Pancreatic Neuroendocrine Tumors (pNET)
Conditions
Keywords
Pancreatic, Neuroendocrine tumors, PNET, BEZ235, Everolimus
Brief summary
This was a multicenter, open label, randomized phase II study to evaluate the efficacy and safety of BEZ235 as compared to everolimus in patients with advanced, low to intermediate grade pancreatic neuroendocrine tumor (pNET).
Detailed description
Patients with advanced (unresectable or metastatic), low to intermediate grade (histologically confirmed well and moderately differentiated) pancreatic neuroendocrine tumor (pNET) were randomized to either BEZ235 or everolimus. The study was planned to include 140 patients, with 70 patients in the BEZ235 treatment group and 70 patients in the everolimus treatment group. An interim analysis was conducted on 62 randomized patients. The study was terminated as the BEZ235 treatment did not demonstrate a progression free survival advantage to everolimus treatment.
Interventions
DRUGBEZ235
BEZ235 400 mg bid p.o. (by mouth, twice daily)
DRUGEverolimus
Everolimus 10 mg qd p.o. (by mouth, daily)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Advanced histologically confirmed well differentiated pancreatic neuroendocrine tumor * Progressive disease within the last 12 months * Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT
Exclusion criteria
* Prior treatment with mTOR or PI3K inhibitors * Patients with more than 2 prior systemic treatment regimens * Previous cytotoxic chemotherapy, targeted therapy, or biotherapy within the last 4 weeks Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | up to approx. 18 months | PFS is defined as the time from the date of randomization until the date of the first radiologically documented disease progression or death due to any cause. PFS is based on local investigator assessment. Patients will be followed up for the duration of the study and for an expected average of every 12 weeks after randomization. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of all target lesions, or unequivocal progression of non-target lesions, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | up to approx. 18 months | Proportion of patients with a best overall response during the study of complete response (CR) or partial response (PR), based on the investigator assessment. 2. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for all target and non-target lesions, as well as new lesions as assessed by CT or MRI: Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of all target lesions; Overall Response (OR) = CR + PR. |
| Overall Survival (OS) | up to approx. 30 months | Time from randomization to the date of death due to any cause |
| Time to Treatment Failure (TTF) | up to approx. 18 months | Time from randomization to the date of the first of the following events:death due to any cause or progressive disease, treatment discontinuation due to toxicity or treatment discontinuation due to patient preference |
Countries
France, Italy, Netherlands, Russia, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Patients were assigned to one of the following 2 treatment arms in a ratio of 1:1: BEZ235 (investigational arm) or everolimus (control arm)
Participants by arm
| Arm | Count |
|---|---|
| BEZ235 Patients received BEZ235 400 mg bid p.o. (by mouth, twice daily) | 31 |
| Everolimus Patients received Everolimus 10 mg qd p.o. (by mouth, daily) | 31 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 5 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease Progression | 11 | 14 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | study terminated by Sponsor | 4 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | BEZ235 | Everolimus | Total |
|---|---|---|---|
| Age, Continuous | 56.3 Years STANDARD_DEVIATION 12.43 | 57.8 Years STANDARD_DEVIATION 11.85 | 57.1 Years STANDARD_DEVIATION 12.07 |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 30 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 31 | 30 / 31 |
| serious Total, serious adverse events | 11 / 31 | 9 / 31 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the time from the date of randomization until the date of the first radiologically documented disease progression or death due to any cause. PFS is based on local investigator assessment. Patients will be followed up for the duration of the study and for an expected average of every 12 weeks after randomization. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of all target lesions, or unequivocal progression of non-target lesions, or the appearance of new lesions.
Time frame: up to approx. 18 months
Population: Full analysis set: The Full analysis set (FAS) comprised all patients who were randomized to study treatment. According to the intent to treat principle, patient was analyzed according to the treatment and strata they had been assigned to during the randomization procedure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BEZ235 | Progression Free Survival (PFS) | 8.2 Months |
| Everolimus | Progression Free Survival (PFS) | 10.8 Months |
Secondary
Objective Response Rate
Proportion of patients with a best overall response during the study of complete response (CR) or partial response (PR), based on the investigator assessment. 2. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for all target and non-target lesions, as well as new lesions as assessed by CT or MRI: Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of all target lesions; Overall Response (OR) = CR + PR.
Time frame: up to approx. 18 months
Population: Trial terminated based on the results of an interim analysis of the primary OM ( which demonstrated BEX235 not having improved PFS (progression free survival) vs everolimus).The secondary OM analyses were not conducted.
Secondary
Overall Survival (OS)
Time from randomization to the date of death due to any cause
Time frame: up to approx. 30 months
Population: Trial terminated based on the results of an interim analysis of the primary OM ( which demonstrated BEX235 not having improved PFS (progression free survival) vs everolimus).The secondary OM analyses were not conducted.
Secondary
Time to Treatment Failure (TTF)
Time from randomization to the date of the first of the following events:death due to any cause or progressive disease, treatment discontinuation due to toxicity or treatment discontinuation due to patient preference
Time frame: up to approx. 18 months
Population: Trial terminated based on the results of an interim analysis of the primary OM ( which demonstrated BEX235 not having improved PFS (progression free survival) vs everolimus).The secondary OM analyses were not conducted.