Advanced and Metastatic Silent Neuro-Endocrine Tumors, Carcinoids, Carcinoma, Neuroendocrine, Non Functioning, Non Functioning Neuroendocrine Tumors (NETs), Non Syndromic Neuroendocrine Tumors
Conditions
Keywords
Neuroendocrine tumors, non functioning neuroendocrine tumors, Non syndromic neuroendocrine tumors, carcinoids, non-functioning carcinoids, adults, everolimus, NET, RAMSETE, CRAD001, non-functioning neuroendocrine tumors carcinoids
Brief summary
To evaluate the preliminary efficacy and safety of RAD001 as monotherapy for first-line treatment of patients with metastatic papillary carcinoma of the kidney.
Interventions
DRUGEverolimus
Everolimus 5 mg tablets were supplied in blister packs
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥ 18 years old 2. Patients with advanced (unresectable or metastatic) biopsy proven non-syndromic neuro-endocrine carcinoma, low or intermediate grade 3. Radiological documentation of disease progression within 12 months prior to study entry. If patients received anti-tumor therapy during the past 12 months, they must have radiological documentation of progressive disease (PD) while on or after receiving the therapy 4. Patients may have received previous treatments (chemotherapy, biotherapy, peptide-receptor radionuclide therapy); an overall maximum of 3 systemic treatment is allowed 5. Patients with at least one measurable lesion 6. Patients with an ECOG (Eastern Cooperative Oncology Group) Performance Status 0-2 7. Adequate bone marrow function 8. Adequate liver function 9. Adequate renal function 10. Adequate lipid profile
Exclusion criteria
1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma 2. Patients with carcinoid with hormone related symptoms (diarrhea ≥ 4 stools per day and/or flushes) 3. Patients with Islet cell carcinomas or pancreatic NET 4. Patients who received prior therapy with Vascular Endothelial Growth Factor (VEGF) pathway inhibitor within 4 weeks prior to study entry 5. Patients who entered peptide receptor radionuclide therapy (PRRT) within 3 months prior to study entry 6. Patients who received CT, biotherapy or radiotherapy within 4 weeks prior to study entry 7. Patients who have previously received systemic (mammalian target of rapamycin) mTOR inhibitors 8. Patients with a known hypersensitivity to everolimus or other rapamycins or to its excipients 9. Patients with uncontrolled central nervous system (CNS) metastases 10. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent 11. Patients with a known history of HIV seropositivity 12. Patients with autoimmune hepatitis 13. Patients with an active, bleeding diathesis 14. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study 15. Patients who have a history of another primary malignancy and off treatment ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix 16. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods 17. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start 18. Patients unwilling to or unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response Rate at 12 Months ITT Set | baseline up to approximately 12 months | Overall Response Rate (ORR) was presented for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CL; computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. |
| Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | baseline up to approximately 12 months | Overall response rate (ORR) was based on RECIST central assessment and defined as the percentage of patients with best overall response (BOR) of a confirmed complete response (CR) or partial response (PR). The BOR was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments obtained within 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions. |
| Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP) | baseline up to approximately 12 months | Overall Response Rate (ORR) was calculated for total PP population based on central review as confirmatory, primary analysis as well as for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CI) computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. The primary analysis was based on the PP Set |
| Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | baseline up to approximately 12 months | The best overall response (BOR) was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed not less than 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets | baseline up to approximately 12 months | DCR was based on central radiologic review and is defined as the percentage of patients with a best overall response of 'Complete response' (CR), 'Partial response' (PR) or 'Stable disease' (SD). Relative frequencies together with their exact 2-sided 80% confidence intervals were presented |
| Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA) | baseline up to approximately 12 months | Biochemical response was defined as level and change from baseline in CgA during the course of the trial. The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers. |
| Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets | baseline up to approximately 12 months | Duration of PFS was defined as the time from first study drug administration to objective tumor progression or death from any cause. Observations from patients not experiencing tumor progression or death at date of database closure were censored with the date of their last adequate tumor assessment. Progression was either 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline or 2) the appearance of a new lesion or 3) the unequivocal progression of non-target lesions. |
| Overall Survival (OS) for Per Protocol (PP) and ITT Sets | baseline up to approximately 15 months | OS was defined as the time from first study drug administration to death from any cause. If a patient was not known to have died at date of database closure, overall survival was censored at the date of last contact. |
Countries
France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom
Participant flow
Pre-assignment details
Eighty-two patients were screened and 73 were treated with study drug.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus 10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | abnormal lab value | 1 |
| Overall Study | Adverse Event | 22 |
| Overall Study | Death | 3 |
| Overall Study | disease progression | 23 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Continuous | 59.9 years STANDARD_DEVIATION 13 |
| Race/Ethnicity, Customized Caucasian | 71 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 40 Participants |
| Time since first diagnosis ≥ 10 years | 6 Participants |
| Time since first diagnosis < 1 year | 19 Participants |
| Time since first diagnosis 1 year to < 3 years | 26 Participants |
| Time since first diagnosis 3 years to < 6 years | 17 Participants |
| Time since first diagnosis 6 years to < 10 years | 3 Participants |
| Time since first diagnosis Missing | 2 Participants |
| Tumor histology/cytology Bronchial (thymic) carcinoid -atypical | 12 Participants |
| Tumor histology/cytology Bronchial (thymic) carcinoid -typical | 9 Participants |
| Tumor histology/cytology Neuroendocrine carcinoma | 36 Participants |
| Tumor histology/cytology Neuroendocrine tumor | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 72 / 73 |
| serious Total, serious adverse events | 48 / 73 |
Outcome results
Primary
Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP)
Overall response rate (ORR) was based on RECIST central assessment and defined as the percentage of patients with best overall response (BOR) of a confirmed complete response (CR) or partial response (PR). The BOR was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments obtained within 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions.
Time frame: baseline up to approximately 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Complete response (CR) | 0.0 percentage of participants |
| Everolimus | Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Partial response | 0.0 percentage of participants |
| Everolimus | Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Stable disease (SD) | 56.7 percentage of participants |
| Everolimus | Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Progressive disease (PD) | 43.3 percentage of participants |
| Everolimus | Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Unknown | 0.0 percentage of participants |
Primary
Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set
The best overall response (BOR) was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed not less than 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions.
Time frame: baseline up to approximately 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | Complete response (CR) | 0.0 percentage of participants |
| Everolimus | Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | Partial response | 0.0 percentage of participants |
| Everolimus | Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | Stable disease (SD) | 74.0 percentage of participants |
| Everolimus | Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | Progressive disease (PD) | 16.4 percentage of participants |
| Everolimus | Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | Unknown | 9.6 percentage of participants |
Primary
Percentage of Participants With Objective Response Rate at 12 Months ITT Set
Overall Response Rate (ORR) was presented for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CL; computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected.
Time frame: baseline up to approximately 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Percentage of Participants With Objective Response Rate at 12 Months ITT Set | 0.0 percentage of participants |
Primary
Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP)
Overall Response Rate (ORR) was calculated for total PP population based on central review as confirmatory, primary analysis as well as for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CI) computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. The primary analysis was based on the PP Set
Time frame: baseline up to approximately 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP) | 0.0 percentage of participants |
Secondary
Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets
Duration of PFS was defined as the time from first study drug administration to objective tumor progression or death from any cause. Observations from patients not experiencing tumor progression or death at date of database closure were censored with the date of their last adequate tumor assessment. Progression was either 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline or 2) the appearance of a new lesion or 3) the unequivocal progression of non-target lesions.
Time frame: baseline up to approximately 12 months
Population: subjects who met required criteria
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets | PFS days for Per protocol set | 185 days |
| Everolimus | Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets | PFS days for Intent to treat set | 190 days |
Secondary
Overall Survival (OS) for Per Protocol (PP) and ITT Sets
OS was defined as the time from first study drug administration to death from any cause. If a patient was not known to have died at date of database closure, overall survival was censored at the date of last contact.
Time frame: baseline up to approximately 15 months
Population: subjects who met required criteria
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Overall Survival (OS) for Per Protocol (PP) and ITT Sets | OS for Per protocol set | 451.8 days | Standard Error 19.8 |
| Everolimus | Overall Survival (OS) for Per Protocol (PP) and ITT Sets | OS for Intent to treat set | 437.1 days | Standard Error 18.6 |
Secondary
Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA)
Biochemical response was defined as level and change from baseline in CgA during the course of the trial. The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers.
Time frame: baseline up to approximately 12 months
Population: The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers.
Secondary
Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets
DCR was based on central radiologic review and is defined as the percentage of patients with a best overall response of 'Complete response' (CR), 'Partial response' (PR) or 'Stable disease' (SD). Relative frequencies together with their exact 2-sided 80% confidence intervals were presented
Time frame: baseline up to approximately 12 months
Population: subjects who met required criteria
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets | DCR for Per protocol set | 56.7 percentage of participants |
| Everolimus | Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets | DCR for Intent to treat set | 50.7 percentage of participants |