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Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28 and octreotide acetate 20 mg IM on day 1.

Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28, octreotide acetate 20 mg IM on day 1 and bevacizumab 10 mg/kg IV on days 1 and 15.

Octreotide Acetate

Matthew H Kulke

This randomized phase II trial studies how well everolimus and octreotide acetate with or without bevacizumab works in treating patients with pancreatic neuroendocrine tumors that cannot be removed by surgery and have spread nearby or to other places in the body. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Octreotide acetate may interfere with and slow the growth of tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab and everolimus also may stop the growth of pancreatic neuroendocrine tumors by blocking blood flow to the tumor. It is not yet known whether giving everolimus and octreotide acetate together is more effective with or without bevacizumab in treating pancreatic neuroendocrine tumors.

PRIMARY OBJECTIVES:

l. To assess the progression-free survival rate of patients with locally advanced or metastatic pancreatic neuroendocrine tumors treated with everolimus alone or everolimus plus bevacizumab.

SECONDARY OBJECTIVES:

I. To compare progression-free survival (PFS) among treatment arms shown to be efficacious.

II. To estimate the overall tumor response rate in patients with metastatic pancreatic neuroendocrine tumors treated with one of two novel regimens.

III. To estimate the overall biochemical response rate (as measured by plasma chromogranin A levels) in patients with metastatic pancreatic neuroendocrine tumors treated with these regimens.

IV. To assess the toxicity of each regimen in patients with metastatic pancreatic neuroendocrine tumors.

V. To assess the overall survival of patients with pancreatic neuroendocrine tumors treated with these regimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive everolimus orally (PO) once daily (QD) on days 1-28 and octreotide acetate intramuscularly (IM) on day 1.

ARM II: Patients receive everolimus and octreotide acetate as in Arm I. Patients also receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 3 years.

Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery

Randomized Phase II Study of Everolimus Alone Versus Everolimus Plus Bevacizumab in Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

Progression Free Survival (PFS) was defined as the time from study entry until disease progression or death, whichever occurs first. The median PFS was estimated using the Kaplan-Meier method. Progression was assessed per RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions (and an absolute increase of at least 0.5 cm) or the appearance of new lesions.

The proportion of patients who respond (completely or partially) to each combination regimen will be estimated. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions.

Overall survival (OS) is defined as the time from study entry to death from any cause. The median OS was estimated using the Kaplan-Meier method.

National Cancer Institute (NCI)

147 participants were evaluable for adverse events.

Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28 and octreotide acetate 20 mg IM on day 1.

Everolimus: Given PO

Octreotide Acetate: Given IM

Arm I (Octreotide Acetate and Everolimus)

Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28, octreotide acetate 20 mg IM on day 1 and bevacizumab 10 mg/kg IV on days 1 and 15.

Bevacizumab: Given IV

Everolimus: Given PO

Octreotide Acetate: Given IM

Arm II (Octreotide Acetate, Everolimus, and Bevacizumab)

Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28 and octreotide acetate 20 mg IM on day 1.\> \> Everolimus: Given PO\>

\> Octreotide Acetate: Given IM

Patients receive 28-day cycles until progression or unacceptable toxicity consisting of: everolimus 10 mg PO QD on days 1-28, octreotide acetate 20 mg IM on day 1 and bevacizumab 10 mg/kg IV on days 1 and 15.\>

\> Bevacizumab: Given IV\>

\> Everolimus: Given PO\>

\> Octreotide Acetate: Given IM

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Matthew Kulke, MD, MMSc

Based on the log rank test, with 130 patients enrolled over 22 months and followed an additional 24 months, the difference in median PFS between 9 months and 14 months can be detected with approximately 90% power (1-sided, α=0.15).

Progression Free Survival

Overall Response Rate

Overall Survival (OS)

Overall Study

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Dactolisib

Stage 1 consisted of a single arm where patients received BEZ235 300mg or 400mg bid. Initially the study started with a dose of 400mg bid. However, following an amendment after the preliminary safety and tolerability data from the first 3 patients treated at the 400mg dose, the dosage was changed to 300mg bid.

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).

BEZ235 (Stage 1)

Novartis Pharmaceuticals

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.

BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.

A Multicenter, Two Stage, Phase II Study, Evaluating the Efficacy of Oral BEZ235 Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in the Treatment of Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.

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.

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.

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.

BEZ235 300 mg Bid

BEZ235 400 mg Bid

Oral BEZ235 300 mg/400 mg bid was investigated in stage 1 of study

BEZ235 300 mg/400 mg Bid

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).

Clinical Disclosure Office

Stage 1 - Progression Free Survival (PFS) Rate Analysis at 16 Weeks as Per Local Radiology Review

Complete response

Partial response

Stage 1- Overall Response Rate (ORR)

Stage 1 - Disease Control Rate

Oral BEZ235 300 mg bid was investigated in stage 1 of study

BEZ235 300 mg

Oral BEZ235 400 mg bid was investigated in stage 1 of study

Immune System Diseases

Hypersensitivity

All patients will be included in a single-arm. Participants will undergo biopsy of tumor tissue for subsequent organoid generation and drug sensitivity tests.

this study conducts drug sensitivity tests on various clinically approved drugs. The most sensitive drug for the patient is selected for treatment, and the study aims to evaluate the clinical effectiveness of the drug and its consistency with in vitro organoid drug sensitivity.

Chemotherapy and targeted-therapy guided by organoid drug sensitivity test

Jiabin JIN, PhD

jiabin JIN, PhD

The purpose of this study is to explore whether chemotherapy and targeted-therapy regimens guided by organoid drug sensitivity test can improve the outcomes of non-resectable locally advanced and metastatic Pancreatic neuroendocrine tumors. At the same time, this study will evaluate the successful stablishment rate of organoid from biopsy tissue , and explore the concordance between drug sensitivity test results and patients' treatment response

Twenty non-resectable locally advanced and metastatic pancreatic neuroendocrine Tumor(p-NET) patients who should receive palliative treatment will be enrolled in this study. Baseline information of the enrolled patients including medical history, physical examination records and clinical examination records will be collected. Tumor material of those patients will be obtained from Pancreatic endoscopic biopsies or surgical resection. Patient-derived organoids (PDOs) will be established and cultured from p-NET tumor specimens. PDOs will then be treated with drugs of the chemotherapeutic and targeted therapeutic regimens for p-NET. Organoid size and growth will be monitored before and after the treatment, and dose-response curves will be generated. As for the assessment of clinical outcomes of patients, treatment responses will be assessed by biomedical imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1). Consistency between treatment responses in PDO models and clinical outcomes of patients will be assessed by correlation analysis.

In Vitro Organoid Drug Sensitivity-Guided Treatment for Advanced Pancreatic Neuroendocrine Tumor

A Prospective, Exploratory Study Evaluating the Effectiveness of Treatment Regimens for Locally Advanced/Metastatic Non-resectable Pancreatic Neuroendocrine Tumor (PNET) Guided by in Vitro Drug Sensitivity Testing of Tumor Organoids

Percentage of patient's measurable disease who have achieved either complete response (CR) or partial response (PR) according to RECIST 1.1.

The time from initiation of treatment to the occurrence of disease progression or death.

The time from the date of randomization to the date of death for any cause. Patients will be followed until their date of death or until final database closure.

The rate of organoid successfully cultured in all the samples collected.

To assess the accuracy of drug sensitivity test in both group. The number of patients with correct prediction of treatment response by organoid drug-sensitivity test divided by the number of patients underwent chemotherapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery	NCT01229943	Advanced Pancre... Locally Advance... Pancreatic Gast... Pancreatic Neur... Pancreatic Neur... Pancreatic Vipo...	Bevacizumab Everolimus Octreotide Acet...	18 Years -	National Cancer Institute (NCI)
BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.	NCT01658436	Pancreatic Neur...	BEZ235 (Stage 1...	18 Years -	Novartis
In Vitro Organoid Drug Sensitivity-Guided Treatment for Advanced Pancreatic Neuroendocrine Tumor	NCT06246630	Advanced Pancre...	Chemotherapy an...	18 Years - 75 Years	Ruijin Hospital
BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.	NCT01658436	Pancreatic Neur...	BEZ235 (Stage 1...	18 Years -	Novartis
Everolimus and Octreotide Acetate With or Without Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery	NCT01229943	Advanced Pancre... Locally Advance... Pancreatic Gast... Pancreatic Neur... Pancreatic Neur... Pancreatic Vipo...	Bevacizumab Everolimus Octreotide Acet...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced pancreatic neuroendocrine tumor