Pancreatic Neuroendocrine Tumors (pNET)
Conditions
Keywords
advanced pancreatic neuroendocrine tumor, BEZ235, pNET
Brief summary
This is a Phase II study in 2 stages, evaluating BEZ235 plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pancreatic neuroendocrine tumors (pNET) after failure of mTOR inhibitor therapy. Study design: This was a Phase II, two-stage, multicenter study, where Stage 1 was a single arm, open label design and Stage 2 was planned to be a randomized, double-blind study. However, at the end of Stage 1, the futility was met and hence the Stage 2 was not initiated.
Interventions
DRUGBEZ235 (Stage 1)
The investigational study drug used in this trial was BEZ235, which was supplied as 50mg, 200mg, 300mg, and 400mg solid dispersion sachets. Supply as 200mg and 50mg were provided for dose reduction. Patients were instructed to take the contents of one sachet of BEZ235 twice a day in the morning within 30 minutes after a light meal (breakfast).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Unresectable or metastatic, histologically confirmed low or intermediate grade pancreatic neuroendocrine tumor with radiological evidence of disease progression since last treatment * Refractory disease to treatment with mTOR inhibitor * Measurable disease per RECIST Version 1.1 using Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) * Prior or concurrent therapy with SSA is permitted; a stable dose at least 2 months prior to study start and must continue on the stable dose while receiving study treatment; SSA is not considered as a systemic treatment. * WHO PS ≤ 1 * Adequate bone marrow function or organ function
Exclusion criteria
* Previous treatment with any PI3K or AKT inhibitor * Discontinuation prior mTOR inhibitor therapy due to toxicity * Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma * Radiotherapy, or major surgery within 4 weeks prior to study treatment start * Hepatic artery embolization or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of study treatment start. * More than 3 prior systemic treatment regimens (including cytotoxic chemotherapy, targeted therapy, immunotherapy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 - Progression Free Survival (PFS) Rate Analysis at 16 Weeks as Per Local Radiology Review | 16 weeks after the first BEZ235 administration. | PFS rate at 16 weeks was defined as a binary variable. Patients were considered as 'progression free' after 16 weeks if they had an overall lesion response of complete response (CR) partial response ('PR) or stable disease (SD)' and progressed if they had an overall lesion response of 'Progressive disease (PD) at the scan which occurred on day 105 after start of treatment, or later. Patients whose 16 weeks tumor assessment was unknown, missing or outside the window was not considered as 'progression free' and was considered a failure and counted only in the denominator for the estimation of the 16 week progression free rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1- Overall Response Rate (ORR) | Baseline, every 8 weeks up to 31 months | Overall Response rate was defined as the proportion of patients with a best overall response of complete response or partial response, based on investigator's assessment as per RECIST criteria version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated. |
| Stage 1 - Disease Control Rate | Baseline, every 8 weeks up to 31 months | Disease control rate was defined as the proportion of patients with a best overall response of Complete Response, Partial response, or Stable disease, based on the investigator's assessment per RECIST version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated. |
Countries
Austria, Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
This was a Phase II, two-stage, multicenter study, where Stage 1 was a singlearm,open label design and Stage 2 was planned to be a randomized, double-blind study. However, at the end of Stage 1, the futility was met and hence the Stage 2 was not initiated.
Pre-assignment details
Initially , the patients were started at BEZ235 400mg bid dose regimen. The preliminary safety & tolerability data fro first 3 patients treated at this dose showed all patients reported AEs leading to dose interruption. It was decided to decrease the dose of BEZ235 to 300mg bid dose regimen.
Participants by arm
| Arm | Count |
|---|---|
| BEZ235 300 mg/400 mg Bid Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 5 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive disease | 12 | 4 |
| Overall Study | Study terminated by sponsor | 0 | 1 |
| Overall Study | Subject/guardian decision | 0 | 1 |
Baseline characteristics
| Characteristic | BEZ235 300 mg/400 mg Bid |
|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 11 / 11 |
| serious Total, serious adverse events | 8 / 20 | 5 / 11 |
Outcome results
Primary
Stage 1 - Progression Free Survival (PFS) Rate Analysis at 16 Weeks as Per Local Radiology Review
PFS rate at 16 weeks was defined as a binary variable. Patients were considered as 'progression free' after 16 weeks if they had an overall lesion response of complete response (CR) partial response ('PR) or stable disease (SD)' and progressed if they had an overall lesion response of 'Progressive disease (PD) at the scan which occurred on day 105 after start of treatment, or later. Patients whose 16 weeks tumor assessment was unknown, missing or outside the window was not considered as 'progression free' and was considered a failure and counted only in the denominator for the estimation of the 16 week progression free rate.
Time frame: 16 weeks after the first BEZ235 administration.
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as 'Analysis Set Stage 1' (AS1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BEZ235 300 mg/400 mg Bid | Stage 1 - Progression Free Survival (PFS) Rate Analysis at 16 Weeks as Per Local Radiology Review | 51.6 Percentage of participants |
Secondary
Stage 1 - Disease Control Rate
Disease control rate was defined as the proportion of patients with a best overall response of Complete Response, Partial response, or Stable disease, based on the investigator's assessment per RECIST version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated.
Time frame: Baseline, every 8 weeks up to 31 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as 'Analysis Set Stage 1' (AS1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BEZ235 300 mg/400 mg Bid | Stage 1 - Disease Control Rate | 71.0 Percentage of participants |
Secondary
Stage 1- Overall Response Rate (ORR)
Overall Response rate was defined as the proportion of patients with a best overall response of complete response or partial response, based on investigator's assessment as per RECIST criteria version 1.1. Based on futility analysis conducted at the end of stage 1, stage 2 was not initiated.
Time frame: Baseline, every 8 weeks up to 31 months
Population: The Full Analysis Set (FAS) comprised of all patients who received at least one dose of study treatment (Stage 1). This set was known as 'Analysis Set Stage 1' (AS1).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BEZ235 300 mg/400 mg Bid | Stage 1- Overall Response Rate (ORR) | Complete response | 0.0 Percentage of participants |
| BEZ235 300 mg/400 mg Bid | Stage 1- Overall Response Rate (ORR) | Partial response | 0.0 Percentage of participants |