A Phase 2 interventional study of Everolimus 10 mg and Octreotide Depot in Islet Cell Carcinoma, Neuroendocrine Carcinoma and Neuroendocrine Tumor, sponsored by Novartis Pharmaceuticals. Completed at 54 sites in 11 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-05-10.
Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 2, Interventional, and Treatment
The purpose of this study was to assess the efficacy and safety of everolimus in the treatment of advanced pancreatic neuroendocrine tumor (NET) not responsive to cytotoxic chemotherapy. All patients were treated with everolimus until either tumor progression was documented using a standard criteria that measures tumor size called Response Evaluation Criteria in Solid tumors (RECIST), or until unacceptable toxicity occurred, or until the patient or investigator requested discontinuation of treatment.
This was a stratified two-stage, single-arm, phase 2 study of treatment with everolimus in patients with advanced (unresectable or metastatic) pancreatic neuroendocrine tumor (NET) after failure of cytotoxic chemotherapy.
Stratum 1, consisted of patients not receiving chronic Octreotide Depot therapy, will receive everolimus monotherapy at 10 mg/day.
Stratum 2, consisting of patients with tumors that have progressed during Octreotide Depot treatment will continue their entry dose of Octreotide Depot plus everolimus 10 mg/day.
33 studies on the registry are indexed under Carcinoma, Islet Cell; 1 is open to participants now.
This study's enrollment of 160 is above the median of 28 across 26 interventional studies indexed under Carcinoma, Islet Cell.
Browse Carcinoma, Islet Cell studies →Novartis Pharmaceuticals is the lead sponsor of 2,711 studies on the registry; 218 are open to participants now.
Of its 582 completed or terminated interventional studies of FDA-regulated products, 435 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion criteria for both strata:
Inclusion criteria for Stratum 2 only:
Exclusion criteria for both strata:
Exclusion Criterion for Stratum 1 only:
Other protocol-defined inclusion/exclusion criteria applied.
Stratum 1 patients who were not receiving regular Octreotide Depot therapy. These patients were to receive everolimus monotherapy at 10 mg/day. Stratum 2 patients who were to receive everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot therapy. Patients were instructed to take two 5 mg tablets of everolimus orally with a glass of water, once daily (preferably in the morning). Dosing was strongly recommended to occur at the same time every day.
Drug: Everolimus 10 mg · Drug: Octreotide Depot
Participants took two 5 mg tablets of Everolimus orally with a glass of water, once daily (preferably in the morning) in a fasting state or after no more than a light, fat-free meal. Dosing was to occur at the same time each day. If vomiting occurred, the vomited dose was not to be replaced.
Also known as: RAD001
Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Objective response rate was defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.
Time frame: from date of randomization/start of treatment until first documented response confirmed 4 weeks later( at least 3 months)
Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review
Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR): * 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. Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
Time frame: from date of first documented confirmed response to time to progression, at least 3 months
Duration of Overall Response (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review
Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR): * 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. Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
Time frame: from date of first documented confirmed response to time to progression, at least 3 months
Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Objective response rate was defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.
Time frame: from date of randomization/start of treatment until first documented response confirmed 4 weeks later (at least 3 months)
Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs)[Stratum 1]
Adverse events 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. Serious adverse events 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: on or after the day of the first intake of study treatment to starting no later than 28 days after study treatment discontinuation, at least every month
Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs) [Stratum 2]
Adverse events 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. Serious adverse events 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: on or after the day of the first intake of study treatment to starting no later than 28 days after study treatment discontinuation, at least every month
Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1)
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 Kaplan-Meier estimate of the PFS survival function was constructed. Median PFS was obtained and displayed along with 95% confidence intervals.
Time frame: from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 September 2010
Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2)
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 Kaplan-Meier estimate of the PFS survival function was constructed. Median PFS was obtained and displayed along with 95% confidence intervals.
Time frame: from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 September 2010
Time to Overall Survival (OS)(Stratum 1)
Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
Time frame: from randomisation to dates of disease progression, death from any cause, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 April 2012
Time to Overall Survival (OS) (Stratum 2)
Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
Time frame: from randomisation to dates of disease progression, death from any cause, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 April 2012
Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2)
For all patients in both strata, a blood sample for everolimus trough level determination will be collected immediately prior to the everolimus administration on Cycle 1 Day 15, Cycle 2 Day 1, and every month thereafter. A treatment cycle was defined as 28 days of consecutive daily treatment with everolimus and treatment continued until tumor progression. It is critical that patients not take their daily everolimus dose before the sample is drawn.
Time frame: Cycle 1 Day 15
Effect of Octreotide Depot on the Trough Concentrations of Everolimus
The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1
| Milestone | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|---|
| Started | 115 | 45 |
| Completed | 77 | 23 |
| Not completed | 38 | 22 |
| Withdrew: Adminstrative problems | 1 | 1 |
| Withdrew: Adverse event | 21 | 12 |
| Withdrew: New cancer therapy | 2 | 1 |
| Withdrew: Withdrawal by subject | 11 | 3 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Protocol violation | 0 | 2 |
| Withdrew: Death | 3 | 2 |
Objective response rate was defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.
| percentage of participants | Stratum 1: Everolimus 10 mg |
|---|---|
| Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 9.6 (4.9 to 16.5) |
Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR): * 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. Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
| Months | Stratum 1: Everolimus 10 mg |
|---|---|
| Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review | 10.64 (9.79 to NA) |
Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR): * 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. Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
No measurements were reported for this outcome.
Objective response rate was defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.
| percentage of participants | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|
| Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 4.4 (0.5 to 15.1) |
Adverse events 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. Serious adverse events 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.
| Participants | Stratum 1: Everolimus 10 mg |
|---|---|
| Adverse Events | 115 |
| Death | 10 |
| Serious Adverse Events | 63 |
Adverse events 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. Serious adverse events 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.
| Participants | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|
| Adverse Events | 45 |
| Death | 2 |
| Serious Adverse Events | 27 |
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 Kaplan-Meier estimate of the PFS survival function was constructed. Median PFS was obtained and displayed along with 95% confidence intervals.
| Months | Stratum 1: Everolimus 10 mg |
|---|---|
| Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1) | 9.69 (8.25 to 13.31) |
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 Kaplan-Meier estimate of the PFS survival function was constructed. Median PFS was obtained and displayed along with 95% confidence intervals.
| Months | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|
| Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2) | 16.69 (11.07 to NA) |
Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
| months | Stratum 1: Everolimus 10 mg |
|---|---|
| Time to Overall Survival (OS)(Stratum 1) | 28.78 (20.24 to 36.37) |
Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
| months | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|
| Time to Overall Survival (OS) (Stratum 2) | 38.77 (29.08 to NA) |
For all patients in both strata, a blood sample for everolimus trough level determination will be collected immediately prior to the everolimus administration on Cycle 1 Day 15, Cycle 2 Day 1, and every month thereafter. A treatment cycle was defined as 28 days of consecutive daily treatment with everolimus and treatment continued until tumor progression. It is critical that patients not take their daily everolimus dose before the sample is drawn.
| ng/ml | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|---|
| Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2) | 15.7 ± 15.82 | 17.3 ± 18.08 |
The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15.
| ng/ml | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|
| Cycle 1 Day 1 (pre-treatment baseline) (n=37) | 3.2 ± 2.81 |
| Cycle 2 Day 1 (n= 38) | 3.7 ± 3.47 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Stratum 1: Everolimus 10 mg | — | 63/115 (54.8%) | 115/115 (100%) |
| Stratum 2: Everolimus 10 mg + Octreotide Depot | — | 27/45 (60%) | 44/45 (97.8%) |
| Event | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|---|
| Abdominal painGastrointestinal disorders | 10/115 | 4/45 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/115 | 3/45 |
| Cardiac failureCardiac disorders | 1/115 | 3/45 |
| VomitingGastrointestinal disorders | 4/115 | 3/45 |
| Renal failureRenal and urinary disorders | 2/115 | 3/45 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 4/115 | 3/45 |
| AstheniaGeneral disorders | 6/115 | 0/45 |
| PyrexiaGeneral disorders | 6/115 | 2/45 |
| Cardiac failure congestiveCardiac disorders | 0/115 | 2/45 |
| NauseaGastrointestinal disorders | 3/115 | 2/45 |
| Event | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot |
|---|---|---|
| DiarrhoeaGastrointestinal disorders | 63/115 | 25/45 |
| StomatitisGastrointestinal disorders | 57/115 | 24/45 |
| NauseaGastrointestinal disorders | 54/115 | 22/45 |
| RashSkin and subcutaneous tissue disorders | 54/115 | 21/45 |
| FatigueGeneral disorders | 53/115 | 20/45 |
| PyrexiaGeneral disorders | 41/115 | 14/45 |
| VomitingGastrointestinal disorders | 40/115 | 12/45 |
| HeadacheNervous system disorders | 40/115 | 9/45 |
| Abdominal painGastrointestinal disorders | 38/115 | 9/45 |
| AstheniaGeneral disorders | 38/115 | 9/45 |
| Age Continuous(years) | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot | Total |
|---|---|---|---|
| Mean | 55.1 ± 11.8 | 53.64 ± 12.478 | 54.33 ± 11.98 |
| Sex: Female, Male(Participants) | Stratum 1: Everolimus 10 mg | Stratum 2: Everolimus 10 mg + Octreotide Depot | Total |
|---|---|---|---|
| Female | 49 | 21 | 70 |
| Male | 66 | 24 | 90 |
The record gives a start of Jun 2006, a primary completion of Jan 2008 and a completion of Apr 2012. It does not say whether these dates are actual or estimated.
Results were first posted in Mar 2012, 4 years 2 months after primary completion.
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Studies of the drug tested here: Everolimus