Carcinoid Tumor, Malignant Carcinoid Syndrome
Conditions
Keywords
Cancer, Carcinoid, Tumor, Neuroendocrine, Carcinoma, Everolimus, Octreotide
Brief summary
The purpose of this study was to evaluate whether everolimus 10 mg / day added to treatment with depot octreotide prolongs progression free survival compared to treatment with octreotide alone in patients with advanced carcinoid tumor.
Interventions
DRUGOctreotide
Octreotide 30 mg intramuscularly (i.m.) every 28 days.
DRUGPlacebo
A 10-mg oral daily dosing regimen (two 5-mg tablets) of matching placebo.
DRUGEverolimus
A 10-mg oral daily dosing regimen (two 5-mg tablets) of everolimus.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Advanced (unresectable or metastatic) carcinoid tumor * Confirmed low-grade or intermediate-grade neuroendocrine carcinoma * Documented progression of disease within 12 months prior to randomization. * Measurable disease determined by triphasic computer tomography (CT) scan or magnetic resonance imaging (MRI).
Exclusion criteria
* Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma. * Hepatic artery embolization within the last 6 months or cryoablation of hepatic metastasis within 2 months of enrollment. * Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (sirolimus, temsirolimus, everolimus) * Intolerance or hypersensitivity to octreotide, everolimus, or other rapamycins. * Severe or uncontrolled medical conditions * Chronic treatment with corticosteroids or other immunosuppressive agent. * Other primary cancer within 3 years. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | 5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median. |
| Overall Survival Using Kaplan-Meier Methodology | Months 12, 24, 36, 48 | Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group. |
| Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression. |
| Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | From first day of treatment up to 28 days after last day of treatment in double blind | AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. |
| Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as Non-elevated. |
| Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | From first day of treatment up to 28 days after last day of treatment in double blind | AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. |
Countries
Australia, Belgium, Canada, Czechia, Finland, France, Germany, Greece, Italy, Netherlands, Slovakia, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Total 429 patients were randomized to double blind phase of treatment. 170 patients moved to the Open Label Phase.
Participants by arm
| Arm | Count |
|---|---|
| Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. | 216 |
| Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. | 213 |
| Total | 429 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Phase | Adverse Event | 61 | 16 |
| Double Blind Phase | Death | 6 | 3 |
| Double Blind Phase | Disease Progression | 101 | 154 |
| Double Blind Phase | Final Primary Analysis | 26 | 14 |
| Double Blind Phase | Lost to Follow-up | 0 | 1 |
| Double Blind Phase | New Cander Therapy | 1 | 1 |
| Double Blind Phase | Protocol Violation | 3 | 4 |
| Double Blind Phase | Withdrawal by Subject | 18 | 20 |
| Open Label Phase | Administrative Problems | 0 | 13 |
| Open Label Phase | Adverse Event | 0 | 46 |
| Open Label Phase | Death | 0 | 7 |
| Open Label Phase | Disease Progression | 0 | 86 |
| Open Label Phase | Lost to Follow-up | 0 | 2 |
| Open Label Phase | New Cancer Therapy | 0 | 1 |
| Open Label Phase | Withdrawal by Subject | 0 | 15 |
Baseline characteristics
| Characteristic | Octreotide+ Everolimus | Octreotide+ Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 10.72 | 59.4 years STANDARD_DEVIATION 11.13 | 59.8 years STANDARD_DEVIATION 10.92 |
| Sex: Female, Male Female | 119 Participants | 89 Participants | 208 Participants |
| Sex: Female, Male Male | 97 Participants | 124 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 214 / 215 | 194 / 211 | 162 / 170 |
| serious Total, serious adverse events | 126 / 215 | 74 / 211 | 93 / 170 |
Outcome results
Primary
Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review
Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method.
Time frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010
Population: The Full Analysis Set (FAS) consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Octreotide+ Everolimus | Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review | 16.43 Months |
| Octreotide+ Placebo | Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review | 11.33 Months |
Secondary
Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)
The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.
Time frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010
Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide+ Everolimus | Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 2.3 Percentage of patients |
| Octreotide+ Placebo | Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 1.9 Percentage of patients |
Secondary
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)
AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time frame: From first day of treatment up to 28 days after last day of treatment in double blind
Population: The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Clinically notable AE | 208 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Grade 3-4 Adverse Events | 162 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | On treatment death | 19 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Serious adverse events | 126 Patients |
| Octreotide+ Placebo | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Serious adverse events | 74 Patients |
| Octreotide+ Placebo | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Clinically notable AE | 146 Patients |
| Octreotide+ Placebo | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | On treatment death | 11 Patients |
| Octreotide+ Placebo | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | Grade 3-4 Adverse Events | 109 Patients |
Secondary
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)
AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time frame: From first day of treatment up to 28 days after last day of treatment in double blind
Population: The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | Clinically notable AE | 154 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | Grade 3-4 Adverse Events | 115 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | On treatment death | 22 Patients |
| Octreotide+ Everolimus | Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | Serious adverse events | 93 Patients |
Secondary
Overall Survival Using Kaplan-Meier Methodology
Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group.
Time frame: Months 12, 24, 36, 48
Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Octreotide+ Everolimus | Overall Survival Using Kaplan-Meier Methodology | 12 Months | 80.5 Percentage of Participants |
| Octreotide+ Everolimus | Overall Survival Using Kaplan-Meier Methodology | 24 Months | 57.0 Percentage of Participants |
| Octreotide+ Everolimus | Overall Survival Using Kaplan-Meier Methodology | 36 Months | 42.9 Percentage of Participants |
| Octreotide+ Everolimus | Overall Survival Using Kaplan-Meier Methodology | 48 Months | 38.0 Percentage of Participants |
| Octreotide+ Placebo | Overall Survival Using Kaplan-Meier Methodology | 48 Months | 41.6 Percentage of Participants |
| Octreotide+ Placebo | Overall Survival Using Kaplan-Meier Methodology | 12 Months | 81.8 Percentage of Participants |
| Octreotide+ Placebo | Overall Survival Using Kaplan-Meier Methodology | 36 Months | 48.5 Percentage of Participants |
| Octreotide+ Placebo | Overall Survival Using Kaplan-Meier Methodology | 24 Months | 63.6 Percentage of Participants |
Secondary
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level
5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median.
Time frame: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010
Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline 5-HIAA data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Octreotide+ Everolimus | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | 5-HIAA <=median (n=93,96) | 21.75 Months |
| Octreotide+ Everolimus | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | 5-HIAA > median (n=94,95) | 13.83 Months |
| Octreotide+ Placebo | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | 5-HIAA <=median (n=93,96) | 13.90 Months |
| Octreotide+ Placebo | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | 5-HIAA > median (n=94,95) | 8.41 Months |
Secondary
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)
Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as Non-elevated.
Time frame: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010
Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline CgA data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Octreotide+ Everolimus | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | CgA<=2x ULN (n=60,78) | 31.31 Months |
| Octreotide+ Everolimus | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | CgA>2x ULN (n=152,130) | 13.93 Months |
| Octreotide+ Placebo | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | CgA<=2x ULN (n=60,78) | 20.07 Months |
| Octreotide+ Placebo | Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | CgA>2x ULN (n=152,130) | 8.41 Months |