Neuroendocrine Tumors
Conditions
Keywords
advanced pNET, everolimus, STZ-5FU, treatment sequence
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
Interventions
DRUGDrug: Everolimus
10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.
DRUGSTZ-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.
Sponsors
European Neuroendocrine Tumor Society
Kantar Health
Novartis Pharmaceuticals
Grupo Espanol de Tumores Neuroendocrinos
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 94 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Progression Free Survival (PFS1) | At 12 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Second Progression Free Survival (Second PFS) | Until the end of study every 12 weeks, approximately up to 5 years | 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 |
| Progression-free Survival (PFS) to First Treatment | Throughout the study period every 12 weeks, approximately up to 5 years | Time from the date of randomization to the date of first disease progression. |
| Adverse Events (AEs) Rate | Throughout the study period in continous monitoring at every visit for approximately up to 5 years | Number of patients expiriencing adverse events, treatment-related AEs and serious adverse events (SAEs) |
| Frequency of Dose Modifications to First Treatment | Throughout the study period, approximately up to 5 years | Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period |
| Best Overall Response (BOR) to First Study Treatment | Throughout the study period, every 12 weeks up to approximately 5 years | Best response achieved with the first study treatment according to RECIST V1.0 |
| Frequency of Dose Modifications to Second Treatment | Throughout the study period, approximately up to 5 years | Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period |
| Overall Survival (OS) | Throughout the study period, up to approximately 5 years | The median OS defined as the time from the date of randomization until death from any cause. This is estimated by kaplan meier method. |
| Best Overall Response (BOR) to Second Study Treatment | Throughout the study period, every 12 weeks up to approximately 5 years | Best response achieved with the second study treatment according to RECIST V1.0 |
| Objective Response Rate (ORR) to Second Study Treatment | Throughout the study period every 12 weeks, up to approximately 5 years | 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. |
| Progression-free Survival (PFS) to Second Treatment | Throughout the study period every 12 weeks, approximately up to 2 years | Time from the date of first dose of second treatment to the date of second disease progression. |
| Objective Response Rate (ORR) to First Study Treatment | Throughout the study period every 12 weeks, up to approximately 5 years | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | 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. | 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. |
Countries
Denmark, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 72 |
| 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. | 69 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Course Treatment | Adverse Event | 9 | 7 |
| First Course Treatment | Death | 3 | 3 |
| First Course Treatment | Not reported reasons | 6 | 7 |
| First Course Treatment | Not treated | 3 | 3 |
| First Course Treatment | Physician Decision | 9 | 9 |
| First Course Treatment | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Sequence A, Drug: Everolimus First | Sequence B, Drug: STZ - 5FU First | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 58 years |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline 0 | 50 Participants | 47 Participants | 97 Participants |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline 1 | 20 Participants | 22 Participants | 42 Participants |
| Eastern cooperative oncology group (ECOG) performance status (PS) at baseline 2 | 2 Participants | 0 Participants | 2 Participants |
| Ki-67 ≤ 2 | 9 Participants | 14 Participants | 23 Participants |
| Ki-67 3-20 | 62 Participants | 51 Participants | 113 Participants |
| Ki-67 Unknown | 1 Participants | 4 Participants | 5 Participants |
| Location of metastases at randomization Bone | 7 Participants | 10 Participants | 17 Participants |
| Location of metastases at randomization Liver | 61 Participants | 56 Participants | 117 Participants |
| Location of metastases at randomization Lung | 2 Participants | 3 Participants | 5 Participants |
| Location of metastases at randomization Lymph nodes | 4 Participants | 6 Participants | 10 Participants |
| M-distant metastases at inclusion M0 | 2 Participants | 6 Participants | 8 Participants |
| M-distant metastases at inclusion M1 | 69 Participants | 62 Participants | 131 Participants |
| M-distant metastases at inclusion Mx | 1 Participants | 1 Participants | 2 Participants |
| Number of previous systemic treatment lines 0 prior treatment lines | 36 Participants | 43 Participants | 79 Participants |
| Number of previous systemic treatment lines 1 prior treatment line | 32 Participants | 22 Participants | 54 Participants |
| Number of previous systemic treatment lines 2 prior treatment lines | 4 Participants | 4 Participants | 8 Participants |
| Previous treatments Others No | 71 Participants | 68 Participants | 139 Participants |
| Previous treatments Others Yes | 1 Participants | 1 Participants | 2 Participants |
| Previous treatments Radiopharmaceuticals No | 68 Participants | 66 Participants | 134 Participants |
| Previous treatments Radiopharmaceuticals Yes | 4 Participants | 3 Participants | 7 Participants |
| Previous treatments Somatostatic analogs No | 41 Participants | 45 Participants | 86 Participants |
| Previous treatments Somatostatic analogs Yes | 31 Participants | 24 Participants | 55 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 31 Participants | 25 Participants | 56 Participants |
| Sex: Female, Male Male | 41 Participants | 44 Participants | 85 Participants |
| Tumor Grade G1 | 9 Participants | 12 Participants | 21 Participants |
| Tumor Grade G2 | 63 Participants | 55 Participants | 118 Participants |
| Tumor Grade Unknown | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 105 | 35 / 104 |
| other Total, other adverse events | 68 / 105 | 62 / 104 |
| serious Total, serious adverse events | 28 / 105 | 26 / 104 |
Outcome results
Primary
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).
Time frame: At 12 months
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sequence A, Drug: Everolimus First | First Progression Free Survival (PFS1) | 71.4 percentage of patients alive and PD-free |
| Sequence B, Drug: STZ - 5FU First | First Progression Free Survival (PFS1) | 61.8 percentage of patients alive and PD-free |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.22995% CI: [0.32, 1.32]Regression, Cox
Secondary
Adverse Events (AEs) Rate
Number of patients expiriencing adverse events, treatment-related AEs and serious adverse events (SAEs)
Time frame: Throughout the study period in continous monitoring at every visit for approximately up to 5 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sequence A, Drug: Everolimus First | Adverse Events (AEs) Rate | AEs | 68 Patients |
| Sequence A, Drug: Everolimus First | Adverse Events (AEs) Rate | SAEs | 28 Patients |
| Sequence A, Drug: Everolimus First | Adverse Events (AEs) Rate | Treatment-related AEs | 66 Patients |
| Sequence B, Drug: STZ - 5FU First | Adverse Events (AEs) Rate | AEs | 62 Patients |
| Sequence B, Drug: STZ - 5FU First | Adverse Events (AEs) Rate | SAEs | 26 Patients |
| Sequence B, Drug: STZ - 5FU First | Adverse Events (AEs) Rate | Treatment-related AEs | 56 Patients |
Secondary
Best Overall Response (BOR) to First Study Treatment
Best response achieved with the first study treatment according to RECIST V1.0
Time frame: Throughout the study period, every 12 weeks up to approximately 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to First Study Treatment | Partial response (PR) | 5 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to First Study Treatment | Progression of the disease (PD) | 2 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to First Study Treatment | Stable disease (SD) | 58 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to First Study Treatment | Not evaluable (NE) | 1 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to First Study Treatment | Complete response (CR) | 3 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to First Study Treatment | Not evaluable (NE) | 2 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to First Study Treatment | Complete response (CR) | 3 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to First Study Treatment | Partial response (PR) | 17 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to First Study Treatment | Stable disease (SD) | 35 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to First Study Treatment | Progression of the disease (PD) | 9 Participants |
Secondary
Best Overall Response (BOR) to Second Study Treatment
Best response achieved with the second study treatment according to RECIST V1.0
Time frame: Throughout the study period, every 12 weeks up to approximately 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving the second treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to Second Study Treatment | Progression of the disease (PD) | 8 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to Second Study Treatment | Not evaluable (NE) | 2 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to Second Study Treatment | Complete response (CR) | 1 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to Second Study Treatment | Partial response (PR) | 10 Participants |
| Sequence A, Drug: Everolimus First | Best Overall Response (BOR) to Second Study Treatment | Stable disease (SD) | 15 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to Second Study Treatment | Stable disease (SD) | 20 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to Second Study Treatment | Progression of the disease (PD) | 8 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to Second Study Treatment | Partial response (PR) | 3 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to Second Study Treatment | Not evaluable (NE) | 2 Participants |
| Sequence B, Drug: STZ - 5FU First | Best Overall Response (BOR) to Second Study Treatment | Complete response (CR) | 0 Participants |
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
Time frame: Throughout the study period, approximately up to 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Frequency of Dose Modifications to First Treatment | 41 Patients |
| Sequence B, Drug: STZ - 5FU First | Frequency of Dose Modifications to First Treatment | 9 Patients |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.001Fisher Exact
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
Time frame: Throughout the study period, approximately up to 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving the second-line study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Frequency of Dose Modifications to Second Treatment | 5 Patients |
| Sequence B, Drug: STZ - 5FU First | Frequency of Dose Modifications to Second Treatment | 18 Patients |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.001Fisher Exact
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.
Time frame: Throughout the study period every 12 weeks, up to approximately 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sequence A, Drug: Everolimus First | Objective Response Rate (ORR) to First Study Treatment | CR / PR | 8 Participants |
| Sequence A, Drug: Everolimus First | Objective Response Rate (ORR) to First Study Treatment | SD / PD / NE | 61 Participants |
| Sequence B, Drug: STZ - 5FU First | Objective Response Rate (ORR) to First Study Treatment | CR / PR | 20 Participants |
| Sequence B, Drug: STZ - 5FU First | Objective Response Rate (ORR) to First Study Treatment | SD / PD / NE | 46 Participants |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.012Fisher Exact
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.
Time frame: Throughout the study period every 12 weeks, up to approximately 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs) receiving second study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sequence A, Drug: Everolimus First | Objective Response Rate (ORR) to Second Study Treatment | SD / PD / NE | 25 Participants |
| Sequence A, Drug: Everolimus First | Objective Response Rate (ORR) to Second Study Treatment | CR / PR | 11 Participants |
| Sequence B, Drug: STZ - 5FU First | Objective Response Rate (ORR) to Second Study Treatment | CR / PR | 3 Participants |
| Sequence B, Drug: STZ - 5FU First | Objective Response Rate (ORR) to Second Study Treatment | SD / PD / NE | 30 Participants |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.072Fisher Exact
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.
Time frame: Throughout the study period, up to approximately 5 years
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Overall Survival (OS) | 61.7 months |
| Sequence B, Drug: STZ - 5FU First | Overall Survival (OS) | 50.6 months |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.16895% CI: [0.86, 2.37]Regression, Cox
Secondary
Progression-free Survival (PFS) to First Treatment
Time from the date of randomization to the date of first disease progression.
Time frame: Throughout the study period every 12 weeks, approximately up to 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Progression-free Survival (PFS) to First Treatment | 19.4 months |
| Sequence B, Drug: STZ - 5FU First | Progression-free Survival (PFS) to First Treatment | 22.7 months |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.47495% CI: [0.77, 1.75]Regression, Cox
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.
Time frame: Throughout the study period every 12 weeks, approximately up to 2 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Progression-free Survival (PFS) to Second Treatment | 8.8 months |
| Sequence B, Drug: STZ - 5FU First | Progression-free Survival (PFS) to Second Treatment | 9.5 months |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.07995% CI: [0.94, 2.73]Log Rank
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
Time frame: Until the end of study every 12 weeks, approximately up to 5 years
Population: Patients diagnosed advanced progressive pancreatic neuroendocrine tumours (pNETs)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence A, Drug: Everolimus First | Second Progression Free Survival (Second PFS) | 37.5 months |
| Sequence B, Drug: STZ - 5FU First | Second Progression Free Survival (Second PFS) | 32.6 months |
Comparison: significant differences between both arms is assumed in case p-val \< 0.05p-value: 0.13595% CI: [0.9, 2.19]Regression, Cox
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.
Time frame: 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.
Population: Patients completing the QLQ questionnaires at any timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sequence A, Drug: Everolimus First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | Basal | 78.3 Score | Standard Deviation 17.6 |
| Sequence A, Drug: Everolimus First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | EOT | 68.4 Score | Standard Deviation 15.2 |
| Sequence A, Drug: Everolimus First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | L2C1 | 75.1 Score | Standard Deviation 16 |
| Sequence B, Drug: STZ - 5FU First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | Basal | 77.8 Score | Standard Deviation 12.1 |
| Sequence B, Drug: STZ - 5FU First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | L2C1 | 84.1 Score | Standard Deviation 9.5 |
| Sequence B, Drug: STZ - 5FU First | Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status | EOT | 75.4 Score | Standard Deviation 17.9 |