by RECIST criteria version 1.0.

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving study treatment

Posted

Count of Participants

Participants

Throughout the study period every 12 weeks, up to approximately 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Frequency of Dose Modifications to Second Treatment

Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving the second-line study treatment.

Posted

Number

Patients

Throughout the study period, approximately up to 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Overall Survival (OS)

The median OS defined as the time from the date of randomization until death from any cause. This is estimated by kaplan meier method.

Intention to treat population. The outcome is reported per arm rather than intervention, as the trial was designed to demonstrate which sequential strategy is the best in overall. Most patients with panNETs progress and therefore will require to go through both treatments. The main scientific interest is the overall safety/efficacy.

Posted

Median

95% Confidence Interval

months

Throughout the study period, up to approximately 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Best Overall Response (BOR) to Second Study Treatment

Best response achieved with the second study treatment according to RECIST V1.0

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving the second treatment.

Posted

Count of Participants

Participants

Throughout the study period, every 12 weeks up to approximately 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Objective Response Rate (ORR) to Second Study Treatment

The ORR is defined as the number of patients having as their BOR to second treatment either Complete response (CR) or Partial Response (PR) measured by RECIST criteria version 1.0.

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving second study treatment

Posted

Count of Participants

Participants

Throughout the study period every 12 weeks, up to approximately 5 years

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.
OG001	Sequence B, Drug: STZ - 5FU First	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Other Pre-specified

Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status

Patient self-reported quality of life (QoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the specific module for NETs, QLQ-GINET21.

These questionnaires have a punctuation that ranges from 100 (best patient performance) to 0 (worse patient performance).

Here we report the total QLQ-C30 score.

Timepoints: Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT). Patients changed treatment line and ended both treatments after progression, therefore this outcome is not linked to specific reference timepoints but rather to a relevant disease stage which may happer early or latter in time. All assessments are performed obviously during trial duration, up to approximately 5 years.

Patients completing the QLQ questionnaires at any timepoint.

Posted

Mean

Standard Deviation

Score

Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT). See outcome measure description for further details.

ID	Title	Description
OG000	Sequence A, Drug: Everolimus First	Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. STZ-5FU: 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.

Secondary

Progression-free Survival (PFS) to Second Treatment

Time from the date of first dose of second treatment to the date of second disease progression.

Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)

Posted

Median

95% Confidence Interval

months

Throughout the study period every 12 weeks, approximately up to 2 years

ID	Title	Description
OG000	Sequence A, Drug: STZ-5FU Second	STZ-5FU: 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.
OG001	Sequence B, Drug: Everolimus Second	STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Everolimus	Drug: Everolimus: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.	26	105	28	105	68	105
EG001	STZ - 5FU	STZ-5FU: 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.	35	104	26	104	62	104

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fever	General disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0014 affected104 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0012 affected104 at risk
Sepsis	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0011 affected104 at risk
Hyperglycemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0002 affected105 at risk EG0010 affected104 at risk
Malaise	General disorders	MedDRA SOC	Systematic Assessment	EG0002 affected105 at risk EG0010 affected104 at risk
Infection without focus	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0002 affected105 at risk EG0010 affected104 at risk
Constipation	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0011 affected104 at risk
Hypertriglyceridemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Pain	General disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Dizziness	Nervous system disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Biliary tract infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Eczema	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Fatigue	General disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Nausea	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0011 affected104 at risk
Urinary tract infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0012 affected104 at risk
Anemia	Blood and lymphatic system disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Weight loss	Investigations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Lung infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0011 affected104 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Creatinine increased	Investigations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0011 affected104 at risk
Non-cardiac chest pain	General disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Gastritis	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0011 affected104 at risk
Infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Localized edema	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Dental caries	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Chronic kidney disease	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Enterocolitis	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Acute cholangitis	Hepatobiliary disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0012 affected104 at risk
Appendicitis	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Bacteremia	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Increased urea	Investigations	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Presyncope	Nervous system disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0010 affected104 at risk
Renal Calculi	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0012 affected104 at risk
Vomiting	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0012 affected104 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0012 affected104 at risk
Ascites	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Gastric hemorrhage	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Diarrhea	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Thromboembolic event	Vascular disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Rash acneiform	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Stomach pain	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Hematuria	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Urotelial carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Urinary tract obstruction	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Liver metastasis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Melaena	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Cholecystitis	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Hypertension	Vascular disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Renal colic	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk
Jaundice	Hepatobiliary disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0011 affected104 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fever	General disorders	MedDRA SOC	Systematic Assessment	EG00014 affected105 at risk EG0015 affected104 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00014 affected105 at risk EG00117 affected104 at risk
Hyperglycemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG00023 affected105 at risk EG0019 affected104 at risk
Constipation	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00010 affected105 at risk EG00115 affected104 at risk
Hypertriglyceridemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0008 affected105 at risk EG0010 affected104 at risk
Fatigue	General disorders	MedDRA SOC	Systematic Assessment	EG00039 affected105 at risk EG00137 affected104 at risk
Nausea	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00021 affected105 at risk EG00126 affected104 at risk
Urinary tract infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG00011 affected105 at risk EG0013 affected104 at risk
Anemia	Blood and lymphatic system disorders	MedDRA SOC	Systematic Assessment	EG00010 affected105 at risk EG0013 affected104 at risk
Weight loss	Investigations	MedDRA SOC	Systematic Assessment	EG0009 affected105 at risk EG0015 affected104 at risk
Lung infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0007 affected105 at risk EG0010 affected104 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0010 affected104 at risk
Creatinine increased	Investigations	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0016 affected104 at risk
Non-cardiac chest pain	General disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0014 affected104 at risk
Mucositis oral	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00034 affected105 at risk EG00116 affected104 at risk
Diarrhea	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00026 affected105 at risk EG00119 affected104 at risk
Rash acneiform	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG00026 affected105 at risk EG0014 affected104 at risk
Edema limbs	General disorders	MedDRA SOC	Systematic Assessment	EG00017 affected105 at risk EG0015 affected104 at risk
Anorexia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG00016 affected105 at risk EG00112 affected104 at risk
Vomiting	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG00012 affected105 at risk EG00113 affected104 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG00012 affected105 at risk EG0013 affected104 at risk
Platelet count decreased	Blood and lymphatic system disorders	MedDRA SOC	Systematic Assessment	EG00010 affected105 at risk EG0017 affected104 at risk
Flu like symptoms	General disorders	MedDRA SOC	Systematic Assessment	EG00010 affected105 at risk EG0019 affected104 at risk
Cholesterol high	Investigations	MedDRA SOC	Systematic Assessment	EG00010 affected105 at risk EG0012 affected104 at risk
Alanine aminotransferase increased	Investigations	MedDRA SOC	Systematic Assessment	EG0008 affected105 at risk EG0012 affected104 at risk
Dysgeusia	Nervous system disorders	MedDRA SOC	Systematic Assessment	EG0008 affected105 at risk EG0015 affected104 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA SOC	Systematic Assessment	EG0008 affected105 at risk EG0015 affected104 at risk
Hypertension	Vascular disorders	MedDRA SOC	Systematic Assessment	EG0008 affected105 at risk EG0011 affected104 at risk
Headache	Nervous system disorders	MedDRA SOC	Systematic Assessment	EG0007 affected105 at risk EG0013 affected104 at risk
Aspartate aminotransferase increased	Investigations	MedDRA SOC	Systematic Assessment	EG0007 affected105 at risk EG0011 affected104 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0007 affected105 at risk EG0018 affected104 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0010 affected104 at risk
Proteinuria	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0015 affected104 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0016 affected104 at risk
Hypophosphatemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0011 affected104 at risk
Stomach pain	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0006 affected105 at risk EG0013 affected104 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA SOC	Systematic Assessment	EG0005 affected105 at risk EG0017 affected104 at risk
Palmar-plantar erythrodysesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0005 affected105 at risk EG0014 affected104 at risk
Hypomagnesemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0011 affected104 at risk
Mouth ulcer	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0012 affected104 at risk
Hypokalemia	Metabolism and nutrition disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0011 affected104 at risk
Nail changes	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0012 affected104 at risk
GGT increased	Investigations	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0010 affected104 at risk
Upper respiratory infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0010 affected104 at risk
Insomnia	Psychiatric disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0018 affected104 at risk
Nail ridging	Skin and subcutaneous tissue disorders	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0010 affected104 at risk
Pharyngitis	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0010 affected104 at risk
Skin infection	Infections and infestations	MedDRA SOC	Systematic Assessment	EG0004 affected105 at risk EG0010 affected104 at risk
Febrile Neutropenia	Blood and lymphatic system disorders	MedDRA SOC	Systematic Assessment	EG0002 affected105 at risk EG0015 affected104 at risk
Thromboembolic event	Vascular disorders	MedDRA SOC	Systematic Assessment	EG0002 affected105 at risk EG0014 affected104 at risk
Pain in extremity	General disorders	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0016 affected104 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0014 affected104 at risk
Cramps	Musculoskeletal and connective tissue disorders	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0014 affected104 at risk
Dizziness	Nervous system disorders	MedDRA SOC	Systematic Assessment	EG0001 affected105 at risk EG0014 affected104 at risk
Alkaline phosphatase increased	Investigations	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0014 affected104 at risk
Dry mouth	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0003 affected105 at risk EG0014 affected104 at risk
Gastroesophageal reflux disease	Gastrointestinal disorders	MedDRA SOC	Systematic Assessment	EG0000 affected105 at risk EG0014 affected104 at risk

ID	Term
D018358	Neuroendocrine Tumors

ID	Term
D000068338	Everolimus

ID	Term
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D009380	Neoplasms, Nerve Tissue

ID	Term
D020123	Sirolimus
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals