Advanced NET of GI Origin, Advanced NET of Lung Origin, Neuroendocrine Tumors
Conditions
Keywords
Neuroendocrine tumor, NET, progressive, advanced, gastrointestinal, GI or lung origin, nonfunctional, everolimus, Advanced NET of GI origin, Advanced NET of lung origin
Brief summary
The purpose of this study is to compare the antitumor activity of everolimus plus best supportive care versus placebo plus best supportive care in patients with progressive nonfunctional neuroendocrine tumor (NET) of gastrointestinal (GI) or lung origin without a history of, or current symptoms of carcinoid syndrome.
Detailed description
This was a prospective, multi-center, randomized, double-blind, parallel-group, placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus 10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history of, or current symptoms of carcinoid syndrome. After assessment of eligibility, participants qualifying for the study were randomized in a 2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was combined with best supportive care and treatment cycles were defined as 28 days. Participants were treated until disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal. Regardless of the reason for study drug discontinuation, participants had a safety follow-up visit scheduled 30 days after the last dose of the study drug. Per data monitoring committee recommendation, all participants on treatment with placebo were allowed to crossover to open-label treatment with everolimus. This change was implemented through protocol amendment 3 (issued on 06-May-2016) after which remaining participants entered into open-label phase of the study.
Interventions
DRUGEverolimus
Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken
DRUGPlacebo
Participants were treated with two tablets of matching placebo once daily orally taken.
OTHERBest suportive care (BSC)
Best supportive care includes all care provided to participants deemed necessary by the treating physician, such as but not restricted to anti-diarrheals and analgesics. The optimal care of the patient is based on the treating physician's best medical judgment.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin * No history of and no active symptoms related to carcinoid syndrome * In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment * Radiological documented disease progression within 6 months prior to randomization * Measurable disease * WHO performance status ≤1 * Adequate bone marrow, liver and renal function
Exclusion criteria
* Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma * Patients with pancreatic NET or NET of origins other than GI or Lung * Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea) * Patients with more than one line of prior chemotherapy * Prior targeted therapy * Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization * Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus) * Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) * Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus * Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy * Patients who had any severe and/or uncontrolled medical conditions such as: * unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia * active or uncontrolled severe infection * liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) * Chronic treatment with corticosteroids or other immunosuppressive agents * Known history of HIV seropositivity * Pregnant or nursing (lactating) women Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | From date of randomization to progression or death, whichever comes first, assessed up to 27 months | PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI). For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation | From randomization until end of treatment, assessed up to approximately 2.5 years | ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0. CR: disappearance of all target lesions. PR: 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. |
| Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment | From randomization until end of treatment, assessed up to approximately 2.5 years | DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment. CR: disappearance of all target lesions. PR: 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. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. |
| Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score | From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years | FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: Not at all to 4: Very much. The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life. Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement. Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment. |
| Overall Survival (OS) | From date of randomization to date of death, assessed up to approximately 8 years | OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored. |
| Change From Baseline in Neuron Specific Enolase (NSE) Levels | From baseline (every 4 weeks) up to Week 116 | NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline. |
| Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change | From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years | WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment. |
| Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 | Pre-dose at Day 29. | A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications |
| Change From Baseline in Chromogranin A (CgA) Levels | From baseline (every 4 weeks) up to 116 weeks | CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline. |
Countries
Austria, Belgium, Canada, China, Colombia, Czechia, Germany, Greece, Hungary, Italy, Japan, Lebanon, Netherlands, Poland, Russia, Saudi Arabia, Slovakia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
At baseline, participants were randomized to either everolimus+BSC or placebo+BSC arm. Two patients randomized to the everolimus arm were not treated due to withdrawal of consent and protocol deviation. As per Data Monitoring Committee recommendation (03-Jun-2015), implemented through protocol amendment 3 (issued on 06-May-2016), remaining participants entered the open-label part of the study, where participants in the placebo arm were allowed to crossover to open-label treatment with everolimus
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + BSC Participants received everolimus 10 mg once daily BSC throughout the study | 205 |
| Placebo+BSC Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period | 97 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Period | Adverse Event | 64 | 7 | 0 |
| Blinded Period | Death | 5 | 2 | 0 |
| Blinded Period | Disease Progression | 89 | 75 | 0 |
| Blinded Period | Protocol deviation | 2 | 1 | 0 |
| Blinded Period | Withdrawal by Subject | 19 | 6 | 0 |
| Open-label Period | Administrative problems | 5 | 0 | 2 |
| Open-label Period | Adverse Event | 5 | 0 | 1 |
| Open-label Period | Disease progression | 13 | 0 | 2 |
| Open-label Period | Protocol deviation | 1 | 0 | 0 |
| Open-label Period | Withdrawal by Subject | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo+BSC | Everolimus + BSC | Total |
|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 12.89 | 62.9 years STANDARD_DEVIATION 11.7 | 61.7 years STANDARD_DEVIATION 12.18 |
| Race/Ethnicity, Customized Asian | 18 Participants | 32 Participants | 50 Participants |
| Race/Ethnicity, Customized Black | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized Caucasian | 68 Participants | 162 Participants | 230 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Female | 44 Participants | 116 Participants | 160 Participants |
| Sex: Female, Male Male | 53 Participants | 89 Participants | 142 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 202 | 0 / 6 | 10 / 208 | 5 / 98 |
| other Total, other adverse events | 197 / 202 | 6 / 6 | 203 / 208 | 81 / 98 |
| serious Total, serious adverse events | 93 / 202 | 1 / 6 | 94 / 208 | 21 / 98 |
Outcome results
Primary
Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment
PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI). For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point.
Time frame: From date of randomization to progression or death, whichever comes first, assessed up to 27 months
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 8 months | 62.4 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 15 months | 40.1 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 6 months | 72.1 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 18 months | 31.8 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 10 months | 51.7 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 21 months | 27.6 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 4 months | 81.2 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 24 months | 22.0 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 12 months | 44.4 Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 27 months | NA Percent event-free probability in PFS |
| Everolimus + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 2 months | 90.1 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 27 months | 17.4 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 2 months | 74.6 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 4 months | 49.1 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 6 months | 40.1 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 8 months | 35.8 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 10 months | 31.3 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 12 months | 28.1 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 15 months | 26.4 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 18 months | 24.4 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 21 months | 17.4 Percent event-free probability in PFS |
| Placebo + BSC | Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | 24 months | 17.4 Percent event-free probability in PFS |
p-value: <0.00195% CI: [0.35, 0.67]Log Rank
Secondary
Change From Baseline in Chromogranin A (CgA) Levels
CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.
Time frame: From baseline (every 4 weeks) up to 116 weeks
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization. Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 4 | 434.8 microgram/liter (ug/L) | Standard Deviation 2306.7 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 8 | 162.3 microgram/liter (ug/L) | Standard Deviation 2550.65 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 12 | 396.7 microgram/liter (ug/L) | Standard Deviation 2401.78 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 16 | 263.5 microgram/liter (ug/L) | Standard Deviation 2946.76 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 20 | 162.1 microgram/liter (ug/L) | Standard Deviation 2464.47 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 24 | 253.2 microgram/liter (ug/L) | Standard Deviation 3487.27 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 28 | 587.2 microgram/liter (ug/L) | Standard Deviation 4861.35 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 32 | 508.5 microgram/liter (ug/L) | Standard Deviation 6102.61 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 36 | 94.7 microgram/liter (ug/L) | Standard Deviation 4905.17 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 40 | 511.4 microgram/liter (ug/L) | Standard Deviation 6180.67 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 44 | 552.8 microgram/liter (ug/L) | Standard Deviation 4173.44 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 48 | 1326.2 microgram/liter (ug/L) | Standard Deviation 8718.92 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 52 | 1196.2 microgram/liter (ug/L) | Standard Deviation 7737.76 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 56 | 1920.6 microgram/liter (ug/L) | Standard Deviation 11250.07 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 60 | 1722.0 microgram/liter (ug/L) | Standard Deviation 13155.03 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 64 | 3811.0 microgram/liter (ug/L) | Standard Deviation 26656.45 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 68 | 1413.3 microgram/liter (ug/L) | Standard Deviation 9588.68 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 72 | 239.5 microgram/liter (ug/L) | Standard Deviation 2318.79 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 76 | 3256.5 microgram/liter (ug/L) | Standard Deviation 19395.4 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 80 | 5421.0 microgram/liter (ug/L) | Standard Deviation 32471.22 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 84 | 4379.9 microgram/liter (ug/L) | Standard Deviation 28302.84 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 88 | 571.2 microgram/liter (ug/L) | Standard Deviation 2694.44 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 92 | 765.5 microgram/liter (ug/L) | Standard Deviation 2913.15 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 96 | 984.6 microgram/liter (ug/L) | Standard Deviation 3379.28 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 100 | 935.3 microgram/liter (ug/L) | Standard Deviation 2961.6 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 104 | 1466.4 microgram/liter (ug/L) | Standard Deviation 4257.03 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 108 | 2245.8 microgram/liter (ug/L) | Standard Deviation 6077.99 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 112 | 2817.0 microgram/liter (ug/L) | Standard Deviation 7786.28 |
| Everolimus + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 116 | 2951.8 microgram/liter (ug/L) | Standard Deviation 6745.06 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 60 | 120.9 microgram/liter (ug/L) | Standard Deviation 415.73 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 4 | 1154.3 microgram/liter (ug/L) | Standard Deviation 9083.39 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 104 | -21.7 microgram/liter (ug/L) | Standard Deviation 285.99 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 8 | 2697.6 microgram/liter (ug/L) | Standard Deviation 19956.9 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 64 | 141.6 microgram/liter (ug/L) | Standard Deviation 281.38 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 12 | 1176.0 microgram/liter (ug/L) | Standard Deviation 3322.13 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 92 | 63.7 microgram/liter (ug/L) | Standard Deviation 477.53 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 16 | 1450.4 microgram/liter (ug/L) | Standard Deviation 4825.78 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 68 | 222.6 microgram/liter (ug/L) | Standard Deviation 333.93 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 20 | 3640.1 microgram/liter (ug/L) | Standard Deviation 12653.42 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 112 | 514.5 microgram/liter (ug/L) | Standard Deviation 661.8 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 24 | 1783.9 microgram/liter (ug/L) | Standard Deviation 5399.98 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 72 | 233.7 microgram/liter (ug/L) | Standard Deviation 400.43 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 28 | 1350.3 microgram/liter (ug/L) | Standard Deviation 5701.7 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 96 | 146.5 microgram/liter (ug/L) | Standard Deviation 468.24 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 32 | 2000.7 microgram/liter (ug/L) | Standard Deviation 6362.83 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 76 | 210.9 microgram/liter (ug/L) | Standard Deviation 522.62 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 36 | 180.9 microgram/liter (ug/L) | Standard Deviation 383.93 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 108 | 215.9 microgram/liter (ug/L) | Standard Deviation 293.87 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 40 | 207.6 microgram/liter (ug/L) | Standard Deviation 403.3 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 80 | 286.3 microgram/liter (ug/L) | Standard Deviation 425.45 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 44 | 140.6 microgram/liter (ug/L) | Standard Deviation 328.02 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 100 | -12.7 microgram/liter (ug/L) | Standard Deviation 399.25 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 48 | 129.0 microgram/liter (ug/L) | Standard Deviation 326.69 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 84 | 175.4 microgram/liter (ug/L) | Standard Deviation 575.98 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 52 | 124.2 microgram/liter (ug/L) | Standard Deviation 452.38 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 116 | 99.6 microgram/liter (ug/L) | Standard Deviation 92.91 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 56 | 134.9 microgram/liter (ug/L) | Standard Deviation 346.33 |
| Placebo + BSC | Change From Baseline in Chromogranin A (CgA) Levels | Week 88 | -9.4 microgram/liter (ug/L) | Standard Deviation 473.66 |
Secondary
Change From Baseline in Neuron Specific Enolase (NSE) Levels
NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.
Time frame: From baseline (every 4 weeks) up to Week 116
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization. Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 60 | 2.4 microgram/liter (ug/L) | Standard Deviation 8.19 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 32 | 1.5 microgram/liter (ug/L) | Standard Deviation 14.24 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 64 | 4.4 microgram/liter (ug/L) | Standard Deviation 23.22 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 4 | 0.1 microgram/liter (ug/L) | Standard Deviation 5.21 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 68 | 1.1 microgram/liter (ug/L) | Standard Deviation 4.68 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 36 | 2.0 microgram/liter (ug/L) | Standard Deviation 15.11 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 72 | 1.6 microgram/liter (ug/L) | Standard Deviation 4.46 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 20 | 0.8 microgram/liter (ug/L) | Standard Deviation 6.21 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 76 | 1.7 microgram/liter (ug/L) | Standard Deviation 5.11 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 40 | 1.2 microgram/liter (ug/L) | Standard Deviation 6.48 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 80 | 2.9 microgram/liter (ug/L) | Standard Deviation 10.15 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 12 | -0.3 microgram/liter (ug/L) | Standard Deviation 8.37 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 84 | 8.0 microgram/liter (ug/L) | Standard Deviation 33.13 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 44 | 0.8 microgram/liter (ug/L) | Standard Deviation 5.1 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 88 | 2.2 microgram/liter (ug/L) | Standard Deviation 3.89 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 24 | 1.7 microgram/liter (ug/L) | Standard Deviation 8.99 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 92 | 4.0 microgram/liter (ug/L) | Standard Deviation 7.24 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 48 | 2.0 microgram/liter (ug/L) | Standard Deviation 9.2 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 96 | 4.3 microgram/liter (ug/L) | Standard Deviation 5.96 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 100 | 1.8 microgram/liter (ug/L) | Standard Deviation 3.79 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 8 | 0.3 microgram/liter (ug/L) | Standard Deviation 8.71 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 104 | 2.9 microgram/liter (ug/L) | Standard Deviation 4.11 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 52 | 1.5 microgram/liter (ug/L) | Standard Deviation 5.82 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 108 | 5.5 microgram/liter (ug/L) | Standard Deviation 13.48 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 28 | 1.1 microgram/liter (ug/L) | Standard Deviation 6.37 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 112 | 2.8 microgram/liter (ug/L) | Standard Deviation 5.72 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 56 | 3.6 microgram/liter (ug/L) | Standard Deviation 18.56 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 116 | 10.6 microgram/liter (ug/L) | Standard Deviation 14.92 |
| Everolimus + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 16 | 2.0 microgram/liter (ug/L) | Standard Deviation 8.34 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 72 | 0.7 microgram/liter (ug/L) | Standard Deviation 3.91 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 4 | -2.2 microgram/liter (ug/L) | Standard Deviation 39.87 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 8 | -4.2 microgram/liter (ug/L) | Standard Deviation 36.71 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 12 | 15.5 microgram/liter (ug/L) | Standard Deviation 163.75 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 16 | 4.1 microgram/liter (ug/L) | Standard Deviation 19.44 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 20 | 5.3 microgram/liter (ug/L) | Standard Deviation 18.26 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 24 | 6.7 microgram/liter (ug/L) | Standard Deviation 23.47 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 28 | 0.4 microgram/liter (ug/L) | Standard Deviation 9.16 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 32 | 3.1 microgram/liter (ug/L) | Standard Deviation 8.96 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 36 | 2.0 microgram/liter (ug/L) | Standard Deviation 5.9 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 40 | 1.2 microgram/liter (ug/L) | Standard Deviation 4.49 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 44 | 1.2 microgram/liter (ug/L) | Standard Deviation 4.46 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 48 | 0.6 microgram/liter (ug/L) | Standard Deviation 4.06 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 52 | 0.7 microgram/liter (ug/L) | Standard Deviation 4.19 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 56 | 0.9 microgram/liter (ug/L) | Standard Deviation 5.89 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 60 | 0.1 microgram/liter (ug/L) | Standard Deviation 3.35 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 64 | 0.9 microgram/liter (ug/L) | Standard Deviation 3.8 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 68 | 1.9 microgram/liter (ug/L) | Standard Deviation 4.48 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 96 | 0.0 microgram/liter (ug/L) | Standard Deviation 2.99 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 76 | 0.6 microgram/liter (ug/L) | Standard Deviation 3.89 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 80 | 0.7 microgram/liter (ug/L) | Standard Deviation 2.83 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 84 | 0.1 microgram/liter (ug/L) | Standard Deviation 3.47 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 88 | 0.6 microgram/liter (ug/L) | Standard Deviation 2.47 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 92 | 0.1 microgram/liter (ug/L) | Standard Deviation 3.79 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 100 | -0.2 microgram/liter (ug/L) | Standard Deviation 5.1 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 104 | -1.7 microgram/liter (ug/L) | Standard Deviation 4.76 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 108 | -0.5 microgram/liter (ug/L) | Standard Deviation 4.33 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 112 | -3.2 microgram/liter (ug/L) | Standard Deviation 3.3 |
| Placebo + BSC | Change From Baseline in Neuron Specific Enolase (NSE) Levels | Week 116 | 0.2 microgram/liter (ug/L) | Standard Deviation 4.17 |
Secondary
Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment
DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment. CR: disappearance of all target lesions. PR: 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. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.
Time frame: From randomization until end of treatment, assessed up to approximately 2.5 years
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + BSC | Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment | 82.4 Percentage of participants |
| Placebo + BSC | Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment | 64.9 Percentage of participants |
Secondary
Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation
ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0. CR: disappearance of all target lesions. PR: 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.
Time frame: From randomization until end of treatment, assessed up to approximately 2.5 years
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + BSC | Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation | 2.0 Percentage of participants |
| Placebo + BSC | Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation | 1.0 Percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored.
Time frame: From date of randomization to date of death, assessed up to approximately 8 years
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + BSC | Overall Survival (OS) | 43.1 Months |
| Placebo + BSC | Overall Survival (OS) | 41.76 Months |
p-value: 0.25995% CI: [0.66, 1.24]Log Rank
Secondary
Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29
A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications
Time frame: Pre-dose at Day 29.
Population: All patients who received at least one dose of the study drug with evaluable blood samples for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + BSC | Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 | 10mg daily dose | 16.382 nanogram/milliliter (ng/mL) | Standard Deviation 13.2767 |
| Everolimus + BSC | Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 | 5mg daily dose | 4.700 nanogram/milliliter (ng/mL) | Standard Deviation 3.8396 |
Secondary
Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score
FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: Not at all to 4: Very much. The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life. Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement. Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Time frame: From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + BSC | Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score | 13.01 Months |
| Placebo + BSC | Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score | 9.23 Months |
p-value: 0.07395% CI: [0.5, 1.1]Log Rank
Secondary
Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change
WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Time frame: From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years
Population: The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + BSC | Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change | 24.08 Months |
| Placebo + BSC | Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change | 24.15 Months |
p-value: 0.53995% CI: [0.65, 1.61]Log Rank
Post Hoc
All Collected Deaths
Deaths on-treatment were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approximately 8 years. Total Deaths were collected from first dose of study treatment until end of post-treatment survival follow, up to maximum duration of approximately 8 years.
Time frame: On-treatment deaths: up to approximately 8 years. All deaths: up to approximately 8 years
Population: The safety set consists of all participants who received at least one dose of the study drug and had at least one post-baseline safety evaluation. Participants were analyzed according to treatment actually received: One participant randomized to everolimus arm received only placebo and therefore, appears in the placebo arm in the safety set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + BSC | All Collected Deaths | On-treatment deaths | 10 Participants |
| Everolimus + BSC | All Collected Deaths | Total deaths | 126 Participants |
| Placebo + BSC | All Collected Deaths | Total deaths | 1 Participants |
| Placebo + BSC | All Collected Deaths | On-treatment deaths | 0 Participants |
| Everolimus+BSC (All) | All Collected Deaths | On-treatment deaths | 10 Participants |
| Everolimus+BSC (All) | All Collected Deaths | Total deaths | 127 Participants |
| Placebo + BSC (Blinded Period) | All Collected Deaths | On-treatment deaths | 5 Participants |
| Placebo + BSC (Blinded Period) | All Collected Deaths | Total deaths | 57 Participants |