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Everolimus

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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.

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.

Everolimus 10 mg

Octreotide Depot

Novartis Pharmaceuticals

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.

Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy

An Open Label, Stratified, Single-arm Phase II Study of Everolimus in Patients With Advanced Pancreatic Neuroendocrine Tumor (NET) After Failure of Cytotoxic Chemotherapy

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.

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

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.

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.

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.

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.

The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15.

Stratum 1 patients who were not receiving regular Octreotide Depot therapy. These patients were to receive everolimus monotherapy at 10 mg/day. 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.

Stratum 1: Everolimus 10 mg

Stratum 2 participants who had received at least three consecutive months of Octreotide Long Acting Depot therapy prior to enrollment. These patients also received Everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot.

Stratum 2: Everolimus 10 mg + Octreotide Depot

Total

Age Continuous

Sex: Female, Male

Novartis Study Director

The full analysis set (FAS) consisted of all patients who received at least one dose of everolimus.

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)

Full Analysis Set (FAS) consisted of all patients who received at least one dose of everolimus. Only those patients whose best overall response was complete response (CR) or partial response (PR) were included in this analysis.

Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review

Stratum 2 participants who had received at least three consecutive months of Octreotide Long Acting Depot therapy prior to enrollment. These patients also received Everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot.

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.

Very low number of patients demonstrated a partial response, the median duration of response as per central review has not been calculated.

Duration of Overall Response (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review

Full Analysis Set (FAS) was consisted of all patients who received at least one dose of everolimus.

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)

Adverse Events

Death

Serious Adverse Events

The safety population consists of all patients who received at least one dose of everolimus and had at least one post-baseline safety assessment.

Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs)[Stratum 1]

Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs) [Stratum 2]

Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1)

Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2)

The full analysis set consisted of all patients who received at least one dose of everolimus.

Time to Overall Survival (OS)(Stratum 1)

Time to Overall Survival (OS) (Stratum 2)

Full Analysis Set (FAS) is consisted of all patients who received at least one dose of everolimus. Patients with everolimus pharmacokinteic samples, with nonzero concentration, at Cycle 1 Day 15 were included

Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2)

Cycle 1 Day 1 (pre-treatment baseline) (n=37)

Cycle 2 Day 1 (n= 38)

Full Analysis Set (FAS) is consisted of all patients who received at least one dose of everolimus. Patients with Octreotide Depot pharmacokinetic samples, with nonzero concentration, at Cycle 1 Day 1 or Cycle 2 Day 1 were included.

Spots Global Cancer Trial Database for atypical carcinoid