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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

Symptoms and General Pathology

Recurrence

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Lactitol

Patients in the octreotide group received octreotide LAR (Sandostatin® LAR, Novartis Pharmaceuticals Corporation) treatment by deep intramuscular injection at a dose of 30 mg every 28 days for 6-12 months, with the start of clinical intervention following surgery.

Octreotide LAR (Sandostatin® LAR, Novartis Pharmaceuticals Corporation) treatment by deep intramuscular injection at a dose of 30 mg every 28 days for 6-12 months。

Octreotide LAR

Adjuvant therapy in pancreatic neuroendocrine tumors (pNETs) after radical resection lacks evidence-based data and is controversial. Real-world data were clustered to validate whether the long-acting octreotide is a potential candidate for adjuvant therapy in high recurrence risk G2 pNET patients.

Adjuvant therapy for pNETs was proposed as an unmet clinical need by the European Neuroendocrine Tumor Society Group in 2016.1The Clinical Practice Guidelines for pNETs in China recommended initiation of clinical trials to investigate the role of adjuvant therapy for patients with a high-risk of recurrence. To address this unmet clinical need, the investigators initiated this real-world study. The aim of the current study was to assess the impact of octreotide LAR as an adjuvant therapy in reducing recurrence and prolonging survival in Chinese non-metastatic pNETs patients at risk for recurrence.

Real-world Study on Adjuvant Octreotide Therapy in pNETs

Real-world Effectiveness of Adjuvant Octreotide Therapy in High Recurrence Risk Patients With Pancreatic Neuroendocrine Tumors

Changhai Hospital

Clinical Professor

Patients receive sapanisertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Sapanisertib

Lakshmi Rajdev

This phase II trial studies how well sapanisertib works in treating patients with pancreatic neuroendocrine tumor that has spread to other places in the body (metastatic), does not respond to treatment (refractory), or cannot be surgically removed. Drugs such as sapanisertib may stop the growth or shrink tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To evaluate overall response rate associated with sapanisertib (MLN0128 \[TAK-228\]) in patients with advanced pancreatic neuroendocrine tumors (PNETs).

SECONDARY ENDPOINTS:

I. To evaluate progression-free survival (PFS) associated with MLN0128 (TAK-228) in patients with advanced pancreatic neuroendocrine tumors (PNETs).

II. To measure the safety and tolerability of MLN0128 (TAK-228) in patients with advanced PNETs.

III. To evaluate disease control rate associated with MLN0128 (TAK-228) in patients with advanced PNETs.

IV. To measure duration of response rate associated with MLN0128 (TAK-228) in patients with advanced PNETs.

OUTLINE:

Patients receive sapanisertib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 1 year, and then yearly for 2 years.

Sapanisertib in Treating Patients With Metastatic or Refractory Pancreatic Neuroendocrine Tumor That Cannot Be Removed by Surgery

A Phase II Study of MLN0128 (TAK-228) in Rapalog-Resistant Advanced Pancreatic Neuroendocrine Tumors (PNET)

Response includes complete response (CR) and partial response (PR). CR is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

PFS was defined as time from study registration to disease progression (as defined by the RECIST criteria) or to death without progression, whichever occurred first. If date of death was greater than 4 months after the date of last documented to be free of progression or if patients were alive and free of progression at the time of the analysis, patients were censored at the time of last disease assessment. If such a date was not available, patients were censored at the time of registration.

Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions is also considered progression.

Disease control rate was defined as the proportion of patients with best overall response of CR, PR, or stable disease (SD) among all eligible patients who started protocol treatment. CR is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.

Duration of response was defined as the time from the onset of response (CR or PR, whichever status was recorded first) to first documentation of disease progression. Patients with responses but without documented disease progression were censored at the time of last disease evaluation.

CR is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions is also considered progression.

Serious adverse events are defined as those adverse events of grade 3 or higher that are possibly, probably, or definitely related to protocol treatment. Other adverse events are defined as those adverse events of grade 1 or grade 2 that are possibly, probably, or definitely related to protocol treatment with a frequency of at least 5% in a given arm.

Patients receive MLN0128 orally (PO) daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm A (MLN0128)

Only eligible and treated patients are included in this analysis.

Study Statistician

Progression-free Survival (PFS)

Disease Control Rate

Only patients who achieved a response (CR or PR) are included in the analysis of duration of response. No patients on this study had a response (CR or PR).

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)
Real-world Study on Adjuvant Octreotide Therapy in pNETs	NCT06080204	Pancreatic Neur...	Octreotide LAR	18 Years - 80 Years	Changhai Hospital
Real-world Study on Adjuvant Octreotide Therapy in pNETs	NCT06080204	Pancreatic Neur...	Octreotide LAR	18 Years - 80 Years	Changhai Hospital
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)
Real-world Study on Adjuvant Octreotide Therapy in pNETs	NCT06080204	Pancreatic Neur...	Octreotide LAR	18 Years - 80 Years	Changhai Hospital
Sapanisertib in Treating Patients With Metastatic or Refractory Pancreatic Neuroendocrine Tumor That Cannot Be Removed by Surgery	NCT02893930	Pancreatic Neur... Pancreatic Neur... Refractory Panc...	Sapanisertib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for pancreatic neuroendocrine tumor g2